![ການຂຶ້ນທະບຽນຜະລິດຕະພັນຢາໃນໄນຈີເຣຍGuidelinesfortherregistration ofpharmaceuticalproductsinNigeriaQUALITYGUIDELINESFORTHEREGISTRATIONOFPHARMACEUTICALPRODUCTSINNIGERIALexArtifexLLP, ບໍລິສັດກົດຫມາຍໃນໄນຈີເລຍ, ໄດ້ນໍາສະເຫນີ F&D Helpdesk ການຊ່ວຍເຫຼືອບຸກຄົນແລະບໍລິສັດມີສ່ວນຮ່ວມໃນການຜະລິດ, ການແຜ່ກະຈາຍ, ການສົ່ງອອກແລະການນໍາເຂົ້າອາຫານແລະຢາທີ່ມີການຄວບຄຸມຕາມຄວາມຕ້ອງການທີ່ກໍານົດໄວ້ໂດຍ NigeriaE28099s ອົງການແຫ່ງຊາດສໍາລັບອາຫານແລະຢາບໍລິຫານແລະການຄວບຄຸມ ("Nafdac"). ການຈັດພິມນີ້ໃຫ້ຄຳແນະນຳດ້ານຄຸນນະພາບສຳລັບການລົງທະບຽນຜະລິດຕະພັນຢາໃນປະເທດໄນຈີເຣຍ. ການຮັບຮູ້ອົງການຮັບຮູ້ສະຫນັບສະຫນູນດ້ານເຕັກນິກຂອງອົງການສຸຂະພາບໂລກ (WHO), ອົງການຈັດຕັ້ງສຸຂະພາບອາຟຣິກາຕາເວັນຕົກ (WAHO) ແລະກອງປະຊຸມສາກົນກ່ຽວກັບການປະສົມປະສານ (ICH) ການພັດທະນາຂອງຄໍາແນະນໍານີ້. ຈຸດປະສົງນີ້ບົດຄວາມໃຫ້ຄໍາແນະນໍາສໍາລັບການກະກຽມຂອງກົດລະບຽບການຍື່ນສະເຫນີການລົງIະບຽນຢາສໍາລັບມະນຸດNigeriainline ທີ່ມີຮູບແບບທີ່ໄດ້ຮັບການຍອມຮັບຢ່າງກວ້າງຂວາງແລະຄວາມຕ້ອງການທົ່ວໄປບັຢູ່ນອກຸໄດ້ໂດຍຜ່ານຂະບວນການຂອງສະພາສາກົນເພື່ອຄວາມສາມັກຄີ (ICH) ຂອງກົດລະບຽບຄວາມຕ້ອງການສໍາລັບການຈົດທະບຽນຜະລິດຕະພັນຢາສໍາລັບມະນຸດ. In particular, ThedocumentseekstoaligntheAgencyE28099srequirement forregulatorysubmission for the registration of medicines for humanuse withharmonizationdrive intheEconomicCommunity of WestAfricanStates Sanchored bytheWestAfrican HealthOrganization (WAHO). Therefore, ການແນະນໍາຂອງເອກະສານນີ້ໃນທີ່ສຸດຈະຊ່ວຍເຫຼືອດັ່ງຕໍ່ໄປນີ້; Preparation of regulatory submission for pharmaceutical products by providing guidance on the organization and formatting of product dossier. The adoption of the Common Technical Document (CTD) as developed through the ICH processes and adopted by the World Health Organization in the WHO prequalification programme and the West African Health Organization in the promotion of the harmonization of regulatory requirement for the registration medicinal products for human use· Promotion of regulatory harmonization in ECOWAS member States; Collaboration and information sharing among medicines regulatory agencies Provision of guidance on other technical and general requirements Elaborate on requirements for Active Pharmaceutical Ingredients (API) and the Finished Pharmaceutical Products; Facilitates ease of submission and assessment; Enhanced access to quality essential medicine; Promotion of a more transparent regulatory system LIST OF ABBREVIATIONS AIDS Acquired Immune Deficiency Syndrome API Active Pharmaceutical Ingredient APIMF Active Pharmaceutical Ingredient Master File .ATC Anatomical Therapeutical and Chemical Classification CEP Certificate of Suitability issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM) CPP Certificate of Pharmaceutical Product CTD Common Technical Document DMF Drug Master File ECOWAS Economic Community for West African States FPP Finished Pharmaceutical Products GMP Good Manufacturing Practices HIV Human Immunodeficiency Virus ICH International Council for Harmonisation of Technical Requirements for the Registration of Medicines for human use INN International Non-Proprietary Name MA Market Authorization NCE New Chemical Entities NMRA National Medicines Regulatory Authority OTC Over the Counter Medicines PIL Patient Information Leaflet POM Prescription-only Medicines SmPC Summary of Product Characteristics WAHO West African Health Organization WHO World Health Organization GENERAL PRINCIPLES FOR THE PRESENTATION OF APPLICATION FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA Language Applications for products seeking marketing authorization shall be submitted in English. ໃນກໍລະນີມີຢູ່ບ່ອນນັ້ນຕ້ອງແປເອກະສານຈາກແຫຼ່ງພາສາພາສາອັງກິດເປັນພາສາອັງກິດ, ຄວາມຖືກຕ້ອງຂອງການແປພາສາມີຄວາມຮັບຜິດຊອບຂອງຜູ້ສະຫມັກແລະການແປພາສາຈະໄດ້ຮັບການຮັບຮອງຄວາມງາມໂດຍການຮັບຮອງຈາກປະເທດຕົ້ນກໍາເນີດ. ການນໍາສະເຫນີຂໍ້ມູນ Dossiers ຄວນຈະຖືກສົ່ງກັບຮູບແບບເອເລັກໂຕຣນິກແລະຄວນຈະປະຕິບັດຕາມຮູບແບບ CTD. ໂຟນເດີແຍກຕ່າງຫາກຄວນຈະຖືກສ້າງຂື້ນສໍາລັບໂມດູນທີ່ແຕກຕ່າງກັນແລະໂຟນເດີຍ່ອຍສໍາລັບສ່ວນທີ່ແຕກຕ່າງSoftheCTDກັບໂມດູນ. ເອກະສານດັ່ງກ່າວຄວນຈະຖືກສົ່ງມາໃນແບບຟອມ PDF ທີ່ສາມາດຄົ້ນຫາໄດ້ດ້ວຍຂໍ້ຍົກເວັ້ນຂອງ QIS ເຊິ່ງຄວນຈະຢູ່ໃນMSWord. ເອກະສານອ້າງອິງແລະຂໍ້ຄວາມC2B7ມາດຕະຖານສາກົນເພື່ອການອ້າງອິງອ້າງອີງຈາກພາກສ່ວນທີ່ຊອບທຳຕ້ອງປະຕິບັດຕາມ. Thelatestitionofanyreferencesource, ການລະບຸປີຂອງການພິມເຜີຍແຜ່ຕ້ອງໄດ້ນໍາໃຊ້. C2B7 ວັນນະຄະດີການອ້າງອິງຄວນຈະຖືກອ້າງອີງກັບສະບັບປະຈຸບັນຂອງ UniformRequirements for Manuscripts ສົ່ງໄປວາລະສານຊີວະແພດ, International Committee of Medical JournalsEditors (ICMJE). C2B7 ຫຍໍ້ມາຈາກຄຳຫຍໍ້ຄວນຖືກກຳນົດໄວ້ເປັນຄັ້ງທຳອິດທີ່ນຳໃຊ້ໃນໂມດູນ. ບ່ອນທີ່ມີຄວາມຈໍາເປັນ, ໂດຍສະເພາະແມ່ນວິທີການສໍາລັບການວິເຄາະ, ສະເພາະ ແລະຂັ້ນຕອນ, copysoftherelevantportionsofthereferencesource(s) ຕ້ອງລວມທັງ. C2B7Allin-houseprocessesquotedinthedocumentationmusthavebeenvalidatedand propriatereferencescited. ອຳນວຍຄວາມສະດວກໃນການກະກຽມຂອງ PD, these guidelines are organized in accordance with the structure of the ICH Common technical document – quality (M4Q) guideline. The text of the M4Q (CTD-Q) guideline has been restated verbatim in these guidelines in bold text, with minor modifications to accommodate NAFDAC terminology and to include certain text that would be appropriate for pharmaceutical products, notably: a) “Drug substance” is replaced with “active pharmaceutical ingredient” or “API” b) “Drug product” is replaced with “finished pharmaceutical product” or “FPP”. c) “Application” is replaced with “product dossier” or “PD”. d) “Combination product” is replaced with “fixed-dose combination” or “FDC”. ການແນະນຳເພີ່ມເຕີມໂດຍNAFDAC ເຊິ່ງໄດ້ມາຈາກ WHOGuidelinesonsubmissionofdocumentationforamultisource (generic) finished product, ຕໍ່ໄປນີ້ບົດຄວາມທີ່ຜະລິດຈາກ M4Q (CTD-Q) guideline (2), ໄດ້ຖືກພິມອອກເປັນຂໍ້ຄວາມປົກກະຕິທີ່ສາມາດແຍກແຍະໄດ້ຢ່າງງ່າຍດາຍຈາກ ICH ຂໍ້ຄວາມແລະລວມເຖິງການປັບປຸງຄວາມຊັດເຈນຂອງ NAFDACE28099 ຄວາມຄາດຫວັງສໍາລັບເນື້ອໃນຂອງ PDs. ວິທີການນີ້ແມ່ນເພື່ອອໍານວຍຄວາມສະດວກໃນການກໍານົດຕົວຕົນແລະຕົ້ນກໍາເນີດຂອງຂໍ້ຄວາມໃນຂໍ້ແນະນໍາເຫຼົ່ານີ້ (i.e. ຈາກICHorfromWHO). ເນື້ອໃນຂອງຂໍ້ແນະນໍາເຫຼົ່ານີ້ຄວນອ່ານຮ່ວມກັນກັບຂໍ້ມູນທີ່ກ່ຽວຂ້ອງທີ່ອະທິບາຍວ່າບໍ່ມີຢູ່ບ່ອນອື່ນ WHOorICH ເອກະສານອ້າງອີງແລະຂໍ້ແນະນໍາ. ຄຸນນະພາບຂອງ APIs ທີ່ມີຢູ່ແລ້ວແລະຜະລິດຕະພັນຫຼາຍແຫຼ່ງທີ່ສອດຄ້ອງກັນບໍ່ຄວນຖືກຕ່ໍາກວ່າ APIsandinnovator (comparator) FPPs. Therefore, ຫຼັກການພື້ນຖານຂຜະລິດຕະພັນສໍາເລັດຮູບມືແນະນໍາທີ່ອ້າງອີງໃນທົ່ວເອກະສານນີ້ແລະອື່ນໆWHOguidelinesmayelyapplytoexistingAPIs and multisourceproducts. ວັນນະຄະດີວິທະຍາສາດອາດຈະເໝາະສົມກັບຄວາມຕ້ອງການສໍາລັບບາງຂໍ້ມູນ ຫຼືຕົວກໍານົດການກໍານົດບົດແນະນໍາເຫຼົ່ານີ້ (e.g. ຄຸນນະສົມບັດຂອງການລະບຸຄວາມສະອາດ). Furthermore, ຂໍ້ກໍານົດທີ່ລະບຸໄວ້ໃນຕອນຕົ້ນອາດຈະບໍ່ສາມາດນຳໃຊ້ໄດ້ກັບ APIorFPP ທີ່ສະເໜີໃຫ້. ຄວາມບໍ່ສະຫງົບ, ບໍ່ວ່າບົດສະຫຼຸບຫຼືການອ້າງອິງເຕັມທີ່ກ່ຽວກັບວັນນະຄະດີວິທະຍາສາດຄວນຈະສະຫນອງໃຫ້, orthenon-applicability oftherequested informations should be clearly indicated with an accompanying explanatorynote. ຄໍາແນະນໍາກ່ຽວກັບຮູບແບບຂໍ້ສະເຫນີແນະໃນຫົວຂໍ້ການແນະນໍາທົ່ວໄປຂອງWHO (generic) finished product: ຮູບແບບທົ່ວໄປ: ການກະກຽມຜະລິດຕະພັນເອກະສານເອກະສານທີ່ມີລັກສະນະທົ່ວໄປຄວນປະຕິບັດຕາມຮູບແບບແລະການນໍາສະເຫນີຂອງ PD. ບາງທີອາດມີຈຳນວນບັນຊີຢູ່ບ່ອນການຊໍ້າຄືນຂອງພາກສ່ວນສາມາດພິຈາລະນາວ່າເໝາະສົມ. ເມື່ອໃດກໍຕາມການດໍາເນີນການເຮັດເລື້ມຄືນ, ມັນຄວນຈະເປັນທີ່ຈະແຈ້ງກ່ຽວກັບສິ່ງເຫຼົ່ານີ້ໂດຍອ້າງອີງເຖິງການສ້າງຄວາມແຕກຕ່າງຂອງຫົວຂໍ້ຢູ່ໃນວົງເລັບດັ່ງຕໍ່ໄປນີ້ M4Q (CTD-Q) ຫົວຂໍ້ແນະນໍາ, e.g. 3.2.ສານເສບຕິດ SD (orAPI) (name, ຜູ້ຜະລິດA). ຕໍ່ໄປນີ້ແມ່ນຂໍ້ສະເຫນີແນະສໍາລັບການນໍາສະເຫນີຂອງຂໍ້ມູນໃນຄຸນນະພາບໂມດູນການມີຄວາມແຕກຕ່າງຂອງສະຖານະການທີ່ອາດຈະໄດ້ພົບ: TheOpenpart (non-proprietary information) ofeachAPIMF ຄວນຈະຖືກລວມເອົາຢ່າງສະເໝີຕົ້ນສະເໝີປາຍຂອງ PD, asanannexto3.2.S. ForanFPP ປະກອບດ້ວຍmorethanoneAPI, onecompleteE2809C3.2.SE2809Dsection should beprovidedforoneAPI, ຕາມດ້ວຍອັນອື່ນທີ່ສົມບູນE2809C3.2.SE2809DsectionforeachoftheotherAPIs. ForanAPIfrom ຫຼາຍຜູ້ຜະລິດ, onecompleteE2809C3.2.SE2809Dsections should beprovided for theAPIfromonemanufacturer, ປະຕິບັດຕາມໂດຍອັນອື່ນທີ່ສົມບູນE2809C3.2.SE2809DsectionfortheAPIromeachoftheotherAPImanufacturers. ForanFPP ມີຄວາມເຂັ້ມແຂງຫຼາຍ (e.g. 10, 50, 100 mg) ຫນຶ່ງຄົບຖ້ວນສົມບູນE2809C3.2.PE2809ພາກສ່ວນຄວນຈະໄດ້ຮັບການສະຫນອງຂໍ້ມູນທີ່ມີຄວາມເຂັ້ມແຂງທີ່ແຕກຕ່າງກັນ, ສະຫນອງໃຫ້ພາຍໃນພາກສ່ວນຍ່ອຍ.. 1 ສະບັບສົມບູນຂອງPD ຄວນຈະໄດ້ຮັບການສະຫນອງforeachFPPstrength. ForanFPP ກັບລະບົບປິດຕູ້ຄອນເທນເນີຫຼາຍອັນ (e.g. bottlesandunitdoseblisters) ຫນຶ່ງຄົບຖ້ວນສົມບູນE2809C3.2.PE2809ພາກສ່ວນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ກັບຂໍ້ມູນຂ່າວສານສໍາລັບການນໍາສະເຫນີທີ່ແຕກຕ່າງກັນສະຫນອງໃຫ້ພາຍໃນພາກສ່ວນຍ່ອຍ.. FormultipleFPPs (e.g. tabletsandaparenteral ຜະລິດຕະພັນ) asseparatedossierisrequiredforeachFPP. ForanFPP ສະໜອງໃຫ້ໂດຍມີການປັບປ່ຽນລັດຖະທຳມະນູນ(s) onecompleteE2809C3.2.PE2809Dsection should beprovided for theFPP, ປະຕິບັດຕາມໂດຍຂໍ້ມູນຂ່າວສານ(s) inaseparatepartE2809C3.2.PE2809D, as appropriate. Foraco-blisteredFPPonecompleteE2809C3.2.PE2809Dsections should beprovidedforeachproduct. ໂຄງສ້າງຂອງໂຄງສ້າງຂໍ້ມູນໃນ CTD ໄດ້ຖືກຈັດເປັນຊຸດເອກະສານທີ່ມີໂຄງສ້າງ, ເຊິ່ງມີການຈັດລະບຽບໃນຕົວໂມດູນ. TheM4guidanceOrganization of theCommonTechnicalDocumentandICH ຄຳຖາມທົ່ວໄປ ແລະຄຳຕອບໃຫ້ຄຳນິຍາມຂອງເອກະສານ ແລະຄຳແນະນຳໃນຕາຕະລາງເນື້ອໃນ (ToC) ການຈັດຮູບແບບ, ການອ້າງອີງຂ້າມພາຍໃນCTDandfordocumentpagination, ການແບ່ງແຍກແລະຈໍານວນພາກສ່ວນ. ຕາຕະລາງ 1: MAINSECTIONHEADINGSINTHECOMMONTECHNICALDOCUMENT (CTD) FORMATNumberTitleandMainSectionHeadings 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.A Module 1: ຂໍ້ມູນການບໍລິຫານແລະຜະລິດຕະພັນCoverLetterTableofContents (Modules 1 to 5) ApplicationInformationProductInformationRegionalSummariesElectronicReviewDocumentsProductSample(s) (ຖ້າມີຢູ່ໃນເວລາຍື່ນສະເໜີ) Appendix 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Module 2: Common Technical Document (CTD) ສະຫຼຸບCTDTຕາຕະລາງເນື້ອໃນ (Modules 2 to 5) CTDIntroductionQualityOverallSummaryNonclinicalOverviewClinicalOverviewNonclinicalWrittenandTabulatedSummariesClinicalSummary 3.1 3.2 3.3 Module 3: ຕາຕະລາງຄຸນະພາບຂອງເນື້ອໃນຂອງໂມດູນ 3 BodyofDataLiteratureReferences 4.1 4.2 4.3 Module 4: NonclinicalStudyReports ບໍ່ຈໍາເປັນສໍາລັບຕາຕະລາງເນື້ອໃນຂອງໂມດູນ 4 ຜະລິດຕະພັນການສຶກສາ ບົດລາຍງານວັນນະຄະດີອ້າງອີງ 5.1 5.2 5.3 5.4 Module 5: ClinicalStudyReportsBioequivalenceorTableofContentsofModule 5 Biowaiverrequired forgenerics asapplicableTabularListing of AllClinicalStudiesClinicalStudyReportsLiteratureReferencesMODULE 1 (ຂໍ້ມູນການບໍລິຫານແລະຜະລິດຕະພັນ) 1.0 ຈົດໝາຍປົກຫຸ້ມ: C2B7Acoverletters shouldaccompany databeings submit to the regulatory authority. ຈົດຫມາຍສະບັບດັ່ງກ່າວຄວນຈະແຈ້ງຢ່າງຊັດເຈນວ່າສິ່ງທີ່ຖືກສົ່ງມາ, ລວມທັງການອ້າງອິງເຖິງການຮ້ອງຂໍຈົດຫມາຍສະບັບ (if applicable) ແລະລາຍລະອຽດຫຍໍ້ຂອງຊຸດ. C2B7 ຈົToCຫມາຍສະບັບດັ່ງກ່າວບໍ່ຄວນມີຂໍ້ມູນວິທະຍາສາດ. C2B7 ເອກະສານກົດລະບຽບການອ້າງອິງໃດໆກໍຕາມຄວນຈະຖືກລະບຸໄວ້ຢ່າງຈະແຈ້ງໃນຈົດໝາຍປົກປິດ, ແລະຂໍ້ມູນຕໍ່ໄປນີ້ຄວນຈະຖືກລວມເຂົ້າ: ປະເພດຄໍາຮ້ອງສະຫມັກ E280A2, ລະບຸວ່າໃໝ່, ການປ່ຽນແປງໃຫມ່; ໝາຍເລກສະໝັກ E280A2NMRA (ອອກໂດຍ NMRA); E280A2 ວັນທີຂອງລະບຽບການອະນຸຍາດສາມາດໃຊ້ໄດ້. ຊື່ຍີ່ຫໍ້ E280A2, DCI, ປະລິມານ, ການນໍາສະເຫນີ, dosage form; E280A2ManufacturerE28099snameE280A2ApplicantE28099snameE280A2NumberofsamplessubmittedAsamplecoverletterisprovidedinAnnexB: ແບບຟອມ 1.1 ຕາຕະລາງເນື້ອໃນຂອງຄໍາຮ້ອງສະຫມັກອ່ອນ, ລວມທັງໂມດູນ 1 (module 1-5) ຕາຕະລາງເນື້ອໃນ (ToC) for the entire regulatory dossier should be placed in this section. It should list all documents included in Modules 1-5. A module-specific ToC is included with each Module. 1.2 Application information 1.2.1 ຄໍາຮ້ອງສະຫມັກຈົດຫມາຍສະບັບ 1.2.2 Registration Form 1.2.3 Certificate of Incorporation 1.2.4 ພະລັງງານຂອງທະນາຍຄວາມ 1.2.5 Notarized Declaration of the applicant. (The applicant should declare that the information submitted is true and correct. Information on the name, position and signature of the applicant, product particulars should be provided in the notarized declaration and should be dated, signed and stamped by a notary public) 1.2.6 Power of Attorney /Contract Manufacturing Agreement 1.2.7 ໃບຢັ້ງຢືນຜະລິດຕະພັນຢາ 1.2.8 Certificate of Good Manufacturing Practice 1.2.9 Manufacturing Authorization 1.2.10 Evidence of Trademark Registration 1.2.11 Superintendent Pharmacist’s Annual Licence to Practice 1.2.12 Certificate of Registration and Retention of Premises 1.2.13 ຫຼັກຖານການອະນຸຍາດການຕະຫຼາດກ່ອນໜ້ານີ້ (If applicable) 1.2.14 ຈົດໝາຍເຊີນສຳລັບການກວດກາ GMP 1.2.15 ສຳເນົາໃບຮັບຮອງຄວາມເໝາະສົມຂອງຢາປົວພະຍາດເອີຣົບ (where applicable) 1.2.16 Letter of Access for APIMF(s) (where applicable) 1.2.17 BiowaiverRequestinlation toconducting BCS-based bioavailabilitystudy 1.2.18 Biowaiverrequestion toconductingAdditional Strengthbioavailability Study 1.3. ຂໍ້ມູນຜະລິດຕະພັນ 1.3.1. Summary of Product Characteristics (SmPC) AcopyoftheSummaryofProduct ລັກສະນະ (SmPC) is to be placed in this section. ເມື່ອການທົບທວນຖືກຮ້ອງຂໍໃນລະຫວ່າງຫຼັກສູດການປະເມີນຜົນ, ສະບັບ anannotatedofthereviເອກະສານເຕັກນິກທົ່ວໄປອະທິບາຍຄວນລະບຸວ່າມີການປ່ຽນແປງທັງໝົດ, ບໍ່ວ່າຈະເປັນທີ່ກ່ຽວຂ້ອງກັບການອະນຸມັດຫຼ້າສຸດ SmPCorinresponsetoare ຮ້ອງຂໍໃຫ້ເຮັດໂດຍອໍານາດການປົກຄອງ. 1.3.2. Labelling (ນອກ & ປ້າຍພາຍໃນ) C2B7Allcontainerlabels, ລວມທັງປ້າຍພາຍໃນແລະນອກ, ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ໃນພາກນີ້istobeplaced ພາກນີ້ນຮວມເອົາປ້າຍກຳກັບສຳລັບຄວາມເຂັ້ມແຂງທັງໝົດ, dosageformsandreconstitutions ສານປະກອບ. C2B7 ເມື່ອມີການດັດແກ້ເພີ່ມເຕີມແມ່ນໄດ້ຮ້ອງຂໍໃນລະຫວ່າງຫຼັກສູດການທົບທວນ, anannotatedversionoftherevisedlabelmayberrequested, ແລະຄວນຈະຖືກຈັດໃສ່ໃນພາກສ່ວນນີ້. 1.3.3. PackageInsert (ຂໍ້ມູນຄົນເຈັບທີ່ຮູ້ຈັກPIL) C2B7AcopyofthePatientInformationLeaflet (PIL) is to be placed in this section. 1.4. ບົດສະຫຼຸບພາກພື້ນ 1.4.1. Bioequivalence Trial Information Form (BTIF) 1.4.2. ສັງລວມຂໍ້ມູນຄຸນນະພາບ (QIS) 1.5. ElectronicReviewDocumentsElectronicversions ofapplicationsareencouraged ຮູບແບບເອກະສານທີ່ສາມາດຄົ້ນຫາໄດ້ (PDF). ເອກະສານອີເລັກໂທຣນິກນີ້ຄວນຈະຖືກບັນທຶກໄວ້ໃນ CD-ROM. All electronic media submitted to support the drug regulatory document should be placed in this section 1.6. Samples · A sample of the product in the same packaging intended for commercial purposes should be submitted along with the application. Please note that mock-up packaging may be used when the final product packaging is not available. Module 2: Common Technical Document (CTD) Summaries Module 2 includes the following 7 sections. For multisource (generic) pharmaceutical products, Modules 2.4-2.7 are not usually needed. 2.1 CTD Table of Contents (Modules 2-5) 2.2 CTD Introduction 2.3 Quality Overall Summary 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Written and Tabulated Summaries 2.7 Clinical Summary 2.1 CTD Table of Contents (Module 2-5) The table of contents for Module 2 to 5 should be provided. 2.2 CTD Introduction The introduction should include proprietary name, non-proprietary name or common name of the drug substance, company name, dosage form(s), strength(s), ເສັ້ນທາງການບໍລິຫານ, ແລະການສະເຫນີແນະ(s). ມັນຄວນຈະອະທິບາຍໂດຍຫຍໍ້ກ່ຽວໂດຍສະເພາະນື້ອໃນ softheModules 2 to 5 withappropriatecross-referencestothem. 2.3 QualityOverallSummaryTheQualityOverallSummary (QOS) isasummarythat ປະຕິບັດຕາມຂອບເຂດແລະເສັ້ນທາງອອກຂອງBodyofDatainModule 3. TheQOS ປະກອບຂອງ APIsection (2.3.ສ), anFPPsection (2.3.ປ), Appendices (2.3.A) ແລະຂໍ້ມູນພາກພື້ນ (2.3.ຣ). TheQOS ບໍ່ຄວນລວມເອົາຂໍ້ມູນ, dataorjustification ທີ່ບໍ່ໄດ້ລວມຢູ່ໃນໂມດູນແລ້ວ 3 orinotherpartsoftheCTD. TheQOS-PDTemplate ຄວນຈະສໍາເລັດປະຕິບັດຕາມຄໍາແນະນໍາໃນສ່ວນນີ້. ອ້າງອີງICHM4Q (R1). 2.3. SDrugSubstanceFordrugproduct ມີສານປະກອບຢາຫຼາຍກວ່ານັ້ນ, theinformationinmodule2.3.S.1to2.3.S.7 should besubmittedforeachdrugsubstance, clearly identifying the substance name and manufacturer in the title of each module. 2.3. S.1 General Information (name, manufacturer) Include information from Module 3.2.S.1 2.3. S.2 Manufacture (name, ທີ່ຢູ່ທາງດ້ານຮ່າງກາຍ, i.e., site) Include information from Module 3.2.S.2 Information on the manufacturer, • Provide the name, address and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing. • A brief description of the manufacturing process (including, for example, reference to starting materials, critical steps, and reprocessing) and the controls that are intended to result in the routine and consistent production of material(s) of appropriate quality; this could be presented as a flow diagram. • A flow diagram, as provided in 3.2.S.2.2; • A description of the Source and Starting Material and raw materials of biological origin used in the manufacture of the API, as described in 3.2.S.2.3; • Highlight critical process intermediates, as described in 3.2.S.2.4; • A description of process validation and/or evaluation, as described in 3.2.S.2.5. 2.3. S.3 Characterisation (name, manufacturer) A summary of the interpretation of evidence of structure and isomerism, as described in 3.2.S.3.1, should be included. A tabulated summary of the data provided in 3.2.S.3.2, with graphical representation, where appropriate should be included. 2.3. S.4 Control of Drug Substance (name, manufacturer) A brief summary of the justification of the specification(s), the analytical procedures, ແລະການກວດສອບຄວນຈະຖືກລວມເອົາ. ຂໍ້ມູນຈໍາເພາະຈາກ 3.2.S.4.1 ຄວນຖືກຈັດໃຫ້. Atabulatedsummaryofthebatchanalysesfrom3.2.S.4.4, with graphical representation where appropriate, should be provided. 2.3. S.5ReferenceStandardsorMaterials (name, manufacturer) ຂໍ້ມູນຈາກ 3.2.S.5 (tabulated presentation, where appropriate) should be included. 2.3. S.6ContainerClosureSystem (name, manufacturer) ຄຳອະທິບາຍຫຍໍ້ແລະການສົນທະນາຂອງຂໍ້ມູນ, ຈາກ 3.2.S.6 ຄວນຖືກລວມເຂົ້າ. 2.3. S.7 Stability (name, manufacturer) ພາກສ່ວນນີ້ຄວນປະກອບມີບົດສະຫຼຸບຂອງການສຶກສາທີ່ດໍາເນີນ (conditions, batches, analytical procedures) ແລະການສົນທະນາໂດຍຫຍໍ້ທີ່ມີຜົນໄດ້ຮັບແລະຂໍ້ສະຫຼຸບ, ເງື່ອນໄຂການເກັບຮັກສາສະເຫນີ, ທົດສອບຄືນໃຫມ່ຂອງຊີວິດ, where relevant, as described in 3.2. S.7.1. The post-approval stability protocol, asdescribedin3.2.S.7.2, should be included. ສະຫຼຸບສັງລວມຄວາມອາດສາມາດໄດ້ຜົນມາຈາກ 3.2.S.7.3, with graphical representation where appropriate, should be provided. 2.3. PFinished PharmaceuticalProduct 2.3. P.1 ຄໍາອະທິບາຍແລະອົງປະກອບຂອງຜະລິດຕະພັນຢາ (name, dosage form) ຂໍ້ມູນຈາກ 3.2.P.1 ຄວນໃຫ້. ອົງປະກອບຈາກ 3.2.P.1 ຄວນໄດ້ຮັບການສະຫນອງ. 2.3. P.2 ການພັດທະນາຢາ (name, dosage form) ການສົນທະນາຂອງຂໍ້ມູນແລະຂໍ້ມູນຈາກ 3.2.P.2 ຄວນຖືກນໍາສະເຫນີ. ສະຫຼຸບສັງລວມຂອງອົງປະກອບຂອງຮູບແບບການນໍາໃຊ້ການທົດລອງທາງດ້ານຄລີນິກແລະການນໍາສະເຫນີຂອງ dissolutionprofile ຄວນໄດ້ຮັບການສະຫນອງໃຫ້, where relevant. 2.3. P.3 Manufacture (ອະທິບາຍrm) ຂໍ້ມູນຈາກ 3.2.P.3souldinclude: E280A2ຂໍ້ມູນກ່ຽວກັບຜູ້ຜະລິດ. E280A2 ລາຍລະອຽດຫຍໍ້ຂອງຂະບວນການຜະລິດແລະກການນໍາສະເຫນີຕາຕະລາງການຄວບຄຸມແມ່ນໄດ້ຕິດຕັ້ງຢູ່ໃນຕົວກໍານົດເອງແລະສອດຄ່ອງການຜະລິດຜະລິດຕະພັນທີ່ມີຄຸນນະພາບທີ່ເຫມາະສົມ. • A flow diagram, ສະຫນອງໃຫ້ພາຍໃຕ້ການ 3.2. P.3.3. • A brief description ofຊຸດocຂັ້ນຕອນການວິເຄາະ evaluation, as described in 3.2. P.3.5. 2.3. P.4 Control of Exciການນໍາສະເຫນີຮູບພາບທີ່ເຫມາະສົມthe quality of excipients, as described in 3.2.P.4, should be included. 2.3. P.5 Control of Drug Product (name, dosage form) A brief summary of the justification of the specification(s), a summary of the analytical procedures and validation, and characterisation of impurities should be provided. ຂໍ້ມູນຈໍາເພາະ(s) from 3.2.P.5.1 should be provided. A tabulated summary of the batch analyses provided under 3.2.P.5.4, with graphical representation where appropriate should be included. 2.3. P.6 Reference Standards or MatThepost-approvalstabilityprotocolion from 3.2.P.6 (tabulated presentation, where appropriate) should be included. 2.3. P.7 Container Closure System (name, dosage form) A brief description and discussion of the information in 3.2.P.7 should be included. 2.3. P.8 Stability (name, dosage form) A summary of the studies undertaken (conditions, batches, analytical procedures) ແລະການສົນທະນາໂດຍຫຍໍ້ຂອງຜົນໄດ້ຮັບແລະຂໍ້ສະຫຼຸບຂອງຄວາມຫມັ້ນຄົງຂອງການສຶກສາແລະການວິເຄາະຂໍ້ມູນຄວນຈະຖືກລວມເອົາ. ສະຫຼຸບກ່ຽວກັບສະພາບການການເກັບຮັກສາແລະຊີວິດຊັ້ນວາງ, if applicable, ເງື່ອນໄຂການເກັບຮັກສາແລະຊີວິດໃນຊັ້ນວາງຄວນຖືກເລີ່ມຕົ້ນ. ສະຫຼຸບສັງລວມຄວາມອາດສາມາດໄດ້ຜົນມາຈາກ 3.2.P.8.3, with graphical representation where appropriate, should be included. The post-approval stability protocol, asdescribedin3.2.P.8.2, should be provided. 2.3. Appendices 2.3. ຂໍ້ມູນພາກພື້ນ 2.4. ສະພາບລວມທີ່ບໍ່ແມ່ນທາງດ້ານຄລີນິກTheNonclinicalOverview ຄວນຈະສະໜອງການວິເຄາະລວມທັງໝົດຂອງຂໍ້ມູນໃນໂມດູນ 4. In general, TheNonclinicalOverview ບໍ່ຄວນເກີນກວ່າ 30 ໜ້າ. TheNonclinicalOverview ຄວນຈະຖືກສະແດງຢູ່ໃນລໍາດັບຕໍ່ໄປນີ້: E280A2Overview ofthenonclinicaltestingstrategyE280A2 PharmacologyE280A2 PharmacokineticsE280A2ToxicologyE280A2Integratedoverview and ConclusionsE2 80A2 ບັນຊີລາຍຊື່ວັນນະຄະດີອ້າງອີງTheIntegratedOverviews thenonclinicalstudiesandriveatlogical, ຂໍ້ສະຫຼຸບທີ່ມີການໂຕ້ຖຽງກັນດີທີ່ສະຫນັບສະຫນູນຄວາມປອດໄພຂອງຜະລິດຕະພັນສໍາລັບການນໍາໃຊ້ທາງດ້ານການຊ່ວຍ. ການກິນຢາປົວພະຍາດ, ການຢາ, andtoxicology ຜົນການບັນຊີ, ການຄົ້ນພົບທາງຄລີນິກອ່ອນເພຍເພື່ອຄວາມປອດໄພຂອງມະນຸດຂອງການໃຊ້ຢາຄວນປຶກສາຫາລື. (i.e., asapplicabletolabelling). ICH M4S (R2) Module 2.4 ສະຫນອງຄໍາແນະນໍາສໍາລັບເນື້ອໃນ softheNon-clinicalOverview. Thenon-clinicalinformationinModule 2.4 ແລະໂມດູນ 4 ບໍ່ແມ່ນປົກກະຕິຕ້ອງການແຫຼ່ງຂໍ້ມູນ (generic) ຜະລິດຕະພັນຢາ. ຢ່າງໃດກໍຕາມ, ໃນບາງກໍລະນີ, ມີການປ່ຽນແປງ profile insafetyimpurity, ການປະເມີນຄວາມປອດໄພຄວນຈະຖືກປະຕິບັດ. 2.5 ພາບລວມທາງດ້ານຄລີນິກTheClinical Overview isintended toprovideacritical analysis of theclinicaldataintheCommonTechnicalDocument. ສະພາບລວມທາງດ້ານຄລີນິກຈະຕ້ອງອ້າງອີງຂໍ້ມູນການສະໝັກທີ່ສະໜອງໃຫ້ໂດຍສະຫຼຸບສັງລວມທາງດ້ານຄລີນິກ, theindividualclinicalstudyreports (ICHE3), ແລະບົດລາຍງານອື່ນໆທີ່ກ່ຽວຂ້ອງ; ແຕ່ຕົ້ນຕໍຄວນຈະນໍາສະເຫນີຂໍ້ສະຫຼຸບແລະຂໍ້ສະຫຼຸບແລະຂໍ້ມູນການບົ່ງມະຕິ, ແລະບໍ່ຄວນຂຽນຄືນໃຫ້ເຂົາເຈົ້າ. Specifically, ສະຫຼຸຂໍ້ມູນທີ່ບໍ່ແມ່ນຊັບສິນງດ້ານຄລີນິກຄວນໃຫ້ລາຍລະອຽດລາຍລະອຽດຂອງການສະຫຼຸບຄວາມເປັນຈິງຂອງຂໍ້ມູນທາງດ້ານການຊ່ວຍໃນCTD, ແລະພາບລວມທາງດ້ານຄລີນິກຄວນໃຫ້ຂໍ້ສະຫຼຸບການປຶກສາຫາລືແລະການຕີຄວາມໝາຍຂອງການຄົ້ນຄວ້າເຫຼົ່ານີ້ຮ່ວມກັນກັບຂໍ້ມູນທີ່ກ່ຽວຂ້ອງອື່ນໆ. (e.g., pertinentanimaldataorproductqualityissueshat ອາດຈະມີຄວາມກ່ຽວຂ້ອງທາງດ້ານການປິ່ນປົວ). ສະພາບລວມທາງດ້ານຄລີນິກຄວນຈະຖືກສະແດງຢູ່ໃນຄໍາສັ່ງຕໍ່ໄປນີ້: Table of Contents 2.5.1 ເຫດຜົນການພັດທະນາຜະລິດຕະພັນ 2.5.2 ພາບລວມຂອງຊີວະຢາ 2.5.3 ພາບລວມຂອງຄລີນິກຢາ 2.5.4 ພາບລວມຂອງປະສິດທິພາບ 2.5.5 ພາບລວມຂອງຄວາມປອດໄພ 2.5.6 ຜົນປະໂຫຍດແລະຄວາມສ່ຽງສະຫຼຸບ 2.5.7 ວັນນະຄະດີອ້າງອີງICHM4E (R1) Module 2.5 ສະຫນອງຄໍາແນະນໍາສໍາລັບເນື້ອໃນSoftheClinicalOverview. Module 3: QualityTheQualitymodule ປະຕິບັດຕາມໂຄງສ້າງແລະການອະທິບາຍການແຕ້ມຮູບທີ່ສະແດງຢູ່ໃນເສັ້ນ ICHM4Q (R1). Text is only duplicated from document in cases where emphasis is desired. 3.1 Table of Contents (Module 3) The table of contents should give the location of each study report in Module 3 3.2. S Body of Data - Drug Substance The following information may be submitted as information for the API as applicable: Option 1 - Confirmation of API prequalification document Option 2- A Certificate of Suitability of European Pharmacopeia (CEP) Option 3 - Active Pharmaceutical Ingredient Master File (APIMF) procedure Option 4 – Full Details in the Product Dossier For a drug product containing more than one drug substance, the information should be submitted for each drug substance. Where reference is made to a CEP, the applicant must provide a letter of access from the CEP holder. The letter of access should be provided in Module 1.2.16. Evidence of WHO Prequalification should also be provided under this section when applicable. The applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used. Option 1: Confirmation of API prequalification document. A complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant. The applicant should supply the following information in the dossier, with data summarized in the QOS-PD. - 3.2. S.1.3 ຄຸນສົມບັດທົ່ວໄປE28093discussionsonanya ເພີ່ມເຕີມສາມາດນໍາໃຊ້ໄດ້ທາງກາຍະພາບທາງເຄມີແລະທີ່ກ່ຽວຂ້ອງອື່ນໆAPIpropertiestharenotcontrolledbytheAPImanufacturerE28099sspecifications, e.g. solubilities and polymorphs according to the guidance in this section. - 3.2. S.2E28093if thesterility oftheFPPis baseduponthesterilemanufacture oftheAPIthendataonthesterilizationprocesstogether withfullvalidationdata should beprovided. - 3.2. S.3.1Elucidation ofstructureandother characteristicsE28093studiestoidentifypolymorphsandparticlesized distribution, where applicable, according to the guidance in this section. - 3.2.S.4.1SpecificationE28093thespecificationsoftheFPPmanufacturerincludingalltestsandlimitsoftheAPImanufacturerE28099sspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099sspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099specificationsspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099spo Specifications. - 3.2. S.4.22F3.2.S.4.3ຂັ້ນຕອນການວິເຄາະແລະການກວດສອບE28093anymethodsedbytheFPPmanufacturerinadditiontothoseintheAPImanufacturerE28099specifications. - 3.2. S.4.4 Batch analysis – results from two batches of at least pilot scale, demonstrating compliance with the FPP manufacturer’s API specifications. - 3.2. S.5 Reference standards or materials – information on the FPP manufacturer’s reference standards. - 3.2.S.7 Stability – data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API. ■ Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP) A complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be duly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programmed who refers to the CEP. In addition, a written commitment should be included that the applicant wiມກ inform NAFDAC in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1. Together with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD. 3.2. S.1.3 General properties – discussionsການລະລາຍ ແລະ ໂພລິມະຊັບທີ່ສອດຄ້ອງກັບແນວທາງໃນຂໍ້ນີ້erties of the API that are not controlled by the CEP and Ph.Eur. Monograph, e.g. solubilities and polymorphs according to the guidance in this section. 3.2. S.3.1 Elucidatioອີງຕາມການຊີ້ນໍາໃນພາກນີ້– studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, where applicable, according to the guidance in this section. 3.2. S.4.1SpecificationE28093thespecificationsoftheFPPmanufacturerincludingalltestsandlimitsoftheCEPandPh.Eur. MonographandanyadditionaltestsandcceptancecriteriathatarenotcontrolledintheCEPandPh.Eur. Monograph, ເຊັ່ນ: ໂພລີມໍຟຊາຍ ແລະ 2 ການແຜ່ກະຈາຍອະນຸພາກ. 3.2. S.4.22F3.2. S.4.3 ຂັ້ນຕອນການວິເຄາະແລະການກວດສອບE28093ສໍາລັບກາS.4.4BatchanalysisE28093ໄດ້ຜົນຈາກສອງຊຸດນັກບິນນ້ອຍສຸດnoສະແດງໃຫ້ເຫັນການປະຕິບັດຕາມ FPP ຜູ້ຜະລິດE28099sAPIspecifications pilot S.5ReferencestandardsormaterialsE28093informationontheFPPmanufacturerE28099sreferencestandards standards or materials – information on the FPP manufacturer’s reference standards. 3.2.S.6ລະບົບການປິດຕູ້ຄອນເທນເນີE28093ສະເພາະລວມທັງລາຍລະອຽດການລະບຸການກໍານົດການຫຸ້ມຫໍ່ຫຼັກ ຍົກເວັ້ນບ່ອນທີ່CEPspecifiesacontainer-closuresystemandtheapplicantdeclarestheintenttousethesamecontainer-closuresystem. 3.2.S.7 Stability – except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant. In the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD. Option 3: Active pharmaceutical ingredient master file (APIMF) procedure Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer In such cases, the Open part (non-proprietary information) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections: General information S.1.1–S.1.3 Manufacture S.2 Manufacturer(s) S.2.1 Description of manufacturing process and process controls S.2.2 Controls of critical steps and intermediates S.2.4 Elucidation of structure and other characteristics S.3.1 Impurities S.3.2 Control of the API S.4.1–S.4.5 Reference standards or materials S.5 Container-closure system S.6 Stability S.7.1ທາງເລືອກ.3 It is the responsibility of the applicant to ensure that the complete APIMF (i.e. ທັງຜູ້ສະຫມັກE28099sOpenpartandtheAPImanufacturerE28099srestrictedpart) issupplied toNAFDAC ໂດຍກົງໂດຍAPImanufacturerand that the applicantthasaccesstotherelevantin information intheAPIMF ກ່ຽວກັບການຜະລິດປະຈຸບັນຂອງAPI. Acopyoftheletterofaccess ຄວນຖືກຈັດໃຫ້ຢູ່ໃນPDModule 1. APIMFholders ສາມາດນໍາໃຊ້ການແນະນໍາທີ່ສະຫນອງໃຫ້ສໍາລັບທາງເລືອກE2809CFulldetailsinthePDE2809D forpreparationoftherelevantsectionsoftheOpenandRestrictedpartsoftheirAPIMFs. ການອ້າງອິງຄວນຈະຖືກສ້າງຂື້ນtotheAPIMFguidelinesinWHOTechnicalReportSeries, No. 948, Annex 4 (4). Option 4: ລາຍລະອຽດເຕັມຢູ່ໃນPDInformationonthe3.2.Sactivepharmaceuticalingການຕິດສະຫຼາກections, ລວມທັງລາຍລະອຽດຂອງເຄມີສາດ, manufacturing process, ການຄວບຄຸມຄຸນນະພາບໃນລະຫວ່າງການຜະລິດແລະຂະບວນການກວດສອບ API, ຄວນຈະຖືກສົ່ງເຂົ້າມາໃນ PDasoutlines ຕໍ່ໄປນີ້ຕາມລໍາດັບຂອງຂໍ້ແນະນໍາ. TheQOS-PD ຄວນຈະສໍາເລັດການປະຕິບັດຕາມຂັ້ນຕອນ 3.1 ຂໍ້ແນະນໍາເຫຼົ່ານີ້. 3.2. S.1 ຂໍ້ມູນທົ່ວໄປ (name, manufacturer) 3.2. S.1.1 ນາມສະກຸນ (name, manufacturer) ຂໍ້ມູນກ່ຽວກັບບັນຊີຂອງສານເສບຕິດຢາຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້. ຕົວຢ່າງ: E280A2RecommendedInternationalNon-proprietaryName (INN); E280A2 ຊື່ຫຍໍ້ທີ່ກ່ຽວຂ້ອງ; E280A2 ຊື່ທາງເຄມີ(s); E280A2 ລະຫັດບໍລິສັດຫ້ອງທົດລອງ; E280A2ຊື່ອື່ນທີ່ບໍ່ແມ່ນຊັບສິນ(s), e.g., ຊື່ແຫ່ງຊາດ, United States AdoptedName (ອາເມລິກາ), ຊື່ຍີ່ປຸ່ນທີ່ຍອມຮັບ (ມັງກອນ); ຊື່ທີ່ອະນຸມັດຈາກອັງກິດ (ຫ້າມ), ແລະການບໍລິການ Abstracts ເຄມີ (CAS) ໝາຍເລກທະບຽນ. ຊື່ທາງເຄມີຄວນຈະສອດຄ່ອງກັນກັບທີ່ປາກົດຢູ່ໃນວັນນະຄະດີວິທະຍາສາດແລະທີ່ປາກົດຢູ່ໃນຜະລິດຕະພັນການປ້າຍຊື່ຂໍ້ມູນ (e.g. in the summary of product characteristics (SmPC) ແລະpackageleaflet, ຍັງຮູ້ຈັກເປັນເອກະສານຂໍ້ມູນຄົນເຈັບ (PIL)). ຊື່ໃດນຶ່ງທີ່ມີຊື່ທີ່ມັກຄວນຖືກລະບຸໄວ້. 3.2. S.1.2 ໂຄງສ້າງ (name, manufacturer) ສູດໂຄງສ້າງ, ລວມທັງການກ່ຽວຂ້ອງກັບສະເຕີຣິໂອເຄມີ, the molecular formula, ແລະ ຄວນສະໜອງໃຫ້ມວນສານໂມເລກຸນ. ຂໍ້ມູນນີ້ຄວນຈະສອດຄ່ອງກັບການສະຫນອງໃຫ້ 3.2. S.1.1. ສໍາລັບAPIsexistingassaltsthemolecularmassສູດໂມເລກຸນidshouldalsobeprovided. 3.2. S.1.3 ຄຸນສົມບັດທົ່ວໄປ (name, manufacturer) ໂຄງສ້າງ, molecular formula, ນ້ ຳ ໜັກ ໂມເລກຸນແລະສູດໂຄງສ້າງຖືກ ກຳ ນົດ. Thechiralcentresifanyareidentified. ຂໍ້ມູນນີ້ສາມາດນໍາໃຊ້ໃນການພັດທະນາສະເພາະ, ໃຫ້ຂໍ້ມູນ FPPsandinthetesting forrelease andstability purposes. ຄຸນສົມບັດທາງກາຍະພາບ ແລະເຄມີຂອງ API ຄວນພິຈາລະນາ, ລວມທັງການອະທິບາຍທາງດ້ານຮ່າງກາຍ, solubilities incommonsolvents (e.g. water, alcohols, dichloromethane and acetone), quantitativeaqueouspHsolubilityprofile (e.g. pH 1.2–6.8, dose2Fsolubilityvolume), polymorphism, pHandpKavalues, ultdaviolet (UV) ການດູດຊຶມສູງສຸດແລະການດູດຊຶມ molarab, melting point, ດັດຊະນີສະທ້ອນແສງ (ນ້ຳລາຍ), hygroscopicity andpartitioncoefficient (seetable ໃນQOS-PD). ບັນຊີລາຍຊື່ນີ້ບໍ່ໄດ້ຕັ້ງໃຈເຮັດຢ່າງເຄັ່ງຄັດແຕ່ໃຫ້ຂໍ້ບົ່ງຊີ້ເຖິງປະເພດຂອງຂໍ້ມູນລາຍລະອຽດທີ່ອາດຈະລວມເອົາ. ບາງສ່ວນຂອງຄຸນສົມບັດທີ່ກ່ຽວຂ້ອງທີ່ສຸດທີ່ຈະພິຈາລະນາສໍາລັບ APIs ໄດ້ປຶກສາຫາລືຂ້າງລຸ່ມນີ້ລາຍລະອຽດເພີ່ມເຕີມ. ຄຳອເຫຼົ້າdichloromethaneandacetoneະພາບຄວນລວມເຖິງຮູບລັກສະນະ, ສະຖານະການສີ. ຮູບແບບແຂງຄວນຖືກລະບຸວ່າເປັນກ້ອນຫີນເປັນຮູບຊົງກົມ (ເບິ່ງ3.2.S.3.1ຂໍ້ມູນເພີ່ມເຕີມກ່ຽວກັບAPIsolidforms). ການລະລາຍ ແລະປະລິມານການເກີດ aqueouspH solubilityprofile ຕໍ່ໄປນີ້ຄວນຖືກຈັດໃຫ້ສໍາລັບalloptions ສໍາລັບpH1.2E280936.8່ນສະເຫນີ APIdata. Thesolubilitiesinanumber ofcommonsolvents ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ (e.g. in water, alcohols, dichloromethane and acetone). Thesolubilities overthephysiologicalpHrange (pH 1.2–6.8) inseveralbufferedmedia ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ໃນmg2Fml. ຖ້າຂໍ້ມູນນີ້ບໍ່ສາມາດໃຊ້ໄດ້ (e.g. ຈາກການອ້າງອີງວັນນະຄະດີ), ມັນຄວນຈະຖືກສ້າງຂື້ນໃນເຮືອນ. For solid oral dosage forms, thedose2Fsolubilityvolumes ຄວນຖືກຈັດໃຫ້ຖືກກຳນົດຕາມສູດ: ປະລິມານຢາທີ່ໃຫຍ່ທີ່ສຸດ (mg) Dose2Fsolubilityvolume3DTheminumum concentration ofthedrug (mg2Fml) * * ທີ່ສອດຄ້ອງກັນກັບລະດັບການລະລາຍຕໍ່າສຸດທີ່ກຳນົດຢູ່ເໜືອລະດັບຄວາມສູງທາງສະລີລະວິທະຍາ (pH 1.2–6.8) ແລະອຸນຫະພູມ (37 ± 0.5 C2B0C). ອີງຕາມລະບົບການຈັດປະເພດ Biopharmaceutics (BCS), ລະລາຍສູງ (ຫຼືລະລາຍນ້ຳສູງ) APIsarethosewithadose2FsolubilityvolumeofE289A4 250 ml. For example, compoundAhasasits ການລະລາຍຕໍ່າສຸດ 37 C2B10.5C2B0C, 1.0 mg2FmlatpH 6.8 ແລະສາມາດໃຊ້ໄດ້ໃນ 100 mg, 200 mgand 400 ຄວາມເຂັ້ມແຂງ mg. API ນີ້ຈະບໍ່ຖືກພິຈາລະມລ BCS ສູງທີ່ລະລາຍ APIasitsdose2F solubilityvolumeisgreaterthan 250 ml (400 mg2F1.0mg2Fml3D 400 ml). Polymorphism As recommended in ICH’s CTD-Q Questions and answers/location issues document (5) the following list explains where specific data should be located in the PD: ■ The polymorphic form(s) present in the proposed API should be listed in section 3.2. S.1.3. ■ The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, where relevant. ■ The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2. S.3.1. ■ If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in 3.2.S.4.1– 3.2. S.4.5. ຂໍ້ມູນເພີ່ມເຕີມແມ່ນລວມເອົາຂໍ້ກໍານົດຂໍ້ກໍານົດການແນະນໍາ. Particlesized DistributionAsrecommendedinICHE28099sCTD-QQuesionsand Answers2Flocationissuesdocument (5), ການສຶກສາໄດ້ຖືກປະຕິບັດເພື່ອກໍານົດການແຜ່ກະຈາຍອະນຸພາກຂອງ API ຄວນຖືກຈັດໃຫ້ຢູ່ໃນພາກ 3.2.S.3.1 (ອ້າງເຖິງພາກສ່ວນຂອງຂໍ້ແນະນໍາເຫຼົ່ານີ້ສໍາລັບຂໍ້ມູນເພີ່ມເຕີມ). ຂໍ້ມູນຈາກວັນນະຄະດີສະຫນັບສະຫນູນຂໍ້ມູນແລະຜົນໄດ້ຮັບຈາກການສຶກສາສະເພາະຫຼືການພິມເຜີຍແຜ່ໃນວັນນະຄະດີສາມາດລວມເຂົ້າກັບການຕິດຕໍ່ກັບພາກນີ້. ເອກະສານອ້າງອີງICHGuidelines: Q6AandQ6B 3.2. S.2 ການຜະລິດ (name, manufacturer) 3.2. S.2.1 ຜູ້ຜະລິດ(s) (name, manufacturer) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. The facilities involved in the manufacturing, packaging, labelling, ການທົດສອບແລະການເກັບຮັກສາຂອງ API ຄວນຖືກບັນລຸໄດ້. If certain companies are responsible only for specific steps (e.g. milling ຂອງ API) this should be clearly indicated. ບັນຊີລາຍຊື່ຜູ້ຜະລິດຫຼືບໍລິສັດຄວນລະບຸທີ່ຢູ່ທີ່ຢູ່ຂອງການຜະລິດຫຼືສະຖານທີ່ການຜະລິດ(s) involved (including block(s) andunits(s)), rather than the administrative offices. ເບີໂທລະສັບ(s), ເບີແຟັກ(s) ທີ່ຢູ່ອີເມວວິນຍານ (es) should be provided. ການຜະລິດການອະນຸຍາດທີ່ຖືກຕ້ອງຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບການຜະລິດ APIs. If available, ໃບຢັ້ງຢືນການປະຕິບັດຕາມກັບ GMP ຄວນຈະໄດ້ຮັບການສະຫນອງໃນ PDinModule 1. 3.2. S.2.2Descriptionofmanufacturingprocess andprocesscontrols (name, Manufacturer) Thedescription oftheAPImanufacturingprocessrepresnts the applicantE28099s commitment forthemanufacture oftheAPI. Information should be provided to adequately describe the manufacturing process and process controls. For example: A flow diagram of the synthetic process(es) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents. A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, for example, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, and time). Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing ຂັ້ນຕອນຄວນຈະຖືກລະບຸແລະຍຸຕິທໍາ. ຂໍ້ມູນໃດໆທີ່ຈະສະຫນັບສະຫນູນການສະຫນັບສະຫນູນນີ້ຄວນຈະເປັນເອກະສານອ້າງອີງ doorfiledin3.2.S.2.5. Where the APIMF procedure is used, ການອ້າງອິງຂ້າມພາກສ່ວນທີ່ຈຳກັດຂອງAPIMF ອາດຈະຖືກລະບຸໄວ້ສຳລັບຂໍ້ມູນລັບ. ໃນນີ້, ຖ້າຫາກວ່າຂໍ້ມູນລະອຽດຖືກນໍາສະເຫນີຢູ່ໃນສ່ວນຈໍາກັດ, ຂໍ້ມູນທີ່ໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບພາກສ່ວນນີ້ຂອງPD ໄດ້ລວມທັງຕາຕະລາງ (ລວມທັງໂຄງສ້າງໂມເລກຸນ ແລະທາດລະລາຍ ແລະທາດລະລາຍ) ແລະຫຍໍ້ກ່ຽວກັບຂະບວນການຜະລິດ, ດ້ວຍການເນັ້ນໜັກເປັນພິເສດໃນຂັ້ນຕອນສຸດທ້າຍ, ລວມທັງຂັ້ນຕອນການຊໍາລະລ້າງ. However, forsterileAPIs, ຂໍ້ມູນຄວາມຖືກຕ້ອງເຕັມທີ່ກ່ຽວກັບຂະບວນການເຮັດເປັນໝັນຄວນຈະໄດ້ຮັບການສະໜອງໃຫ້ໃນພາກເປີດ (ໃນກໍລະນີທີ່ບໍ່ມີການເຮັດໝັນຕື່ມອີກຂອງຜະລິດຕະພັນສຸດທ້າຍ). The following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier. AsdiscussedinICHQ7andWHOTechnicalReportSeries, No. 957, Annex 2, ຈຸດທີ່ເອພີເອກະສານການເລີ່ມຕົ້ນແມ່ນນໍາສະເຫນີໃນຂະບວນການການຜະລິດແມ່ນຈຸດເລີ່ມຕົ້ນສໍາລັບການນໍາໃຊ້ຂອງຂໍ້ກໍານົດ GMPrequirements. TheAPIstartingmaterialitself needstobeproposedanditschoicejustified bythemanufacturerandacceptedassuchbyassessors. ວັດສະດຸເລີ່ມຕົ້ນ API ຄວນຖືກສະເໜີໃຫ້ເຂົ້າບັນຊີຄວາມຊັບຊ້ອນຂອງໂມເລກຸນ, ຄວາມໃກ້ຊິດຂອງ API ເລີ່ມຕົ້ນວັດສະດຸໄປຫາ API ສຸດທ້າຍ, ຄວາມພ້ອມຂອງ API ເລີ່ມຕົ້ນວັດສະດຸເປັນການຄ້າທາງເຄມີແລະການຄວບຄຸມຄຸນນະພາບສະຖານທີ່ API ເລີ່ມຕົ້ນວັດສະດຸ. This justification should be documented in the dossier and be available for review by NAFDAC GMP inspectors. In situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified by the applicant. The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity. A one-step synthesis may be accepted in exceptional cases, for example, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programmed, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide. In addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, if any, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times of mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates. Where there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences. All solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however, their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7. Where polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated. Where particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described. Justification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2. It is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to NAFDAC according to the requirements of the NAFDAC variation guidelines. 3.2. S.2.3 Control of materials (name, manufacturerຄວາມຕ້ອງການຕໍ່ໄປນີ້ແມ່ນໃຊ້ກັບສີ່ຂັ້ນຕອນຂອງການຍື່ນສະເຫນີຂໍ້ມູນ API sບ່ອນໃດທີ່ລາຍລະອຽດມີສະໜອງໃຫ້ໄດ້ identifying where each material is used in the process. Information on the quality and control of these materials should be provided. ຂໍ້ມູນສະແດງໃຫ້ເຫັນວ່າອຸປະກອນການໄດ້ຮັບມາດຕະຖານທີ່ເຫມາະສົມສໍາລັບການນໍາໃຊ້ຂອງເຂົາເຈົ້າຄວນຈະສະຫນອງໃຫ້, as appropriate (details in 3.2.A.2). Where the APIMF procedure is used, ຂ້າມການອ້າງອີງເຖິງພາກສ່ວນທີ່ຈຳກັດຂອງAPIMFis ພິຈາລະນາວ່າມີຄວາມພຽງພໍສຳລັບພາກສ່ວນນີ້. The following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier. ວັດສະດຸເລີ່ມຕົ້ນ API ຄວນຈະມີລັກສະນະຄົບຖ້ວນ ແລະ ເໝາະ ສົມກັບການສະ ເໜີ ແລະຖືກແກ້ໄຂ, including, at a minimum, ການຄວບຄຸມ, assay, ເນື້ອໃນ impurity ແລະຄຸນລັກສະນະທີ່ສໍາຄັນອື່ນໆຂອຍິ່ງໄປກວ່ານັ້ນະດຸ. ForeachAPIstartingmaterial, ຊື່ແລະທີ່ຢູ່ຂອງໂຮງງານຜະລິດ(s) ຂອງຜູ້ຜະລິດ(s) ຄວນຊີ້ບອກ. ລາຍລະອຽດຫຍໍ້ຂອງການກະກຽມຂອງ API ການເລີ່ມຕົ້ນອຸປະກອນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບຜູ້ຜະລິດ, ລວມທັງສານລະລາຍ, catalystsandreagentsused. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified. As indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should: a) be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the race mate of a single enantiomer API, are not considered final intermediates; b) be a well characterized, isolated and purified substance with its structure fully elucidated includinultravioletochemistry (when applicable); c) have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities; d) be incorporated as a significant structural fragment into the structure of the API. Copies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD. Thecarry-overofimpuritiesofthestartingmaterials forsynthesisintothefinalAPI ຄວນພິຈາລະນາ ແລະ ປຶກສາຫາລື. Aletterofattestation ຄວນຈະໄດ້ຮັບການຢັ້ງຢືນວ່າAPI ແລະອຸປະກອນການເລີ່ມຕົ້ນແລະຜະລິດຕະພັນທີ່ຖືກນໍາໃຊ້ເພື່ອການຜະລິດຂອງAPIare ໂດຍບໍ່ມີຄວາມສ່ຽງຕໍ່ການແຜ່ກະຈາຍຂອງສັດປີກແລະພະຍາດທາງດ້ານການອັກເສບ.. ເມື່ອມີໃຫ້CEP ສະແດງໃຫ້ເຫັນການປະຕິບັດຕາມຂໍ້ສະເຫນີແນະໂດຍ Sonmissiblespongiformencephalopathy (TSE) should be provided. A complete copy of the CEP (incບ່ອນທີ່APIMFprocedureisedvided in Module 1. Reference documents: ICH Q6A. 3.2. S.2.4Controlsofcriticalstepsandintermediates (name, manufacturer) Critical steps: Tests and acceptance criteria (withjustification ລວມທັງຂໍ້ມູນການທົດລອງ) ປະຕິບັດຢ່າງເຂັ້ມງວດໃນຂັ້ນຕອນsidentifiedin3.2.S.2.2ຂອງຂະບວນການຜະລິດການຜະລິດເພື່ອຄວາມໝັ້ນໃຈວ່າຂະບວນການຄວບຄຸມຄວນຈະໄດ້ຮັບການສະໜອງໃຫ້.. Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant. The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier. The critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral center or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms. Specifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, where applicable. Reference documents: ICH Q6A. 3.2. S.2.5 Process validation and/or evaluation (name, manufacturer) Process validation and/or evaluation studies for aseptic processing and sterilization should be included. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD. The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier. It is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected). 3.2. S.2.6 Manufacturing process development (name, manufacturer) ຄໍາບັນຍາຍແລະການສົນທະນາຄວນຈະໄດ້ຮັບການສະຫນອງຂອງການປ່ຽນແປງທີ່ສໍາຄັນທີ່ໄດ້ເຮັດກັບຂະບວນການຜະລິດແລະ2Formanufacturingsite oftheAPIusedin producingcomparativebioavailability orbiowaiver, ຂະຫນາດຂຶ້ນ, pilot, and, if available, ຂະໜາດການຜະລິດ. ການອ້າງອິງຄວນຈະເຮັດກັບພາກສ່ວນ APIdataprovidedin 3.2. S.4.4. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD. 3.2. S.3 ລັກສະນະ (name, manufacturer) 3.2. S.3.1Elucidation ofstructure ແລະລັກສະນະອື່ນໆ (name, manufacturer) ການຢືນຢັນໂຄງສ້າງໂດຍອີງໃສ່, e.g. syntheticroute ແລະspectralanalyses ຄວນໃຫ້. ຂໍ້ມູນຂ່າວສານທີ່ມີອໍານາດສໍາລັບການ forisomerism, ການລະບຸຕົວຂອງສະເຕີຣິເຄມີສາດ, orthepotential forformingpolymorphsshouldalsobe ລວມມີ. Elucidation ofstructureThePD ຄວນລວມເຖິງການຮັບປະກັນຄວາມສະເໝີພາບ (QA) ໃບຢັ້ງຢືນການສໍາເນົາ softhespectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure). For APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). For APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each of the proposed manufacturer(s) ດໍາເນີນການພ້ອມກັນກັບມາດຕະຖານການຮັບຮູ້ຢ່າງເປັນທາງການ. Seesection3.2.S.5fordetailsonacceptablereferencestandardsormaterials. Isomerism2FstereochemistryWhenanAPIischiral, ມັນຄວນຈະຖືກລະບຸໄວ້ບໍ່ວ່າຈະເປັນສະເຕີຣອຍໄອໂຊມີໂຊຣາມິກຂອງສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄດ້ນຳໃຊ້ໃນການສຶກສາຊີວະພາບປຽບທຽບ, ແລະຂໍ້ມູນຄວນຈະຖືກມອບໃຫ້ stereoisomer ຂອງ API ທີ່ຖືກນໍາໃຊ້ໃນ FPP. ບ່ອນທີ່ມີທ່າແຮງສໍາລັບ stereoisomerismexists, ການສົນທະນາຄວນຈະຖືກລວມເອົາເຖິງຄວາມເປັນໄປໄດ້ຂອງ isomers ທີ່ສາມາດເປັນຜົນມາຈາກຂະບວນການຜະລິດແລະຂັ້ນຕອນຂອງບ່ອນທີ່chirality ໄດ້ຖືກນໍາສະເຫນີ. ໂດຍວິທີທາງການຂອງອົງປະກອບຂອງໄອໂຊມິກຂອງAPItotha ຂອງ APIinthecomparator ຄວນໄດ້ຮັບການສ້າງຕັ້ງຂຶ້ນ. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity. The potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed. When a single enantiomer of the API is claimed for non-pharmacopoeia APIs, unequivocal proof of absolute configuration of asymmetric centers should be provided, such as determined by X-ray of a single crystal. If, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect. Polymorphism Many APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates. Polymorphic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences. Applicants intending to register products with NAFDAC and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, ສິດທິບັດ, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions. A number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them. Decision tree 4 of ICH Q6A can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. ຮູບແບບວິທີການຄວບຄຸມໂພລີໂມຟິກຄວນຖືກສະແດງໂດຍສະເພາະສໍາລັບຮູບແບບທີ່ຕ້ອງການ. Polymorphismcanalsoincludessolvation orhydrationproducts (ເປັນທີ່ຮູ້ຈັກກັນວ່າ aspseudopolymorphs). IftheAPIisusedinasolvatedform, ຂໍ້ມູນດັ່ງຕໍ່ໄປນີ້ຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້: E296A0Specificationsforthesolvent-freeAPIin3.2.S.2.4, ifthatcompoundisasyntheticprecursor; E296A0Specifications forthesolvatedAPI ຮວມເຖິງການຈຳກັດຄວາມເໝາະສົມຂອງອັດຕາສ່ວນນ້ຳໜັກຂອງAPItosolvent (ກັບຂໍ້ມູນເພື່ອສະຫນັບສະຫນູນຂອບເຂດຈໍາກັດທີ່ສະເຫນີ); E296A0 ລາຍລະອຽດຂອງວິທີການນໍາໃຊ້ເພື່ອpreparethesolvatein 3.2. S.2.2. ການແຜ່ກະຈາຍອະນຸພາກສຳລັບ APIsthaarenotBCS ທີ່ມີທາດລະລາຍສູງໃນດິນແຂງ FPPs, orliquidFPPscontainingundissolvedAPI, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g. delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions. If particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch (es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch (es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits: ▪ d10 not more than (NMT) 10% of total volume less than X µm; ▪ d50 XX µm–XXX µm; ▪ D90 not less than (NLT) 90% of total volume less than XXXX µm. Other controls on particle size distribution can be considered acceptable, if scientifically justified. Reference documents: ICH Q6A. 3.2. S.3.2 Impurities (name, manufacturer) Information on impurities should be provided. Details on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10–12). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below. Regardless of whether a pharmacopoeia standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeia APIs should not be limited to the impurities specified in the API monograph. The tables in the QOS-PD template should be used to summarize the information on the APIrelated and process-related impurities. In the QOSPD, thetermE2809CoriginE2809Dreferstohow and wheretheimpurity wasintroduction (e.g. E2809CSyntheticintermediatefromຂັ້ນຕອນ 4 ofthesynthesisE2809DorE2809CPທ່າແຮງໂດຍຜະລິດຕະພັນ ການຈັດລຽງຕາມຂັ້ນຕອນ 6 ofthesisE2809D). ມັນຄວນຈະໄດ້ຮັບການຊີ້ບອກເຖິງຄວາມບໍ່ບໍລິສຸດແມ່ນametaboliteຂອງ API. TheICHthresholds ສໍາລັບການລາຍງານ, identification (ໃຊ້ເພື່ອກໍານົດຂອບເຂດສໍາລັບຄວາມບໍ່ສະອາດສ່ວນບຸກຄົນ) ແລະຄຸນວຸດທິແມ່ນຖືກກໍານົດໂດຍພື້ນຖານຂອງຄວາມສາມາດເປີດເຜີຍຕໍ່ກັບຄວາມບໍລິສຸດ, e.g. ໂດຍປະລິມານສູງສຸດປະຈໍາວັນ (MDD) ຂອງ API. ສໍາລັບAPIsavailableinmultipledosageformsandstrengthshavingdifferentMDDvalues, itisimperative thatthethresholdsandcorrespondingcontrolsforeachofthepresentations beconsidered toensurehattherisksposedbyimpuritieshaveenaddressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included. It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs. Identification of impurities It is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendia monograph. As a result, each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD ≤ 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendia monograph, which could potentially be higher than the applicable ICH limit. Qualification of impurities The ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs: The limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles. Levels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified. AspecifiedimpuritypresentintheexistingAPIisconsideredqualifiediftheamountoftheimpurityintheexistingAPIreflectsthelevelsobservedintheinnovatororprequalifiedFPP. ພື້ນຖານສໍາລັບການຍອມຮັບເງື່ອນໄຂການຍອມຮັບThe ພື້ນຖານສໍາລັບການຍອມຮັບເງື່ອນໄຂການຍອມຮັບສໍາລັບຄວາມບໍ່ສະອາດຄວນໄດ້ຮັບການສະຫນອງໃຫ້. ນີ້ຖືກສ້າງຕັ້ງຂຶ້ນໂດຍພິຈາລະນາການກໍານົດຕົວຕົນແລະເງື່ອນໄຂເງື່ອນໄຂສໍາລັບຄວາມບໍ່ສະອາດທີ່ກ່ຽວຂ້ອງກັບ API (e.g. starting materials, by-products, intermediates, chiralimpurities ຜະລິດຕະພັນການເຊື່ອມໂຊມ) ແລະຂໍ້ຈຳກັດຄວາມເຂັ້ມຂຸ້ນສຳລັບຄວາມບໍ່ສະອາດທີ່ກ່ຽວຂ້ອງກັບຂະບວນການ (e.g. residualsolvents) ອີງຕາມຂໍ້ແນະນຳICH (e.g. Q3A, Q3C). ລະດັບທີ່ມີຄຸນວຸດທິຄວນຈະຖືກພິຈາລະນາເປັນຂອບເຂດຈໍາກັດສູງສຸດ. However, ຂອບເຂດຈໍາກັດທີ່ພິຈາລະນາຢ່າງກວ້າງຂວາງກວ່າຄວາມສາມາດໃນການດໍາເນີນການຜະລິດຕົວຈິງແມ່ນທໍ້ຖອຍໃຈໂດຍທົ່ວໄປ. ເຫດຜົນນີ້, the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results. If there are identified impurities specified in an official compendia monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. “Impurities D, E and F listed in The International Pharmacopoeia (Ph.Int.) Monograph are not potential impurities from the proposed route of synthesis used by manufacturer X”). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendia monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeia method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia. ICH class II solvent(s) ໃຊ້ກ່ອນຂັ້ນຕອນການຜະລິດຂັ້ນຕອນການຜະລິດອາດຈະຖືກຍົກເວັ້ນຈາກລະບົບການຄວບຄຸມໃນAPI ຂໍ້ມູນສະເພາະທີ່ເໝາະສົມແມ່ນສະໜອງໃຫ້. ການຍື່ນສະເຫນີຜົນໄດ້ສະແດງໃຫ້ເຫັນຫນ້ອຍກວ່າ 10% ຂອງ ICHQ3Climit (ທາງເລືອກ I) ofthesolvent(s) inthreeconsecutiveproduction-scalebatchesorsixconsecutivepilot-scalebatchesoftheAPIorasuitable intermediatewould beconsidered to acceptablejustification. The Laststepsolvents ນໍາໃຊ້ຂະບວນການທີ່ຄວນຈະປົກຄອງຢ່າງເປັນປົກກະຕິໃນ API ສຸດທ້າຍ. Forguidanceonacceptableresidualsolvent limititsrefertoICHQ3C. ຂອບເຂດຈໍາກັດສໍາລັບ residuesoftrimethylamine (ຊາ) ຄືກັນ 320 ppmonthebasisofICHQ3CoptionIor 3.2 mg2Fdayonthebsisof permitted dailyexposure (PDE). ການບໍ່ມີທີ່ຮູ້ຈັກ, ການສ້າງຕັ້ງເປັນສານພິດສູງ (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches) or by providing experimental safety data or published data in peer-reviewed journals. Residues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). ຄູ່ມືການກໍານົດຂອບເຂດຈໍາກັດສໍາລັບ residuesofmetalcatalystsormetalreagents (EMEA2FCHMP2FSWP2F44462F2000) ຫຼືວິທີການທຽບເທົ່າສາມາດຖືກນໍາໃຊ້ເພື່ອແກ້ໄຂບັນຫານີ້. ຕາມກົດລະບຽບ, ບໍ່ນໍາໃຊ້ກັບ extraneousmetalcontaminants ທີ່ຢູ່ ເຫມາະສົມກວ່າໂດຍ GMP, ການປະຕິບັດການແຈກຢາຍທີ່ດີ (GDP) ຄຸນນະພາບທີ່ກ່ຽວຂ້ອງກັນຢ່າງອື່ນແມ່ນໄດ້ມາຈາກການຜະລິດອຸປະກອນການຜະລິດ ແລະ ສິ່ງແວດລ້ອມ.. Reference documents: ICH Q6A, Q3A, Q3C. 3.2. S.4ControloftheAPI (name, manufacturer) 3.2. S.4.1 ຂໍ້ມູນຈໍາເພາະ (name, manufacturer) ຂໍ້ມູນຈໍາເພາະສໍາລັບ API ຄວນໄດ້ຮັບການສະຫນອງໃຫ້. As defined in ICH’s Q6A guideline (6), a speciS.7 ຄວາມໝັ້ນຄົງE28098E28098Alistoftests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. ‘Conformance to specifications’ means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.’’ Copies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer. The FPP manufacturer’s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versioເງື່ອນໄຂ methods). ▪ The standard declared by the applicant could be an officially recognized compendia standard (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard. ▪ The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes. ▪ For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, and Ph.Eur. Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes. In cases where there is more than one API manufacturer, the FPP manufacturer’s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method for a single parameter with the statement “for API from manufacturer A” (e.g. in the case of residual solvents). Any non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing. The ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs. Reference documents: ICH Q6A, Q3A, Q3C and officially recognized pharmacopoeias. 3.2. S.4.2 Analytical procedures (name, manufacturer) ຂັ້ນຕອນການວິເຄາະແມ່ນໃຊ້ເພື່ອທົດສອບ API ຄUVນໃຫ້. Copysofthein-houseanalytical procedures ນໍາໃຊ້ເພື່ອຜະລິດການທົດສອບຜົນໄດ້ຮັບສະຫນອງໃຫ້ PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. ເວັ້ນເສຍແຕ່ວ່າມີການດັດແກ້ການດັດແກ້ບໍ່ຈໍາເປັນຂອງ toprovided copyes of officiallyrecognized compendiaanalyticalprocedures. Tables for summarizing a number of the different analytical procedures and validation information (e.g. HPLCassay2Fimpuritymethods, gaschromatography (GC) ວິທີການ) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). ຕາຕະລາງເຫຼົ່ານີ້ບໍ່ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບຂັ້ນຕອນການວິເຄາະໃນຄົວເຮືອນsoftheFPP ຜູ້ຜະລິດສໍາລັບການກໍານົດຂອງສານລະລາຍໃນບ່ອນຢູ່ບ່ອນນັ້ນ., assay and purity of the API, insection2.3.S.4.2oftheQOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendia methods need not be summarized unless modifications have been made. Although HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), ຈາກແຫຼ່ງການຄ້າ sorpreparedin-house. ຖືວ່າຍອມຮັບໄດ້ໃນການນຳໃຊ້ APIasanexternal ມາດຕະຖານເພື່ອປະເມີນລະດັບຄວາມບໍລິສຸດ, ສະໜອງໃຫ້ໄດ້ຕາມຄວາມຮັບຜິດຊອບຂອງສານສະກັດຈາກທໍ່ລະບາຍນ້ຳສະອາດຢ່າງພຽງພໍທີ່ໃກ້ຄຽງກັບ API, i.e. ລະຫວ່າງ 80 and 120%. ໃນກໍລະນີທີ່ມີຄວາມຮັບຜິດຊອບຢູ່ນອກຂອບເຂດນີ້ມັນອາດຈະຍອມຮັບໄດ້ເພື່ອໃຊ້ API, ສະຫນອງການແກ້ໄຂປັດໄຈນໍາໃຊ້. ຂໍ້ມູນການສະຫນັບສະຫນູນການຄິດໄລ່ຂອງການແກ້ໄຂປັດໄຈຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ foranin-housemethod. Unspecified impurities maybebequantifiedusingasolution oftheAPIasthereferencestandarddataconcentrationcorrespondingtothelimited for individualunspecified impurities (e.g. 0.10%). ThetestforrelatedsinthePh.Int. Monographforlamivudineservesasatypical ຕົວຢ່າງ. ການທົດສອບຄວາມເໝາະສົມຂອງລະບົບ (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the caswellasthoseproposed forroutinetestingoftheAPIbytheFPPmanufacturerrity). In accordance with the Ph.Int. Section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities). Reference documents: ICH Q2, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.4.3 Validation of analytical procedures (name, manufacturer) Analytical validation information, including experimental data for the analytical procedures ການກວດສອບແລະຄວາມບໍລິສຸດຂອງ APIhould be provided. Copies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer. Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). ຕາຕະລາງເຫຼົ່ານີ້ບໍ່ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບຂໍ້ມູນການກວດສອບຄວາມຖືກຕ້ອງຂອງຂັ້ນຕອນການວິເຄາະSoftheFPP ຜູ້ຜະລິດສໍາລັບການກໍານົດຂອງ residualsolvents, assay and purity of the API, insection2.3.S.4.3oftheQOSPD. ຂໍ້ມູນການຮັບຮອງຄວາມຖືກຕ້ອງສໍາລັບວິທີການອື່ນໆທີ່ຖືກນໍາໃຊ້ເພື່ອສ້າງຕັ້ງການປະເມີນຄວາມບໍລິສຸດແລະຄວາມບໍລິສຸດ PDcanbesummarizedin2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. As recognized by regulatory authorities and pharmacopoeias themselves, verification of compendia methods can be necessary. The compendia methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. ແຫຼ່ງທີ່ແຕກຕ່າງຂອງSofthesameAPIorFPPສາມາດບັນຈຸຄວາມບໍລິສຸດແລະ2ການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນທີ່ບໍ່ໄດ້ພິຈາລະນາໃນລະຫວ່າງການພັດທະນາຂອງthemonograph. Therefore, the monograph and compendia method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s). In general verification is not necessary for compendia API assay methods. However, specificity of a specific compendia assay method should be demonstrated if there are any potential impurities that are not specified in the compendia monograph. If an officially recognized compendia method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities. If an officially recognized compendia standard is claimed and an in-house method is usQ3Ain lieu of the compendia method (e.g. for assay or for specified impurities), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods the sample analyzed should be the API spiked with impurities at concentrations equivalent to their specification limits. Reference documents: ICH Q2. 3.2. S.4.4 Batch analyses (name, manufacturer) Description of batches and results of batch analyses should be provided. The information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, pilot, scale up and, if available, production-scale batches. These data are used to establish the specifications and evaluate consistency in API quality. Analytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer’s test results should be summarized in the QOS-PD. The discussion of results should focus on obsທີ່ເຫມາະສົມd for the various tests, rather than reporting comments such as “all tests meet specifications”. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. A discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification). Reference documents: ICH Q6A, Q3A, Q3C). 3.2. S.4.5 Justification of specification (name, manufacturer) Justification for the API specification should be provided. A discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendia standard(s). If the officially recognized compendia methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included. The justification for certain tests, ຂັ້ນຕອນການວິເຄາະແລະການຍອມຮັບມາດຕະການມີການສົນທະນາພາກສ່ວນອື່ນໆsofthePD (e.g. forimpuritiesorparticlesized distribution) ແລະບໍ່ຈໍາເປັນຕ້ອງເຮັດຊ້ຳຢູ່ບ່ອນນີ້, although a cross-reference should be provided. Reference documents: ICH Q6A, Q3A, Q3C, ແລະຮັບຮູ້ຢ່າງເປັນທາງການຢາປົວພະຍາດ. 3.2. S.5Referencestandardsormaterials (name, manufacturer) ຂໍ້ມູນກ່ຽວກັບການສະຫນອງມາດຕະຖານການສະຫນອງການເອກະສານການນໍາໃຊ້ສໍາລັບການທົດສອບຂອງ API ຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້. ຂໍ້ມູນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ໂດຍສະນັ້ນມາດຕະຖານ(s) ການນໍາໃຊ້ຜະລິດຕະພັນ PD, aswellasthosetobeused bytheFPPmanufacturerinroutineAPIandFPPtesting. ແຫຼ່ງຂໍ້ມູນ(s) ຂອງເອກະສານມາດຕະຖານການດູດຊືມທີ່ນໍາໃຊ້ໃນການທົດສອບຂອງ API ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ (e.g. ທີ່ໃຊ້ສໍາລັບການລະບຸຕົວຕົນ, purityandassaytests). These could be classified as primary or secondary reference standards. A suitable primary reference standard should be obtained from an officially recognized pharmacopoeia source (e.g. BP, JP, and Ph.Eur. Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeia standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeia sources do not need further structural elucidation. Otherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary reference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents). A secondary (or in-house) ມາດຕະຖານການອ້າງອິງສາມາດນຳໃຊ້ໄດ້ໂດຍການສ້າງລະບົບການອ້າງອີງມາດຕະຖານທີ່ເໝາະສົມ, e.g. ໂດຍສະໜອງການສຳເນົາເອກະສານທີ່ອ້າງອີງຈາກຊັ້ນປະຖົມ ແລະ ຊັ້ນສອງ ມາດຕະຖານການດຳເນີນການວິເຄາະ ແລະ ການຢັ້ງຢືນ, ລວມທັງ asassay ກໍານົດຕໍ່ກັບມາດຕະຖານການອ້າງອິງເບື້ອງຕົ້ນ. Assecondaryreferencestandardisoftencharacterized and evaluated foritsintended purpose with ຂັ້ນຕອນການເພີ່ມເຕີມອື່ນໆກ່ຜູ້ຜະລິດດໍາເນີນການກວດສອບປົກກະຕິ. (e.g. ifadditionalsolventsareusedduringthead ຂັ້ນຕອນການເຮັດໃຫ້ບໍລິສຸດແບບດັ້ງເດີມ tharenotused forroutinepurposes). ມາດຕະຖານການອ້າງອິງຄວນຈະຖືກຕັ້ງໄວ້ຕາມປົກກະຕິສໍາລັບການສະເພາະ impurities. ເອກະສານອ້າງອີງ 3.2.S.4.2 foradditionalguidance. Reference documents: ICH Q6A, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.6 ລະບົບປິດຕູ້ຄອນເທນເນີ (name, manufacturer) ລາຍລະອຽດຂອງລະບົບການປິດຕູ້ຄອນເທນເນີ(s) should be provided, ລວມທັງຕົວຕົນຂອງວັດສະດຸຂອງການກໍ່ສ້າງ, ອົງປະກອບການຫຸ້ມຫໍ່ຕົ້ນຕໍ, ແລະສະເພາະຂອງເຂົາເຈົ້າ. The specifications should include description and identification (ແລະວິພາກວິຈານການຖອນຕົວ, where appropriate). Non-compendia methods (with validation) should be included, where appropriate. For non-functional secondary packaging components (e.g. ເຫຼົ່ານັ້ນບໍ່ໄດ້ສະຫນອງການປົກປ້ອງເພີ່ມເຕີມ), only a brief description should be provided. For functional secondary packaging components, additional information should be provided. ຄວາມເໝາະສົມຄວນປຶກສາຫາລືດ້ວຍກັນ, for example, choice of materials, protection from moisture and light, ຄວາມເຂົ້າກັນໄດ້ຂອງວັດສະດຸຂອງການກໍ່ສ້າງກັບ API, including sorption to container and leaching, ແລະ2ດ້ານຄວາມປອດໄພຂອງວັດສະດຸກໍ່ສ້າງ. The WHO Guidelines on packaging for pharmaceutical products and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs. Primary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR). Copies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the container, regardless of whether relabeling is conducted at any stage during the API distribution process. 2. S.7 Stability (name, manufacturer) 3.2. S.7.1 Stability summary and conclusions (name, manufacturer) The types of studies conducted, protocols used, and the results of the studies should be summarized. ບົດສະຫຼຸບຄວນລວມເອົາຜົນໄດ້ຮັບ, for example, ຈາກການເສື່ອມໂຊມຂອງການສຶກສາແລະສະພາບຄວາມເຄັ່ງຕຶງ, aswellas conclusions withrespecttostorageconditionsandretestdateors-ຊີວິດ, as appropriate. ຄຳແນະນຳຂອງອົງການອະນາໄມໂລກ ການທົດສອບຄວາມໝັ້ນຄົງຂອງຜະລິດຕະພັນການຢາທີ່ມີປະໂຫຍດ ແລະຜະລິດຕະພັນຢາສຳເລັດຮູບຄວນໄດ້ຮັບຄຳປຶກສາເພື່ອແນະນຳກ່ຽວກັບຄວາມສາມາດໃນການກວດສອບຂໍ້ມູນການຫຸ້ມຫໍ່ທີ່ຈຳເປັນສຳລັບຄຸນສົມບັດກ່ອນກຳນົດຂອງ APIsandFPPs. As outlined in the WHO stability guidelines, ຈຸດປະສົງຂອງຄວາມຫເງື່ອນໄຂການຍອມຮັບງການທົດສອບ: E2809Cprovidedence of how thequalityofanAPIorFPPvaries withtime undertheinfluence ofvarietyofenvironmentalfactors ອຸນຫະພູມ, humidity and light.” The tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments). Stress Testing As outlined in the ICH Q1A guidance document, stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved. Stress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of WHO Technical Report Series, No. 953, Annex 2, as well as, “A typical set of studies of the degradation paths of an active pharmaceutical ingredient”, in: WHO Technical Report Series, No. 929, Annex 5, Table A1. The objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10–30% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition. ThetablesintheQOS-PDtemplate ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບກ່ຽວກັບການທົດສອບຄວາມເຄັ່ງຕຶງ ແລະຄວນລວມເອົາເງື່ອນໄຂຖ້າມີປິ່ນປົວ (e.g. ອຸນຫະພູມ, ຄວາມຊຸ່ມຊື່ນ, ຄວາມເຂັ້ມຂຸ້ນຂອງການແກ້ໄຂແລະໄລຍະເວລາ) ແລະການສັງເກດການສໍາລັບຕົວກໍານົດການທົດສອບທີ່ແຕກຕ່າງກັນ (e.g. assay, ຜະລິດຕະພັນການເຊື່ອມໂຊມ). ການສົນທະນາຂອງຜົນໄດ້ຮັບຄວນຈະເນັ້ນໃຫ້ເຫັນເຖິງຄວາມສົມດຸນຂອງມະຫາຊົນ. ການທົດສອບຄວາມຄົງທີ່ຂອງຮູບພາບຄວນເປັນສ່ວນລວມຂອງການທົດສອບຄວາມກົດດັນ. ເງື່ອນໄຂມາດຕະຖານໄດ້ອະທິບາຍdinICHQ1B (22). IfE2809CprotectfromlightE2809Disstatedinone ໄດ້ຮັບການຍອມຮັບຢ່າງເປັນທາງການທາງຢາສໍາລັບAPI, itissufficienttostateE2809CprotectfromlightE2809Donlabelling, inlieuofphotostabilitystudies ເມື່ອລະບົບການປິດຕູ້ຄອນເທນນ້ໍາແດງໃຫ້ເຫັນການປ້ອງກັນແສງສະຫວ່າງ. When available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways. Accelerated and long-term testing Available information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified. The required long-term storage conditions for APIs is 30 ºC ± 2 ºC/75% ± 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the Nigerian environmental conditions (i.e. Zone IVB). Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 ºC is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the WHO Technical Report Series, No. 953, Annex 2. APIs intended for storage below −20 °C should be treated on a case-by-case basis. To establish the retest period, ຂໍ້ມູນຄວນຈະໄດ້ຮັບການສະຫນອງບໍ່ຫນ້ອຍກ່ວາສາມຊຸດຂະຫນາດນ້ອຍສຸດຂອງນັກບິນ. The batches ຄວນໄດ້ຮັບການຜະລິດໂດຍthesamesynthesisrouteasproductionbatches ແລະໃຊ້ວິທີການຜະລິດແລະຂັ້ນຕອນການຜະລິດທີ່ simulates thefinalprocesstobeused forproduction batches. ໂຄງການການທົດສອບຄວາມຫມັ້ນຄົງຄວນຈະສະຫຼຸບແລະຜົນການທົດສອບຄວາມຫມັ້ນຄົງຄວນຈະສະຫຼຸບໂດຍຫຍໍ້ໃນ QOS-PD. The information on the stability studies should include details such as storage conditions, batch number, batch size, ລະບົບປິດຕູ້ຄອນເທນເນີແລະສໍາເລັດ (and proposed) test intervals. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. ຂອບເຂດຂອງການວິເຄາະຜົນໄດ້ຮັບທີ່ກ່ຽວຂ້ອງຢູ່ບ່ອນໃດບ່ອນຫນຶ່ງແລະແນວໂນ້ມທີ່ໄດ້ຖືກສັງເກດເຫັນຄວນຈະຖືກລວມເອົາ. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided. The minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1. Table 1 Minimum data required at the time of submitting the dossier Storage (ºC) temperature Relative humidity (%) Minimum time period (months) Accelerated 40 ± 2 75 ± 5 6 Intermediate –a –a Long-term 30 ± 2 65 ± 5 or 75 ± 5 6 aWhere long-term conditions are 30 ºC ± 2 ºC/65% ± 5% RH or 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, No. 953, Annex 2 for further information regarding the storage conditions, container-closure system, test specifications and testing frequency. Proposed storage statement and retest period A storage statement should be established for display on the label, ອີງໃສ່ການປະເມີນຄວາມສາມາດຂອງ API. ຄູ່ມືດ້ານຄວາມໝັ້ນຄົງຂອງອົງການອະນາໄມໂລກ ລວມມີຈຳນວນທີ່ແນະນຳໃຫ້ໃຊ້ໃນຂັ້ນຕອນການເກັບຮັກສາທີ່ຄວນຈະຖືກນຳໃຊ້ເມື່ອໄດ້ຮັບການສະໜັບສະໜູນໂດຍການສຶກສາຄວາມເປັນໄປໄດ້.. ໄລຍະເວລາການສອບເສັງຄວນໄດ້ຮັບຂໍ້ມູນຈາກຂໍ້ມູນຄວາມເປັນໄປໄດ້ແລະຄວນຈະຖືກສະແດງຢູ່ໃນປ້າຍຄອນເທນເນີ. ຫຼັງຈາກນີ້ ໄລຍະທົດລອງທົດລອງຂອງ API ໄດ້ຖືກຕັ້ງໄວ້ເພື່ອນຳໃຊ້ໃນການຜະລິດຂອງ FanFPP ສາມາດທົດສອບໄດ້ແລ້ວ., ຖ້າຫາກວ່າບໍ່ສອດຄ່ອງກັບສະເພາະ, ສາມາດນຳໃຊ້ໄດ້ທັນທີ (e.g. ພາຍໃນ 30 days). ຖ້າຫາກວ່າການທົດສອບແລະພົບເຫັນວ່າສອດຄ່ອງ, The batchdoesnotreceiveanaditional ໄລຍະເວລາທີ່ສອດຄ້ອງກັນກັບໄລຍະເວລາທີ່ຖືກສ້າງຕັ້ງຂື້ນສໍາລັບໄລຍະເວລາທົດສອບໃຫມ່. However, anAPIbatchcanbereted ໄດ້ຫຼາຍຄັ້ງແລະສ່ວນທີ່ແຕກຕ່າງກັນຂອງ thebatchusedaftereachretest, aslongasit ສືບຕໍ່ປະຕິບັດຕາມຂໍ້ກໍານົດສະເພາະ. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period. Limited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months). Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, Annex 2. 3.2. S.7.2 Post-approval stability protocol and stability commitment (name, Manufacturer) The post-approval stability protocol and stability commitment should be provided. Primary stability study commitment When the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant. Commitment stability studies The long-term stability studies for the commitment batches should be conducted through the proposed retest period onລວມທັງ three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier. Thestabilityprotocolforthecommitmentbatches should beprovided and should include, but not be limited to, ຕົວກໍານົດການດັ່ງຕໍ່ໄປນີ້: ຈຳນວນຊຸດ(es) ແລະຂະຫນາດທີ່ແຕກຕ່າງກັນ, if applicable; ທາງດ້ານຮ່າງກາຍທີ່ກ່ຽວຂ້ອງ, ເຄມີ, ວິທີການທົດສອບ microbiological ແລະຊີວະສາດ; Acceptance criteria; ອ້າງອິງວິທີການທົດສອບ; ລາຍລະອຽດຂອງລະບົບປິດຕູ້ຄອນເທນເນີ(s); ຄວາມຖີ່ຂອງການທົດສອບ; ລາຍລະອຽດຂອງເງື່ອນໄຂການເກັບຮັກສາ (ເງື່ອນໄຂມາດຕະຖານສໍາລັບການທົດສອບໄລຍະpolymorphism່ອະທິບາຍບົດແນະນໍາເຫຼົ່ານີ້ແລະສອດຄ່ອງກັບ APIlabelling, ຄວນໃຊ້); EF82A7ພາຣາມິເຕີທີ່ໃຊ້ໄດ້ອື່ນໆສະເພາະຂອງ API. ການສຶກສາຄວາມໝັ້ນຄົງຢ່າງຕໍ່ເນື່ອງຂອງ API ຄວນຈະເປັນໄປຕາມການປະຕິບັດຕາມໂຄງການທີ່ເໝາະສົມຕໍ່ເນື່ອງກັນ. (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches. At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier. Refer to section 2.1.11 of WHO Technical Report Series, No. 953, Annex 2, for further information on ongoing stability studies. Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified. Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, Annex 2. 3.2. S.7.3 Stability data (name, manufacturer) Results of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included. The actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. Reference documents: ICH Q1A, Q1B, Q1D, Q1E, Q2 WHO Technical Report Series, No. 953, Annex 2. 3.2. P Drug product (or finished pharmaceutical product (FPP)) 3.2. P.1 Description and composition of the FPP (name, dosage form) A description of the FPP and its composition should be provided. The information provided should include, for example: ລາຍລະອຽດຂອງຮູບແບບການອະທິບາຍຂອງ FPP ຄວນຈະລວມທັງການອະທິບາຍດ້ານຮ່າງກາຍ, ຄວາມເຂັ້ມແຂງທີ່ມີຢູ່, ກົນໄກການປົດປ່ອຍ (e.g. ແກ້ໄຂທັນທີ (delayedorextended)), ເຊັ່ນດຽວກັນກັບຄຸນລັກສະນະທີ່ແຕກຕ່າງກັນໄດ້, e.g. E2809CTheproposedXYZ50-mgtablets ສາມາດໃຊ້ໄດ້ເປັນສີຂາວ, ຮູບໄຂ່, film-coated tablets, debossed ກັບE280985P.3 ການຜະລິດeandabreak-lineontheotherside. TheproposedXYZ100-mgtabletsare available asyellow, ຮອບ, fiເມັດເຄືອບເງົາdebossed withE28098100E28099ononeside and theotherside.E2809DComposition, i.e. listofallcomponentsofthedosageform, ແລະ theiramountonaperunitbassis (including overages, if any), ການທໍາງານຂອງອົງປະກອບ, and a reference to their quality standards (e.g. compendiamonographsormanufacturerE28099sspecifications). The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable. All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. “1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride”). All overages should be clearly indicated (e.g. “contains 2% overage of the API to compensate for manufacturing losses”). The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) and, if applicable, their grades (e.g. “microcrystalline cellulose NF (PH 102)”) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified). The function of each component (e.g. diluent or filler, binder, disintegrate, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring, blends or imprinting inks). This information (excluding the solvents) istobelisted ໃນຂໍ້ມູນຜະລິດຕະພັນ (e.g. ສະຫຼຸບຄຸນລັກສະນະຜະລິດຕະພັນ, labelling and package leaflet). ລາຍລະອຽດກ່ຽວກັບການປັບປຸງແຕ່ງຕັ້ງ(s) For FPPs supplied with reconstitution diluent(s) ທີ່ເປັນການຄ້າທີ່ມີຢູ່ຫຼືວ່າ Thavebeenassed ແລະພິຈາລະນາຍອມຮັບໄດ້ໃນການເຊື່ອມຕໍ່ກັບຜະForFPPs ສະ ຫນອງ ໃຫ້ ກັບ reconstitutiondiluentັບ NAFDAC, ຄຳອະທິບາຍຫຍໍ້ຂອງຮ່າງລັດຖະທຳມະນູນ(s) should be provided. For FPPs supplied with reconstitution diluent(s) ທີ່ບໍ່ແມ່ນທາງການຄ້າມີໃຫ້ນຳໃຊ້ ຫຼືບໍ່ມີການປະເມີນ ແລະພິຈາລະນາຍອມຮັບໄດ້ໃນການເຊື່ອມຕໍ່ກັບຜະລິດຕະພັນອື່ນທີ່ເຮັດກັບ NAFDAC, ຂໍ້ມູນຂ່າວສານ(s) ຄວນຈະຖືກຈັດໃຫ້ແຍກຕ່າງຫາກ FPPportion (E2809C3.2.PE2809D), as appropriate. ປະເພດຂອງຕູ້ຄອນເທນເນີແລະການປິດທີ່ນໍາໃຊ້ສໍາລັບຮູບແບບການປະກອບແລະການປັບໂຄງສ້າງໃຫມ່, ຖ້ານຳໃຊ້ໄດ້Thecontainer-closeusedfortheFPP (ແລະການປະກອບການດັດແກ້ລັດຖະທໍາມະນູນ, if applicable) should be briefly described, with further details provided under 3.2.P.7 Container-closure system, e.g. “The product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminum foil unit dose blisters (in packages of 100s) (cards of 5 × 2, 10 cards per package).” Reference documents: ICH Q6A (6). 3.2. P.2 Pharmaceutical development (name, dosage form) The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tກsts conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier. Pharmaceutical development information should include, at a minimum: the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability; identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality; discussion of the potential CQAs of the API(s), excipients ແລະລະບົບປິດຕູ້ຄອນເທນເນີ(s) ລວມທັງການເລືອກປະເພດ, gradeandamounttodeliverd ຜະລິດຕະພັນຂອງຄຸນນະພາບທີ່ຕ້ອງການ; ການສົນທະນາກ່ຽວກັບເງື່ອນໄຂການຄັດເລືອກສໍາລັບປ.3.3ວນການຜະລິດແລະຍຸດທະສາດການຄວບຄຸມທີ່ຕ້ອງການເພື່ອການຜະລິດການຄ້າການປະຊຸມ QTPPinaconsistent. ຄຸນນະສົມບັດເຫຼົ່ານີ້ຄວນຈະໄດ້ຮັບການພິຈາລະນາເປັນສ່ວນຫນຶ່ງຂອງການພັດທະນາຜະລິດຕະພັນການນໍາໃຊ້ຫຼັກການຂອງການຄຸ້ມຄອງການຄຸ້ມຄອງຕະຫຼອດຊີວິດຕະຫຼອດຊີວິດຂອງຜະລິດຕະພັນ. (ICH Q8). ການປຶກສາຫາລືກ່ຽວກັບການພັດທະນາການຢາເພີ່ມເຕີມສະເພາະບັນຫາສະເພາະການພັດທະນາຂອງ FDC ການອ້າງອິງຄວນຈະເຮັດການຜ່າຕັດ 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21). Reference documents: ICH Q6A, Q8, Q9, Q10. 3.2. P.2.1ComponentsoftheFPP (name, dosage form) 3.2. P.2.1.1 ສ່ວນປະກອບຢາທີ່ໃຊ້ໄດ້ (name, dosage form) ຄວາມເຂົທີ່ຢູ່ແລະຄວາມຮັບຜິດຊອບຂອງຜູ້ຜະລິດtslistedin3.2.P.1 ຄວແລະແຕ່ລະສະຖານທີ່ການຜະລິດທີ່ສະເຫນີຫຼືສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດແລະການທົດສອບຄວນໄດ້ຮັບການສະຫນອງໃຫ້ສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດsoການຫຸ້ມຫໍ່ particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibຖ້າບໍລິສັດມີຄວາມຮັບຜິດຊອບສະເພາະຂັ້ນຕອນສະເພາະemical characteristics of the API may influenນີ້ຄວນຈະຊີ້ບອກຢ່າງຈະແຈ້ງlity and the performance of the FPP. Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for registration of fixed-dose combination medicinal products (WHO Technical Report Series, No. 929, Annex 5, 2005). In addition to visual examination, chromatographic results (asມີສ່ວນຮ່ວມitລວມທັງຕັນ to demonstrate Aແທນທີ່ຈະເປັນຫ້ອງການບໍລິຫານlity. In general, API–excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product. 3.2. P.2.1.2 Excipients (name, dosage form) The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions. When choosing excipients those with a compendia monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list and the Handbook of pharmaceutical excipients. Use of excipients in concentrations outside established ranges is discouraged and generally requires justification. In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azocolourants as listed in the EMA Guideline CPMP/463/00. Other guidance such as the WHO Guidelines on development of paediatric medicines: points to consider in formulation (32) may provide useful general guidance in this regard. Ranges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch). Where antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies. Antimicrobial preservatives are discussed in 3.2. P.2.5. 3.2. P.2.2 Finished pharmaceutical product (name, dosage form) 3.2. P.2.2.1 Formulation development (name, dosage form) A brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate. An established multisource product is one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2. The requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO rlabelling andpackageleafletTechnical Report Series, No. 937, Annex 7) should be consulted. Product scoring may be recommended or required, for example, when scoring is specified in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology. If the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for other situations) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an illustrative example, the number of units (i.e. the splits) would be 10 ວັດສະດຸທາງເລືອກ tການປົກປ້ອງຈາກຄວາມຊຸ່ມຊື້ນແລະແສງສະຫວ່າງ retained for the test) or 10 quarters for quadrisect tablets (one quarter of each tablet is retained for the test). At least one batch of ລວມທັງການສະຫນອງການບັນຈຸແລະການຊັກstudy should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions can be demonstrated on a one-time basis and does not need to be added to the FPP specification(s). The taເພາະສະນັ້ນຈຶ່ງription in the FPP specification and in the product information (e.g. SmPC, labelling and package leaflet) should reflect the presence of a score. If splitting of a tablet is intended for preparation of a paediatric dose a demonstration of content uniformity of tablet fragments may be required. Where relevant, labelling should state that the score line is only to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In vitro dissolution or drug release A discussion should be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile. The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) should be provided. Data should also be submitted to demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters. Use of a single point test or a dissolution range should be justified based on the solubility and/ or biopharmaceutical classification of the API. For slower dissolving immediate-release products (e.g. Q = 80% in 90 minutes), a second time point may be warranted (e.g. Q = 60% in 45 minutes). Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro–in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form. For extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally, the acceptance range at each intermediate test point should not exceed 25% or ± 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1. 3.2. P.2.2.2 Overages (name, dosage form) Any overages in the formulation(s) described in 3.2.P.1 should be justified. Justification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results). Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable. 3.2. P.2.2.3 Physicochemical and biological properties (name, dosage form) Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed. 3.2. P.2.3 Manufacturing process development (name, dosage form) The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided. Differences between the manufacturing processes (es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influencບາດກ້າວສຳຄັນnce of the product should be diເພາະສະນັ້ນFor products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety. The rationale for choosing the particular pharmaceutical product (e.g. ແບບຟອມຢຕົວກາງsystem) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture). The scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8). 3.2. P.2.4 Container-closure system (name, dosage form) The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP). Testing requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following: - glass containers: - plastic containers: - rubber/elastomeric closures: Table 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials. Table 2: One-time studies to establish the suitability of the container-closure system contact materials Solid Products Oral Liquid and Topical Products Sterile Products (including ophthalmics) Description of any additional × treatmentsa × × (sterilization dehydrogenation components) and of the Extraction studies – × × Interaction studies – (migration/sorption) × × Moisture permeability × (uptake) × (usually loss) × (usually loss) Light transmission ×b × × × Information should be submitted. – Information does not need to be submitted. aE.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials. bNot required if product has been shown to be photostable. For solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable. The suitability of the container-closure system used for the storage, transportation (ການຂົນສົ່ງ) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed. A device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses. In accordance with the Ph.Int. General chapter Liquid preparations for oral use: ‘‘Each dose from a multi-dose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.’’ For a device accompanying a multi-dose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose. A sample of the device should be provided with Module 1. 3.2. P.2.5 Microbiological attributes (name, dosage form) Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed. Where an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria. As outlined in the WHO stability guidelines (WHO Technical Report Series, No. 953, Annex 2, 2009), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelflife acceptance criteria for preservative content. 3.2. P.2.6 Compatibility (name, dosage form) The compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling. Where a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required. Where sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, sub visible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers. Studies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported). 3.2. P.3 Manufacture (name, dosage form) 3.2. P.3.1 Manufacturer(s) (name, dosage form) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. The facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermeກັບate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products). The list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. For a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacture of the final product. Sites for such manufacturing steps should be listed iລວມທັງຄ່າຈ້າງvalid manufacturing authorizatioແລະອ້າງອີງເຖິງມາດຕະຖານຄຸນນະພາບຂອງພວກເຂົາs a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2). For each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2). Justification for any differences to the product in the country or countries issuing the WHOtype certificate(s) When there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide ວັນdation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified. Regulatory situation in other countries A listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferrລາຍລະອຽດໃນ3.2.A.2odule 1, 1.2.2). Reference documents: WHO Technical Report Series, No. 961, Annex 3 and No. 957, Annex 5 3.2. P.3.2 Batch formula ຈຸດ melting form) A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards. The tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch. All components used in the manufacturing process should be included, including those that may not be added to every baທີ່ກ່ຽວຂ້ອງ and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. “1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride”). All overages should be clearly indicated (e.g. “Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses”). The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) and, if applicable, their grades (e.g. “Microcrystalline cellulose NF (PH 102)”) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified). 3.2. P.3.3 Description of manufacturing process and process controls (name, dosage form) A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. A narrative description of the manufacturing process, including packaging that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant. Steps in the process should have the appropriate process parameters identified, such as time, temperature, or ph. associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated. The maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified. Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3). The information above should be summarized in the QOS-PD template and should reflect the production of the proposed commບ່ອນທີ່ເຫມາະສົມee Glossary (section 2) for definitions of pilot-scale and production-scale batches. For the manufacture of sterile products, the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization. Reference documents: ICH Q8, Q9, Q10. 3.2. P.3.4 Controls of critical steps and intermediates (name, dosage form) Critical steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled. Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. Examples of applicable in-process controls include: Granulations: moisture (limits expressed as a range), blend uniformity (e.g. low-dose tablets), bulk and tapped densities and particle size distribution; Solid oral products: average weight, weight variation, hardness, thickness, friability, and disintegration checked periodically throughout compression, weight gain during coating; Semi-solids: viscosity, homogeneity, pH; Transdermal dosage forms: assay of API–adhesive mixture, weight per area of coated patch without backing; Metered dose inhalers: fill weight or volume, leak testing, valve delivery; Dry powder inhalers: assay of API–excipient blend, moisture, weight variation of individually contained doses such as capsules or blisters; Liquids: pH, specific gravity, clarity of solutions; Parenterals: appearance, clarity, fill volume or weight, pH, filter intQ8rity tests, particulate matter, leak testing of ampoules, prefiltration and/or pre-sterilization bioburden testing. Reference documents: ICH Q2, Q6A, Q8, Q9, Q10, WHO Technical Report Series, No. 929, Annex 5. 3.2. P.3.5 Process validation and/or evaluation (name, dosage form) Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary. For products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below. The following information should be provided for all other products: 1. a copy of the process validation protocol, specific to this FPP, described below; 2. a commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the NAFDAC inspection team; 3. if the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. above. One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive AsdefinedinICHE28099sQ6Aguideliner ສະເພາະ control and testing to normຂັ້ນຕອນການວິເຄາະ ແລະເງື່ອນໄຂການການລະບຸຕົວຕົນທີ່ເໝາະສົມ. ຈໍານວນຈໍາກັດl ຊ່ວງd tablets per batch may be weighed to determine unit dose uniformity. The results are then analyzed statistically to verify the “normality” of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendia specifications. ເຊັ່ນດຽວກັນ, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. ດັ່ງນັ້ນຈຶ່ງ, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch. Where ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alteຖ້າໃຊ້ໄດ້eristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification. The process validation protocol should include, but not be limited to, the following: A reference to the current master production document; A discussion of the critical equipment; The process parameters that can affect the quality of the FPP (critical prບ່ອນທີ່ສາມາດນໍາໃຊ້ (CPPs)) including challenge experiments and failure mode operation; Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing oຖ້າຫາກວ່າສາມາດນຊື່ໃຊ້lend); The testing parameters and acceptance criteria including in processນີ້ແມ່ນnd release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies; The analytical procedures or a reference to appropriate section(s) of the dossier; The methods for recording and evaluating results; – the proposed timeframe for completion of the protocol. The manufacture of sterile FPPs needs to take place in aມີຄວາມເຂັ້ມແຂງntrolled manufacturing area (e.g. ຍົກຕົວຢ່າງcontrolled environment using highly reliable procedures and with appropriate inprocess controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following: Washing, treatment, sterilization and dehydrogenation of containers, closures and equipment; Filtration of solutions; Lyophilization process; Leaker test of filled and sealed ampoules; – final inspection of the product; – sterilization cycle. The sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided. The sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as the safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 °C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds. Any filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack oICQ8rption of che API or any of the components. For the validation of asepticຮູບແບບປະລິມານຢາ of parenteral products that cannot be terminally sterilized, simulation process trials shຄໍາຖາມທີ 9ldQ10 conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current NAFDAC or WHO GMP guidelines for details. Reference documents: ICH Q8, Q9, Q10, WHO Technical Report Series, No. 961, Annex 3. 3.2. P.4 Control of excipients (nນັກບິນdosage form) 3.2. P.4.1 Specifications (name, dosage form) The specifications for excipients should be provided. The specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers). If the standard claimed for an excipient is an officially recognized compendia standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendia monograph. If the standard claimed for an excipient is a non-compendia standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendia monograph, a copy of the specification for the excipient should be provided. For products submitted to NAFDAC for registration, only excipients with ສາມາດຄົ້ນພົບໄດ້ໃນ 2.3.RR Regionalinformationsection oftheQOS-PDeptions may be justified. For excipients of natural origin, microbial limit testing should be included in the specifications. Skiptesting is acceptable if justified (submission of acceptable results of five production batches). For oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated. The colours permitted for use are limited to those listed in the “Japanese pharmaceutical excipients”, the European Union (EU) “List of permitted food colours”, and the FDA “Inactive ingredient guide”. For proprietary mixtures, the supplier’s product sheet with the qualitative formulation should be submitted, in addition to the FPP ຕາຕະລາງສໍາລັບການສະຫຼຸບຈໍານວນຂອງຂັ້ນຕອນການວິເຄາະທີ່ແຕກຕ່າງກັນແລະຂໍ້ມູນທີ່ຖືກຕ້ອງthe qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations). Information that R.2considered confidential may be submitted directly to the NAFDAC by the supplier who should make reference in the cover letter to the specific related product. Other certifications of at-risk components may be required on a case-by-case basis. If additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted. Reference documents: ICH Q6A. 3.2. P.4.2 Analytical procedures (name, dosage form) The analytical procedures used for testing the excipients should be provided, where appropriate. Copies of analytical procedures from officially recognized compendia monographs do not need to be submitted. Reference document: ICH Q2. 3.2. P.4.3 Validation of analytical procedures (name, dosage form) Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate. Copies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate. Reference document: ICH Q2. 3.2. P.4.4 Justification of specifications (name, dosage form) Justification for the proposed excipient specifications should be provided, where appropriate. A discussion of the tests that are supplementary to those appearing in the officially recognized compendia monograph should be provided. 3.2. P.4.5 Excipients of human or animal origin (name, dosage forC2B1 For excipients of human or animalໄດ້ຮັບການຍອມຮັບໂດຍອົງການປົກຄອງແລະຮ້ານຂາຍຢາດ້ວຍຕົນເອງ (ການຢັ້ງຢືນຂອງcompendiamethodscanbenecessaryesThecompendiamethodsas ຈັດພີມມາແມ່ນຖືກຕ້ອງຕາມປົກກະຕິໂດຍອີງໃສ່APIoranFPP ທີ່ມາຈາກຜູ້ຜະລິດສະເພາະlatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice. For excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies. Materials of animal origin should be avoided whenever possible. When available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1. Reference documents: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908, Annex 1. 3.2. P.4.6 Novel excipients (name, dosage form) For excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3). Novel excipients are not accepted by NAFDAC. For the purpose of these guidelines, a nQ3Cl excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO. 3.2. P.5 Control of FPP (name, dosage form) 3.2. P.5.1 Specification(s) (name, dosage form) The specification(s) for the FPP should be provided. As defined in ICH’s Q6A guideline, a specification is: ‘‘a list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.’’ A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life. The specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods). The standard declared by the applicant could be an officially recognized compendia standard (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard. The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes. For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur. Ph.Int., USP, in-house) and the version (e.g. code number/version/ date) should be provided for version control purposes. ICH’s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, ນຳໃຊ້ໄດ້, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests. The following information provides guidance on specific tests that are not addressed by ICH’s Q6A guideline: ▪ fixed-dose combination FPPs (FDC-FPPs): Analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated, Acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards, A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit, For the API(s) present at ≥ 5 mg and ≥ 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing; Modified-release products: a meaningful API release method; Inhalation and nasal products: consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss; Suppositories: uniformity of dosage units, melting point; Transdermal dosage forms: peel or shear force, mean weight per unit area and dissolution. Unless there is appropriate justiເຖິງແມ່ນວ່າການອ້າງອິງຂ້າມຄວນຈະໃຫ້ntent of the FPP in the release specifications is ± 5% of the label claim (i.e. 95.0–105.0%). For products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied. Skip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability indicຕົວປຽບທຽບmeters suForsolidoraldosageformsting will be performed at release and at the end of shelf-life during stability studies. Any differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted. Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.2 Analytical procedures (name, dosage form) The analytical procedures used for testing the FPP should be provided. Copies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures descre.gd in officially recognized compendia. Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP. Refer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures. Reference document: ICH Q2 (16). 3.2. P.5.3 Validation of analytical procedures (name, dosage form) Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided. Copies ofຂໍ້ມູນຈໍາເພາະຄວນປະກອບມີຄໍາອະທິບາຍແລະການກໍານົດsed during pharmaceutical development (if used to support testing results provided in the ວິທີທີ່ບໍ່ໄດ້ອ້າງອີງprຢືນຢັນine testing should be provided. Tables foອົງປະກອບການຫຸ້ມຫໍ່ສຳຮອງທີ່ເຮັດວຽກບໍ່ໄດ້l procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOSPD (i.eຄວນໃຫ້ຄຳອະທິບາຍຫຍໍ້ໆເທົ່ານັ້ນsuອົງປະກອບການຫຸ້ມຫໍ່ທີ່ມີປະໂຫຍດຂັ້ນສອງlyຂໍ້ມູນເພີ່ມເຕີມຄວນໄດ້ຮັບການສະຫນອງໃຫ້f the assay, related substances and dissolution of the FPP. As recognized by regulatory authorities and pharmacopoeias themselves, verification of compendia methods can be necessary. The compendia methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the develຕາຕາລາງograph. Therefore, the monograph and compendia method(s) should be demonstrated suitable for the control of the proposed FPP. For officially recognized compendia FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendia method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances. If an officially recognized compendia standard is claທົ່ວໄປd an in-house method is used in lieu of the compendia method (e.g. for assay or for related compounds), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analyzed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits. Reference document: ICH Q2. 3.2. P.5.4 Batch analຕົວຢ່າງ: (name, dosage form) A description of batches and results of batch analyses should be provided. Information on relevant FPP batches used to establis"he specifications and evaluate consistency in manufacturing should be provided and should incluເອກະສານອ້າງອີງch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studiesແລະມັນຄວນຈະຖືກສະຫຼຸບtability, pilot, scale-up and, if available, production-scale batches). Analytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated[1] FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. The results should include those of tests on the batch (es) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provAsoutlinedintheWHOstabilityguidelinesfor generating the testing results should be identified. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided ratherພໍ່ຂອງຂ້ອຍstatements such as “within limits” or “conforms” (e.g. “levels of degradation product A ranged from 0.2 to 0.4 %”). Dissolution results should be expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1. ວິເຄາະcussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification). Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.5 Characterization of impurities (name, sosage form) Information on the characterization of impurities should be provided, if not previously provided in “3.2.S.3.2 Impurities”. A discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP). Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.6 Justification of specification(s) (name, dosage form) Justification for the proposed FPP specification(s) should be provided. A discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognizedຖ້າມi.e.andard(s). If the officially recognized compendia methods have been modified or replaced, a discussion should be ເອກະສານຊ້ອນທ້າຍded. The justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed ຫຼື other sections of the PD and would not need to be repeated here, although a cross-reference should be provR1ed. ICH Q6A should be consulted for the debelopment of specifications for FPPs. 3.2. P.6 Reference standards or materials (name, dosage form) Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in “3.2.S.5 Reference standards or materials”. See section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where noໂມດູນuded in 3.2.S.5. Reference documents: ICH Q6A (6), WHO Technical Report Series, No. 943, Annex 3. 3.2. P.7 Container-closure system (name, dosage form) A description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identificatiຢ່າງໃດກໍຕາມ critical dimensions, with drawings where appropriate). Non-compendiaS.4.4ods (with validation) should be included, where appropriate. For non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided. Suitability information should be located in 3.2.P.2. The WHO Guidelines on packaging for pharmaceutical products (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs. Descriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are: In direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler); Used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension; Used as a protective barICHM4S help ensure stability or sterility; ▪ necessary to ensure FPP quality during storage and shippສະຫຼຸບສັງລວມລັກສະນະຂອງຜະລິດຕະພັນare those that are in direct contact with the API or FPP. The specifications for the primary packaging components should include a specific teເປັນt for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight. Information to establish the suitability (e.g. qualification) of the container closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for R2change in manufacturer of dropper tips). 3.2. P.8 Stability (name, dosage form) 3.2. P.8.1 Stability summary and conclusions (name, dosage form) The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life. The WHO stability guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (19) shouຂໍ້ມູນກ່ຽວກັບຄວາມສາມາດການສຶກສາຄວນຈະລວມທັງລາຍລະອຽດສະພາບການເກັບຮັກສາequalificatiໝາຍເລກຊຸດnd FPPs. As outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as teແລະສະເຫນີumຊ່ວງເວລາທົດສອບt. The stability programme also includes the study of product related factors that influence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials. Stress testing As outlined in the WHO stability guidelines, photo stability testing should be conducted on at least one primary batch of the FPP if appropriate. If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze–thaw studies for liquid products). Accelerated, intermediate (if necessary) and long-term testing Stability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to WHO Technical Report Series, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required longterm storage conditions for the WHO Prequalification of Medicines Programmed are 30 ºC ± 2 ºC/75% ± 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence. Other storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below −20 °C should be treated on a case-by-case basis. Table 3: Minimum data required at the time of submitting the dossier (in the general case) Storage Temperature (ºC) Relative Humidity (%) Minimum Time Period (months) Accelerated 40 ± 2 75 ± 5 6 Intermediate N/A N/A Long-term 30 ± 2 75 ± 5 6 aWhere long-term conditions are 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions. To establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. The stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified. For sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, sub visible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initiຄວນເປັນການລວມເອົາlastic containers should be rNoorted over the shelf-life. Any in-use period and associated storage conditions should be justified with experimental data, for example, after opening, reconstitution and/or dilution oແຕ່ລະບຸກຄົນ ແລະທັງໝົດການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນ of FPPs packed in bulk multidose containSmPC(e.g. bottles of 1000s). If applicable, the inuse period andLetterofAccessforAPIMF be stated in the product information. The information on the stability studies should include details such as storage conditions; strength; batch number, including the API batch number(s) and manufacturer(s); batch size; a container-closure system including orientation (e.g. erect, inverted, on-side) where applicable; completed (and proposed) test interຕໍ່າແບບຟອມຂໍ້ມູນຊີວະພາບທຽບເທົ່າocBTIFn observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The discussion should include PILges of analytical results and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, at a minimum, as both the average and range of individual results. Applicants should consult ICH’s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months). Proposed storage statement and shelf-life The proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided. The recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines. Reference documents: WHO Technical Report Series, No. 953, Annex 2, ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q3B, Q6A. 3.2. P.8.2 Post-approval stability protocol and stability commitment (name, dosage form) The post-approval stability protocol and stability commitment should be provided. Primary stability study commitment When the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier. Commitment stability studies The long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier. Ongoing stability studies As described in the WHO stability guidelines, an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditແລະs on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may ແຕ່ບໍ່ຈໍາກັດten commitment (signed and dated) to this effect should be included in the dossier. Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified. Reference document: ICH Q1A. 3.2. P.8.3 Stability data (name, dosage form) Results of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, and narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included. Information on characterization of impurities is located in 3.2. P.5.5. The actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, at a minimum, as both the average and range of individual results. Reference documents: ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q2. 3.2. A Appendices 3.2. A.1 Facilities and equipment Not applicable (i.e. not a biotech product). 3.2. A.2 Adventitious agent’s safety evaluation 3.2. A.3 Novel excipients Novel excipients are not accepted. 3.2. R Regional information 3.2. R.1 Production documentation 3.2. R.1.1 Executed production documents A minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to bICHQ6Aed to a full production-scale batch. For solid oral dosage forms, pilot scale is generally, at a minimum, one-tenth that of full production scale or 100 000 tablets or capsules, whichever is the larger. Copies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible. If not included in the executed batch records through sufficient in process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the bio batch should involve testing to an extent greater than that required in routine quality control. English translations of executed records should be provided where relevant. 3.2.R.1.2 Master production documents Copies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site. The details in the ດັ່ງຕໍ່ໄປນີ້tion documents should include, but not be limited to, the following: ■ master formula; ■ dispensing, processing and packaging sections with relevant material and operational details; ■ relevant calculations (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis); ■ identification of all equipment by, at a minimum, type and working capacity (including make, model and equipment number, where possible); ■ process parameters (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed ( expressed as target and range)); ■ list of in-process tests (e.g. appearance, pH, assay, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications; ■ sampling plan with regard to the: – steps at which sampling should be done (e.g. drying, lubrication and compression), – number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender), – frequency of testing (e.g. weight variation every x minutes during compression or capsule filling); ■ precautions necessary to ensure product quality (e.g. temperature and humidity control and maximum holding times); ■ for sterile products, reference to standard operating procedures ( SOPs) in appropriate sections and a list of all relevant SOPs at the end of the document; ■ theoretical and actual yield; ■ compliance with the GMP requirements. Reference document: WHO Technical Report Series, No. 961. 3.2. R.2 Analytical procedures and validation information The tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3. S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant. 4.3 Literature references References to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate. Module 4: Non-clinical Summaries This module is not normally needed for multisource (generic) pharmaceutical products. It deals with the toxicity testing intended to justify the stability and safety of the product. The module is included for completeness to indicate the appropriate format and placement of the nonclinical data. Refer to ICH M4S (R2) for additional detail on the organization of Module 4 and for ICH references on study design and data content. 4.1 Table of Contents (Module 4) 4.2 Study Reports The study reports should be presented in the following order: 4.2.1 Pharmacology 4.2.1.1 Primary Pharmacodynamics 4.2.1.2 Secondary Pharmacodynamics 4.2.1.3 Safety Pharmacology 4.2.1.4 Pharmacodynamic Drug Interactions 4.2.2 Pharmacokinetics 4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available) 4.2.2.2 Absorption 4.2.2.3 Distribution 4.2.2.4 Metabolism 4 2.2.5 Excretion 4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical) 4.2.2.7 Other Pharmacokinetic Studies 4.2.3 Toxicology 4.2.3.1 Single-Dose Toxicity (in order by species, by route) 4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations) 4.2.3.3 Genotoxicity 4.2.3.3.1 In vitro 4.2.3.3.2 In vivo (supportive toxicokinetics evaluations) 4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations) 4.2.3.4.1 Long-term studies (in order by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics) 4.2.3.4.2 Short- or medium-term studies (including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics) 4.2.3.4.3 Other studies 4.2.3.5 Reproductive and Developmental Toxicity 4.2.3.5.1 Fertility and early embryonic development 4.2.3.5.2 Embryo-fetal development 4.2.3.5.3 Prenatal and postnatal development, including maternal function 4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated. 4.2.3.6 Local Tolerance 4.2.3.7 Other Toxicity Studies (if available) 4.2.3.7.1 Antigenicity 4.2.3.7.2 Immunotoxicity 4.2.3.7.3 Mechanistic studies (if not included elsewhere) 4.2.3.7.4 Dependence 4.2.3.7.5 Metabolites 4.2.3.7.6 Impurities 4.2.3.7.7 Other 4.3 Literature References Module 5: Clinical Summaries For multisource (generic) pharmaceutical products, only Module 5.3.1 Reports of Biopharmaceutical Studies would normally be needed. However, all parts of the module are included for completeness to indicate the appropriate format and placement of the nonclinical data. ICH E3 provides guidance on the organisation of clinical study reports, other clinical data, and references within a Common Technical Document (CTD). Module 5 provides the recommended organization for the placement of clinical study reports and related information to simplify preparation and review of dossiers and to ensure completeness. The placement of a report should be determined by the primary objective of the study. Each study report should appear in only one section. Where there are multiple objectives, the study should be cross-referenced in the various sections. An explanation such as “not applicable” or “no study conducted” should be provided when no report or information is available for a section or subsection. Refer to ICH M4E (R2) for additional detail on the organization of Module 5 and for additional ICH references on study design and data content. 5.1 Table of Contents (Module 5) A Table of Contents for study reports should be provided. 5.2 Tabular Listing of Clinical Studies 5.3 Clinical Study Reports 5.3.1 Reports of Bio-pharmaceutic Studies Bioavailability (BA) studies evaluate the rate and extent of release of the active substance from the medicinal product. Comparative BA or bioequivalence (BE) studies may use Pharmacokinetic (PK), Pharmacodynamic (PD), clinical or in vitro dissolution endpoints, and may be either single dose or multiple doses. When the primary purpose of a study is to assess the PK of a drug, but also includes BA information, the study report should be submitted in Section 5.3.1, and referenced in Sections 5.3.1.1 and/or 5.3.1.2. 5.3.1.1 Bioavailability (BA) Study Reports BA studies in this section should include • studies comparing the release and systemic availability of a drug substance from a solid oral dosage form to the systemic availability of the drug substance given intravenously or as an oral liquid dosage form • dosage form proportionality studies, and • food-effect studies. 5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports Studies in this section compare the rate and extent of release of the drug substance from similar drug products (e.g., tablet to tablet, tablet to capsule). Comparative BA or BE studies may include comparisons between • the drug product used in clinical studies supporting effectiveness and the to-be-marketed drug product, • the drug product used in clinical studies supporting effectiveness and the drug product used in stability batches, and • similar drug products from different manufacturers. 5.3.1.3 In vitro-In vivo Correlation Study Reports In vitro dissolution studies that provide BA information, including studies used in seeking to correlate in vitro data with in vivo correlations, should be placed in this section. Reports of in vitro dissolution tests used for batch quality control and/or batch release should be placed in the Quality section (module 3) of the CTD. 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Bioanalytical and/or analytical methods for biopharmaceutics studies or in vitro dissolution studies should ordinarily be provided in individual study reports. Where a method is used in multiple studies, the method and its validation should be included once in Section 5.3.1.4 and referenced in the appropriate individual study reports. 5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials 5.3.2.1 Plasma Protein Binding Study Reports 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies 5.3.2.3 Reports of Studies Using Other Human Biomaterials 5.3.3 Reports of Human Pharmacokinetic Studies 5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports 5.3.3.2 Patient PK and Initial Tolerability Study Reports 5.3.3.3 Intrinsic Factor PK Study Reports 5.3.3.4 Extrinsic Factor PK Study Reports 5.3.3.5 Population PK Study Reports 5.3.4 Reports of Human Pharmacodynamic Studies 5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5.3.4.2 Patient PD and PK/PD Study Reports 5.3.5 Reports of Efficacy and Safety Studies 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.3.5.2 Study Reports of Uncontrolled Clinical Studies References 5.3.5.3 Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses 5.3.5.4 Other Clinical Study Reports 5.3.6 Reports of Post-marketing Experience For products that are currently marketed, reports that summarize marketing experience (including all significant safety observations) should be included. 5.3.7 Case Report Forms and Individual Patient Listings (when submitted) Case report forms and individual patient data listings that are described as appendices in the ICH or WHO clinical study report guideline should be placed in this section when submitted in the same order as the clinical study reports and indexed by study. 5.4 Literature References Copies of referenced documents, including important published articles, official meeting minutes, or other regulatory guidance or advice should be provided here. This includes copies of all references cited in the Clinical Overview, and copies of important references cited in the Clinical Summary or in the individual technical reports that were provided in Module 5, Only one copy of each reference should he provided. Copies of references that are not included here should be immediately available on request. Appendix 1 Recommendations for conducting and assessing comparative dissolution profiles The dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f2 must be calculated. For extended release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release. Studies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. International Pharmacopoeia buffers are recommended; other pharmacopoeia buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media tນາທີxtent that the data are unusable. If both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). ຖ້າບໍ່ດັ່ງນັ້ນ: ▪ Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f2): f2 = 50 LOG {[1+1/n ∑nt=1 (Rt−Tt) 2] −0.5 × 100} where Rt and Tt are the mean per cent API dissolved in reference (comparator) and test product, ຕາມລໍາດັບ, at each time-point. An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. ▪ A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached. ▪ At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%. ▪ When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium. ▪ When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice. ▪ Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised. REFERENCES: ICH Common Technical Document References (http://www.ich.org) 1. ICH M4 - Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (2016) 2. ICH M4E(R2) - Common Technical Document for the Registration of Pharmaceuticals for Human Use: Efficacy (2016) 3. ICH M4Q(R1) - Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality (2002) 4. ICH M4S(R2) - Common Technical Document for the Registration of Pharmaceuticals for Human Use: Safety (2002) ICH Quality Guidelines 1. ICH Q1A(R2) - Stability Testing of New Drug Substances and Products (2003) 2. ICH Q1B Stability Testing: Photo stability Testing of New Drug Substances and Products (1996) 3. ICH Q1D - Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (2002) 4. ICH Q1E - Evaluation for Stability Data (2003) 5. ICH Q2(R1) - Validation of Analytical Procedures: Text and Methodology (2005) [combines the previous Q2A and Q2B Guidelines] 6. ICH Q3A(R2) - Impurities in New Drug Substances (2006) 7. ICH Q3B(R2) - Impurities in New Drug Products (2206) 8. ICH Q3C(R6) - Impurities: Guideline For Residual Solvents Q3C(2016) 9. ICH Q5A, Q5B, Q5C, Q5D Quality of Biological Products [not needed for multisource (generic) pharmaceutical products] 10. ICH Q6A - Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999) 11. ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (1999) [not needed for multisource (generic) pharmaceutical products] World Health Organization Guidelines 1. Guidelines on packaging for pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2002 ( WHO Technical Report Series, No. 902), Annex 9 2. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009 (WHO Technical Report Series, No. 953), Annex 2. [Together with 2015 update table Stability Conditions for WHO Member States by Region] 3. Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part, In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2012 (WHO Technical Report Series, No. 970), Annex 4 4. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. . World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 7. 5. Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. World Health Organization, (WHO Technical Report Series, No. 992), Annex 8 2015 6. Guidance for organizations performing in vivo bioequivalence studies (revision), In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fiftieth report. 7. WHO Technical Report Series, No. 996, Annex 9, 2016 World Health Organization Templates [https://extranet.who.int/prequal/content/who-medicines-prequalification-guidance] Quality Templates 1. Quality overall summary - product dossier (QOS-PD) 2. Quality information summary (QIS) Bioequivalence Template 1. Bioequivalence trail information form (BTIF) 2. Biowaiver Application Form (BAF) 3. Make reference to WHO guideline for bioavailability and bioequivalence studies and the WHO Template on Bio waiver] Labelling Templates 1. Patient information leaflet – Template 2. Summary Product Characteristics (SmPC) Template 3. Labelling Template ANNEX A: PRODUCT LABELLING GUIDANCE The Guidance and templates for product labelling shall be based on the NAFDAC Labelling Template guidance ເດືອນe Package Leaflet, Summary of Product Characteristics and labelling which is available from the NAFDAC website at https://extranet.who.int/prequal/content/contents-and-structure-whopar. Module 1.3.1 Summary of Product Characteristics (SmPC) The format of the SmPC document is to be consistent with the NAFDAC SmPC Template. The information should be provided in English language. Refer to NAFDAC SmPC Guidance Use NAFDAC SmPC Template Module 1.3.2 Patient Information Leaflet The format of the PIL is to be consistent with the NAFDAC PIL template. The information should be provided in the English Language Refer to NAFDAC PIL Guidance Use NAFDAC PIL Template Module 1.3.3 Container Labelling (Inner and Outer Labels) The primary and secondary packaging must include the following information in a legible, understandable and indelible manner. The information should be provided in English. The Container Labelling is to be consistent with the WHO template. Refer to NAFDAC Label Guidance ANNEX B: TEMPLATES Refer to NAFDAC Templates found at Quality Overall Summary – product dossier (QOS-PD) Quality information Summary (QIS) ANNEX C: MANAGEMENT OF APPLICATIONS AND STANDARD OPERATING PROCEDURES For pharmaceutical products that have been prequalified by the World Health Organization, registration will be via the Collaborative Procedure for the Accelerated Registration of WHO Prequalified medicines and vaccines. As for other products, including those for specific or neglected tropical diseases, a complete application will be required. 1.4 GENERAL POLICIES ON APPLICATIONS A separate application is required for each product. For purposes of clarification, one application could be submitted for products containing the same active ingredients and the same strength made by the same manufacturer at the same manufacturing site, to the same specifications and dosage form, but differing only in packing or pack sizes. On the other hand, separate applications shall be submitted for products that contain the same active ingredient(s) but of different salts, different strength, dosage form and proprietary or brand name. 1.4.1 Classes of Applications Applications shall be classified into three (3) • New Applications • Renewal of applications (i.e., registration) • Variation of Applications ( i.e., of a registered product ) 1.4.2 New Applications Applications for the registration of a pharmaceutical product either submitted to the Director General NAFDAC and copy the Director Registration and Regulatory Affairs Directorate for the granting of market authorization. In addition to the dossier submitted, the applicant shall provide: ຂ້າພະເຈົ້າ. A site master file of the plant in which the product was manufactured. (submitted in Module 3) ii. For NCEs and innovator products the pharmacovigilance plan shall be submitted. (Submitted in Module 1.2.8 (PSURs). 1.4.3 Applications for Renewal of Registration Applications for renewal of registration shall be made at least 3 months before the expiry of existing registration and shall follow the “Guidelines for the Renewal of Marketing Authorisation Licence for a Pharmaceutical Product” 1.4.4 Application for Variation of a registered product Applications for variation to a registered product shall be made according to requirements “NAFDAC Variation Guidelines” 1.5 SUBMISSION OF APPLICATION Applications for the registration of products for market authorization shall be made to the Director General of NAFDAC and copy Director Registration and Regulatory Affairs NAFDAC in accordance with the approved format. For products meant for marketing authorization in a specific country, the application shall be sent to the Head of the NMRA in that country. 1.6 APPLICATION FEES Application fees shall be paid for each application submitted. -This shall be as per the approved NAFDAC tariff. Others may be charged by various country MRAs as their legislation requires. 1.8 TIMELINES Complete applications for expedited registration (Locally manufactured and Priority Medicines only), Post Approval Variation and Renewal of registration will be processed within 90 working days of receiving the applications. Complete new applications will be processed within 12 months of receipt of the application. The applicant will be required to provide any requested additional data within 6 months. In case additional time is required, a formal request must be submitted. 1.9 WITHDRAWAL OF AN APPLICATION When the applicant fails to submit written responses to queries within 6 months from the date of their issuance, it will be deemed that the applicant has withdrawn the application or if the queries have been reissued for a second time and the applicant provides unsatisfactory responses, the product will be disqualified and the application will be rejected. The applicant will be required to apply afresh. 1.10 VALIDITY OF REGISTRATION The registration of a pharmaceutical product shall be valid for five (5) years unless otherwise suspended or revoked by NAFDAC, or withdrawn by applicant. 1.11 APPEALS Any person aggrieved by a decision in relation to any application for marketing authorization of a pharmaceutical product may within two (2) months from the date of notice of the decision, make representations in writing to NAFDAC and submit additional data to support the appeal. Documentation in support of the manufacturer’s request to appeal a regulatory decision is placed in Module 1.1.5 of the CTD. 1.1.5 of the CTD. NAFDAC Templates Quality Templates 1. Quality overall summary - product dossier (QOS-PD) 2. Quality information summary (QIS) Bioequivalence Template 1. Bioequivalence Trial Information Form (BTIF) 2. Biowaiver Application Form ( BAF ) a. NAFDAC BCS Biowaiver Template b. NAFDAC Additional Strength Biowaiver Template. Labelling Templates 1. Patient information leaflet (PIL)– Template 2. Summary Product Characteristics (SmPC) Template 3. NAFDAC Label Template Administrative Templates 1. Letter of Access for CEP 2. Letter of Access for APIMF [1] The term “complicated FPP” includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under “complicated FPP” include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. ກ່ຽວກັບ LEX ARTIFEX LLP Lex Artifex LLP ແມ່ນປ່ອງຢ້ຽມ ສຳ ລັບຜູ້ຜະລິດ, ຜູ້ສົ່ງອອກ, ແລະຈໍາຫນ່າຍສະບຽງອາຫານແລະຢາເສບຕິດກໍານົດລະບຽບຜະລິດຕະພັນກໍາລັງຊອກຫາອະນຸຍາດໃນໄນຈີເລຍແລະກໍາລັງຊອກຫາການເຂົ້າເຖິງຕະຫຼາດຂອງໄນຈີເຣຍ. ພວກເຮົາເປັນຮ້ານຄ້າປະຕູດຽວ ສຳ ລັບການປະຕິບັດຕາມກົດ ໝາຍ ແລະການບໍລິການຢ່າງດຸ ໝັ່ນ ເນື່ອງໃນປະເທດໄນຈີເຣຍ. ພວກເຮົາໃຫ້ລູກຄ້າມີ ຄຳ ແນະ ນຳ ດ້ານກົດ ໝາຍ ຜ່ານທຸກໆບາດກ້າວຂອງຂະບວນການຄ້າແລະນອກ ເໜືອ ຈາກ. To learn more about the Lex Artifex LLP's F&D Helpdesk and how we can help you with your food and drug warehouse inspection by Nigerian’s NAFDAC, ກະລຸນາສົ່ງອີເມວຫາ: lexartifexllp@lexartifexllp.com; ໂທ +234.803.979.5959.](https://www.lexartifexllp.com/wp-content/uploads/2018/11/medra_translation.png)
Guidelines for the registration of pharmaceutical products in Nigeria
QUALITY GUIDELINES FOR THE REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA
Lex ຈິດຕະນາການ LLP, a business and commercial ບໍລິສັດກົດຫມາຍໃນໄນຈີເລຍ, ໄດ້ນໍາສະເຫນີອາຫານ & ຢາ (F&D) Helpdesktoassistindividualsandcompanies ມີ ສ່ວນ ຮ່ວມ ໃນ ການ ຜະ ລິດ, ການແຜ່ກະຈາຍ, ການສົ່ງອອກແລະການນໍາເຂົ້າອາຫານແລະຢາທີ່ມີການຄວບຄຸມຕາມຄວາມຕ້ອງການທີ່ກໍານົດໄວ້ໂດຍ NigeriaE28099s ອົງການແຫ່ງຊາດສໍາລັບອາຫານແລະຢາບໍລິຫານແລະການຄວບຄຸມ ("Nafdac"). ການຈັດພິມນີ້ໃຫ້ຄຳແນະນຳດ້ານຄຸນນະພາບສຳລັບການລົງທະບຽນຜະລິດຕະພັນຢາໃນປະເທດໄນຈີເຣຍ.
ຄ່າໃຊ້ຈ່າຍໃນການຈົດທະບຽນກັບ Nafdac
ສໍາລັບຂໍ້ມູນກ່ຽວກັບອັດຕາພາສີສາມາດນໍາໃຊ້ແລະຄ່າໃຊ້ຈ່າຍສໍາລັບການສະບຽງອາຫານແລະການຈົດທະບຽນຢາເສບຕິດໃນໄນຈີເລຍ, contact us with the description or image of the specific product(s) ສະແຫວງຫາທີ່ຈະໄດ້ຮັບການລົງທະບຽນ, ແລະພວກເຮົາຈະສົ່ງປະມານຄ່າໃຊ້ຈ່າຍໃນການທີ່ທ່ານ. ອີເມວທີ່ lexartifexllp@lexartifexllp.com, WhatsApp +234 803 979 5959.
THE GUIDELINES
This publication provides guidance for the preparation of regulatory submission for the Registration of Medicines for Human Use in Nigeria in line with the widely accepted format and common requirements achieved through the processes of the International Council for Harmonization (I) ຂອງກົດລະບຽບຄວາມຕ້ອງການສໍາລັບການຈົດທະບຽນຜະລິດຕະພັນຢາສໍາລັບມະນຸດ.
ໂດຍສະເພາະ, ThedocumentseekstoaligntheAgencyE28099srequirement forregulatorysubmission for the registration of medicines for humanuse withharmonizationdrive intheEconomicCommunity of WestAfricanStates Sanchored bytheWestAfrican HealthOrganization (ຢູ່ນອກ).
ເພາະສະນັ້ນ, ການແນະນໍາຂອງເອກະສານນີ້ໃນທີ່ສຸດຈະຊ່ວຍເຫຼືອດັ່ງຕໍ່ໄປນີ້;
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Preparation of regulatory submission for pharmaceutical products by providing guidance on the organization and formatting of product dossier.
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The adoption of the Common Technical Document (CTD) as developed through the ICH processes and adopted by the World Health Organization in the WHO prequalification programme and the West African Health Organization in the promotion of the harmonization of regulatory requirement for the registration medicinal products for human use·
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Promotion of regulatory harmonization in ECOWAS member States;
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Collaboration and information sharing among medicines regulatory agencies Provision of guidance on other technical and general requirements
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Elaborate on requirements for Active Pharmaceutical Ingredients (API) and the Finished Pharmaceutical Products;
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Facilitates ease of submission and assessment;
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Enhanced access to quality essential medicine;
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Promotion of a more transparent regulatory system
LIST OF ABBREVIATIONS
AIDS
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Acquired Immune Deficiency Syndrome
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API
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Active Pharmaceutical Ingredient
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APIMF
|
Active Pharmaceutical Ingredient Master File
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.ATC
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Anatomical Therapeutical and Chemical Classification
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CEP
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Certificate of Suitability issued by the European Directorate for the Quality of
Medicines and Healthcare (EDQM)
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CPP
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ໃບຢັ້ງຢືນຜະລິດຕະພັນຢາ
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CTD
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ເອກະສານເຕັກນິກທົ່ວໄປ
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DMF
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Drug Master File
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ECOWAS
|
Economic Community for West African States
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FPP
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Finished Pharmaceutical Products
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GMP
|
Good Manufacturing Practices
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HIV
|
Human Immunodeficiency Virus
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I
|
International Council for Harmonisation of Technical Requirements for the
Registration of Medicines for human use
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INN
|
International Non-Proprietary Name
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MA
|
Market Authorization
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NCE
|
New Chemical Entities
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NMRA
|
National Medicines Regulatory Authority
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OTC
|
Over the Counter Medicines
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PIL
|
Patient Information Leaflet
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POM
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Prescription-only Medicines
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SmPC
|
ສະຫຼຸບສັງລວມລັກສະນະຂອງຜະລິດຕະພັນ
|
ຢູ່ນອກ
|
ອົງການຈັດຕັ້ງສຸຂະພາບອາຟຣິກາຕາເວັນຕົກ
|
WHO
|
World Health Organization
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GENERAL PRINCIPLES FOR THE PRESENTATION OF APPLICATION FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA
Language
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Applications for products seeking marketing authorization shall be submitted in English.
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ໃນກໍລະນີມີຢູ່ບ່ອນນັ້ນຕ້ອງແປເອກະສານຈາກແຫຼ່ງພາສາພາສາອັງກິດເປັນພາສາອັງກິດ, ຄວາມຖືກຕ້ອງຂອງການແປພາສາມີຄວາມຮັບຜິດຊອບຂອງຜູ້ສະຫມັກແລະການແປພາສາຈະໄດ້ຮັບການຮັບຮອງຄວາມງາມໂດຍການຮັບຮອງຈາກປະເທດຕົ້ນກໍາເນີດ.
Data Presentation
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Dossiers should be submitted in electronic form and should follow the CTD format. ໂຟນເດີແຍກຕ່າງຫາກຄວນຈະຖືກສ້າງຂື້ນສໍາລັບໂມດູນທີ່ແຕກຕ່າງກັນແລະໂຟນເດີຍ່ອຍສໍາລັບສ່ວນທີ່ແຕກຕ່າງSoftheCTDກັບໂມດູນ. ເອກະສານດັ່ງກ່າວຄວນຈະຖືກສົ່ງມາໃນແບບຟອມ PDF ທີ່ສາມາດຄົ້ນຫາໄດ້ດ້ວຍຂໍ້ຍົກເວັ້ນຂອງ QIS ເຊິ່ງຄວນຈະຢູ່ໃນMSWord.
References and Texts
· International standards for citing references in any parts of the dossier must be followed. Thelatestitionofanyreferencesource, ການລະບຸປີຂອງການພິມເຜີຍແຜ່ຕ້ອງໄດ້ນໍາໃຊ້.
C2B7 ວັນນະຄະດີການອ້າງອິງຄວນຈະຖືກອ້າງອີງກັບສະບັບປະຈຸບັນຂອງ UniformRequirements for Manuscripts ສົ່ງໄປວາລະສານຊີວະແພດ, International Committee of Medical JournalsEditors (ICMJE).
C2B7 ຫຍໍ້ມາຈາກຄຳຫຍໍ້ຄວນຖືກກຳນົດໄວ້ເປັນຄັ້ງທຳອິດທີ່ນຳໃຊ້ໃນໂມດູນ. ບ່ອນທີ່ມີຄວາມຈໍາເປັນ, ໂດຍສະເພາະແມ່ນວິທີການສໍາລັບການວິເຄາະ, ສະເພາະ ແລະຂັ້ນຕອນ, copysoftherelevantportionsofthereferencesource(s) ຕ້ອງລວມທັງ.
C2B7Allin-houseprocessesquotedinthedocumentationmusthavebeenvalidatedand propriatereferencescited.
ອຳນວຍຄວາມສະດວກໃນການກະກຽມຂອງ PD, these guidelines are organized in accordance with the structure of the ICH Common technical document – quality (M4Q) guideline.
The text of the M4Q (CTD-Q) guideline has been restated verbatim in these guidelines in bold text, with minor modifications to accommodate NAFDAC terminology and to include certain text that would be appropriate for pharmaceutical products, notably:
ເປັນ) “Drug substance” is replaced with “active pharmaceutical ingredient” or “API”
b) “Drug product” is replaced with “finished pharmaceutical product” or “FPP”.
c) “Application” is replaced with “product dossier” or “PD”.
d) “Combination product” is replaced with “fixed-dose combination” or “FDC”.
ການແນະນຳເພີ່ມເຕີມໂດຍNAFDAC ເຊິ່ງໄດ້ມາຈາກ WHOGuidelinesonsubmissionofdocumentationforamultisource (ທົ່ວໄປ) ຜະລິດຕະພັນສໍາເລັດຮູບ, following the bold text reproduced from the M4Q (CTD-Q) guideline (2), ໄດ້ຖືກພິມອອກເປັນຂໍ້ຄວາມປົກກະຕິທີ່ສາມາດແຍກແຍະໄດ້ຢ່າງງ່າຍດາຍຈາກ ICH ຂໍ້ຄວາມແລະລວມເຖິງການປັບປຸງຄວາມຊັດເຈນຂອງ NAFDACE28099 ຄວາມຄາດຫວັງສໍາລັບເນື້ອໃນຂອງ PDs. ວິທີການນີ້ແມ່ນເພື່ອອໍານວຍຄວາມສະດວກໃນການກໍານົດຕົວຕົນແລະຕົ້ນກໍາເນີດຂອງຂໍ້ຄວາມໃນຂໍ້ແນະນໍາເຫຼົ່ານີ້ (i.e.. ຈາກICHorfromWHO).
ເນື້ອໃນຂອງຂໍ້ແນະນໍາເຫຼົ່ານີ້ຄວນອ່ານຮ່ວມກັນກັບຂໍ້ມູນທີ່ກ່ຽວຂ້ອງທີ່ອະທິບາຍວ່າບໍ່ມີຢູ່ບ່ອນອື່ນ WHOorICH ເອກະສານອ້າງອີງແລະຂໍ້ແນະນໍາ. ຄຸນນະພາບຂອງ APIs ທີ່ມີຢູ່ແລ້ວແລະຜະລິດຕະພັນຫຼາຍແຫຼ່ງທີ່ສອດຄ້ອງກັນບໍ່ຄວນຖືກຕ່ໍາກວ່າ APIsandinnovator (ຕົວປຽບທຽບ) FPPs. ເພາະສະນັ້ນ, ຫຼັກການພື້ນຖານຂອງ ICH ຄູ່ມືແນະນໍາທີ່ອ້າງອີງໃນທົ່ວເອກະສານນີ້ແລະອື່ນໆWHOguidelinesmayelyapplytoexistingAPIs and multisourceproducts.
ວັນນະຄະດີວິທະຍາສາດອາດຈະເໝາະສົມກັບຄວາມຕ້ອງການສໍາລັບບາງຂໍ້ມູນ ຫຼືຕົວກໍານົດການກໍານົດບົດແນະນໍາເຫຼົ່ານີ້ (e.g. ຄຸນນະສົມບັດຂອງການລະບຸຄວາມສະອາດ). ຍິ່ງໄປກວ່ານັ້ນ, ຂໍ້ກໍານົດທີ່ລະບຸໄວ້ໃນຕອນຕົ້ນອາດຈະບໍ່ສາມາດນຳໃຊ້ໄດ້ກັບ APIorFPP ທີ່ສະເໜີໃຫ້. ຄວາມບໍ່ສະຫງົບ, ບໍ່ວ່າບົດສະຫຼຸບຫຼືການອ້າງອິງເຕັມທີ່ກ່ຽວກັບວັນນະຄະດີວິທະຍາສາດຄວນຈະສະຫນອງໃຫ້, orthenon-applicability oftherequested informations should be clearly indicated with an accompanying explanatorynote.
Guidance on format
The recommendations outlined in the WHO general filing guideline Guidelines on submission of documentation for a multisource (ທົ່ວໄປ) ຜະລິດຕະພັນສໍາເລັດຮູບ: ຮູບແບບທົ່ວໄປ: ການກະກຽມຜະລິດຕະພັນເອກະສານເອກະສານທີ່ມີລັກສະນະທົ່ວໄປຄວນປະຕິບັດຕາມຮູບແບບແລະການນໍາສະເຫນີຂອງ PD.
ບາງທີອາດມີຈຳນວນບັນຊີຢູ່ບ່ອນການຊໍ້າຄືນຂອງພາກສ່ວນສາມາດພິຈາລະນາວ່າເໝາະສົມ. ເມື່ອໃດກໍຕາມການດໍາເນີນການເຮັດເລື້ມຄືນ, ມັນຄວນຈະເປັນທີ່ຈະແຈ້ງກ່ຽວກັບສິ່ງເຫຼົ່ານີ້ໂດຍອ້າງອີງເຖິງການສ້າງຄວາມແຕກຕ່າງຂອງຫົວຂໍ້ຢູ່ໃນວົງເລັບດັ່ງຕໍ່ໄປນີ້ M4Q (CTD-Q) ຫົວຂໍ້ແນະນໍາ, e.g. 3.2.ສານເສບຕິດ SD (orAPI) (ຊື່, ຜູ້ຜະລິດA).
ຕໍ່ໄປນີ້ແມ່ນຂໍ້ສະເຫນີແນະສໍາລັບການນໍາສະເຫນີຂອງຂໍ້ມູນໃນຄຸນນະພາບໂມດູນການມີຄວາມແຕກຕ່າງຂອງສະຖານະການທີ່ອາດຈະໄດ້ພົບ:
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TheOpenpart (ຂໍ້ມູນທີ່ບໍ່ແມ່ນຊັບສິນ) ofeachAPIMF ຄວນຈະຖືກລວມເອົາຢ່າງສະເໝີຕົ້ນສະເໝີປາຍຂອງ PD, asanannexto3.2.S.
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ForanFPP ປະກອບດ້ວຍmorethanoneAPI, onecompleteE2809C3.2.SE2809Dsection should beprovidedforoneAPI, ຕາມດ້ວຍອັນອື່ນທີ່ສົມບູນE2809C3.2.SE2809DsectionforeachoftheotherAPIs.
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ForanAPIfrom ຫຼາຍຜູ້ຜະລິດ, onecompleteE2809C3.2.SE2809Dsections should beprovided for theAPIfromonemanufacturer, ປະຕິບັດຕາມໂດຍອັນອື່ນທີ່ສົມບູນE2809C3.2.SE2809DsectionfortheAPIromeachoftheotherAPImanufacturers.
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ForanFPP ມີຄວາມເຂັ້ມແຂງຫຼາຍ (e.g. 10, 50, 100 ມກ) ຫນຶ່ງຄົບຖ້ວນສົມບູນE2809C3.2.PE2809ພາກສ່ວນຄວນຈະໄດ້ຮັບການສະຫນອງຂໍ້ມູນທີ່ມີຄວາມເຂັ້ມແຂງທີ່ແຕກຕ່າງກັນ, ສະຫນອງໃຫ້ພາຍໃນພາກສ່ວນຍ່ອຍ.. 1 ສະບັບສົມບູນຂອງPD ຄວນຈະໄດ້ຮັບການສະຫນອງforeachFPPstrength.
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ForanFPP ກັບລະບົບປິດຕູ້ຄອນເທນເນີຫຼາຍອັນ (e.g. bottlesandunitdoseblisters) ຫນຶ່ງຄົບຖ້ວນສົມບູນE2809C3.2.PE2809ພາກສ່ວນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ກັບຂໍ້ມູນຂ່າວສານສໍາລັບການນໍາສະເຫນີທີ່ແຕກຕ່າງກັນສະຫນອງໃຫ້ພາຍໃນພາກສ່ວນຍ່ອຍ..
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FormultipleFPPs (e.g. tabletsandaparenteral ຜະລິດຕະພັນ) asseparatedossierisrequiredforeachFPP.
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ForanFPP ສະໜອງໃຫ້ໂດຍມີການປັບປ່ຽນລັດຖະທຳມະນູນ(s) onecompleteE2809C3.2.PE2809Dsection should beprovided for theFPP, ປະຕິບັດຕາມໂດຍຂໍ້ມູນຂ່າວສານ(s) inaseparatepartE2809C3.2.PE2809D, ທີ່ເຫມາະສົມ.
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Foraco-blisteredFPPonecompleteE2809C3.2.PE2809Dsections should beprovidedforeachproduct.
STRUCTURE OF THE CTD FORMAT
Information within the CTD is organized into a series of structured documents which are in turn organized into modules. TheM4guidanceOrganization of theCommonTechnicalDocumentandICH ຄຳຖາມທົ່ວໄປ ແລະຄຳຕອບໃຫ້ຄຳນິຍາມຂອງເອກະສານ ແລະຄຳແນະນຳໃນຕາຕະລາງເນື້ອໃນ (ToC) ການຈັດຮູບແບບ, ການອ້າງອີງຂ້າມພາຍໃນCTDandfordocumentpagination, ການແບ່ງແຍກແລະຈໍານວນພາກສ່ວນ.
ຕາຕະລາງ 1: MAINSECTIONHEADINGSINTHECOMMONTECHNICALDOCUMENT (CTD) FORMAT
ຈຳ ນວນ
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Title and Main Section Headings
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1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.ກ
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ໂມດູນ 1: Administrative and Product Information
Cover Letter
ຕາຕາລາງ (ໂມດູນ 1 ກັບ 5)
Application Information
ຂໍ້ມູນຜະລິດຕະພັນ
ບົດສະຫຼຸບພາກພື້ນ
Electronic Review Documents
Product Sample(s) (ຖ້າມີຢູ່ໃນເວລາຍື່ນສະເໜີ)
ເອກະສານຊ້ອນທ້າຍ
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2.1
2.2
2.3
2.4
2.5
2.6
2.7
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ໂມດູນ 2: ເອກະສານເຕັກນິກທົ່ວໄປ (CTD) Summaries
CTD Table of Contents (ໂມດູນ 2 ກັບ 5)
CTD Introduction
Quality Overall Summary
Nonclinical Overview
Clinical Overview
Nonclinical Written and Tabulated Summaries
Clinical Summary
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3.1
3.2
3.3
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ໂມດູນ 3: Quality
Table of Contents of Module 3
Body of Data
Literature References
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4.1
4.2
4.3
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ໂມດູນ 4: Nonclinical Study Reports
Not required for
Table of Contents of Module 4 generic products
Study Reports
Literature References
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5.1
5.2
5.3
5.4
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ໂມດູນ 5: Clinical Study Reports
Bioequivalence or
Table of Contents of Module 5 Biowaiver required for
generics as applicable
Tabular Listing of All Clinical Studies
Clinical Study Reports
Literature References
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MODULE 1 (ຂໍ້ມູນການບໍລິຫານແລະຜະລິດຕະພັນ)
1.0 ຈົດໝາຍປົກຫຸ້ມ:
C2B7Acoverletters shouldaccompany databeings submit to the regulatory authority. ຈົດຫມາຍສະບັບດັ່ງກ່າວຄວນຈະແຈ້ງຢ່າງຊັດເຈນວ່າສິ່ງທີ່ຖືກສົ່ງມາ, ລວມທັງການອ້າງອິງເຖິງການຮ້ອງຂໍຈົດຫມາຍສະບັບ (ຖ້າຫາກວ່າສາມາດນໍາໃຊ້) ແລະລາຍລະອຽດຫຍໍ້ຂອງຊຸດ.
C2B7 ຈົດຫມາຍສະບັບດັ່ງກ່າວບໍ່ຄວນມີຂໍ້ມູນວິທະຍາສາດ.
C2B7 ເອກະສານກົດລະບຽບການອ້າງອິງໃດໆກໍຕາມຄວນຈະຖືກລະບຸໄວ້ຢ່າງຈະແຈ້ງໃນຈົດໝາຍປົກປິດ, ແລະຂໍ້ມູນຕໍ່ໄປນີ້ຄວນຈະຖືກລວມເຂົ້າ:
ປະເພດຄໍາຮ້ອງສະຫມັກ E280A2, ລະບຸວ່າໃໝ່, ການປ່ຽນແປງໃຫມ່;
ໝາຍເລກສະໝັກ E280A2NMRA (ອອກໂດຍ NMRA);
E280A2 ວັນທີຂອງລະບຽບການອະນຸຍາດສາມາດໃຊ້ໄດ້.
ຊື່ຍີ່ຫໍ້ E280A2, DCI, ປະລິມານ, ການນໍາສະເຫນີ, ຮູບແບບປະລິມານຢາ;
• Manufacturer’s name
• Applicant’s name
• Number of samples submitted
A sample cover letter is provided in Annex B: ແບບຟອມ
1.1 ຕາຕະລາງເນື້ອໃນຂອງຄໍາຮ້ອງສະຫມັກອ່ອນ, ລວມທັງໂມດູນ 1 (ໂມດູນ 1-5)
ຕາຕະລາງເນື້ອໃນ (ToC) for the entire regulatory dossier should be placed in this section. It should list all documents included in Modules 1-5. A module-specific ToC is included with each Module.
1.2 Application information
1.2.1 ຄໍາຮ້ອງສະຫມັກຈົດຫມາຍສະບັບ
1.2.2 Registration Form
1.2.3 Certificate of Incorporation
1.2.4 ພະລັງງານຂອງທະນາຍຄວາມ
1.2.5 Notarized Declaration of the applicant. (The applicant should declare that the information submitted is true and correct. Information on the name, position and signature of the applicant, product particulars should be provided in the notarized declaration and should be dated, signed and stamped by a notary public)
1.2.6 Power of Attorney /Contract Manufacturing Agreement
1.2.7 ໃບຢັ້ງຢືນຜະລິດຕະພັນຢາ
1.2.8 Certificate of Good Manufacturing Practice
1.2.9 Manufacturing Authorization
1.2.10 Evidence of Trademark Registration
1.2.11 Superintendent Pharmacist’s Annual Licence to Practice
1.2.12 Certificate of Registration and Retention of Premises
1.2.13 ຫຼັກຖານການອະນຸຍາດການຕະຫຼາດກ່ອນໜ້ານີ້ (ຖ້າໃຊ້ໄດ້)
1.2.14 ຈົດໝາຍເຊີນສຳລັບການກວດກາ GMP
1.2.15 ສຳເນົາໃບຮັບຮອງຄວາມເໝາະສົມຂອງຢາປົວພະຍາດເອີຣົບ (ບ່ອນທີ່ສາມາດນໍາໃຊ້)
1.2.16 LetterofAccessforAPIMF(s) (ບ່ອນທີ່ສາມາດນໍາໃຊ້)
1.2.17 BiowaiverRequestinlation toconducting BCS-based bioavailabilitystudy
1.2.18 Biowaiverrequestion toconductingAdditional Strengthbioavailability Study
1.3. ຂໍ້ມູນຜະລິດຕະພັນ
1.3.1. ສະຫຼຸບສັງລວມລັກສະນະຂອງຜະລິດຕະພັນ (SmPC)
AcopyoftheSummaryofProduct ລັກສະນະ (SmPC) istobeplaced ພາກນີ້. ເມື່ອການທົບທວນຖືກຮ້ອງຂໍໃນລະຫວ່າງຫຼັກສູດການປະເມີນຜົນ, ສະບັບ anannotatedoftherevisedSmPCisrequired. ຄຳອະທິບາຍຄວນລະບຸວ່າມີການປ່ຽນແປງທັງໝົດ, ບໍ່ວ່າຈະເປັນທີ່ກ່ຽວຂ້ອງກັບການອະນຸມັດຫຼ້າສຸດ SmPCorinresponsetoare ຮ້ອງຂໍໃຫ້ເຮັດໂດຍອໍານາດການປົກຄອງ.
1.3.2. ການຕິດສະຫຼາກ (ນອກ & ປ້າຍພາຍໃນ)
C2B7Allcontainerlabels, ລວມທັງປ້າຍພາຍໃນແລະນອກ, ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ໃນພາກນີ້.
C2B7 ອັນນີ້ຄວນຮວມເອົາປ້າຍກຳກັບສຳລັບຄວາມເຂັ້ມແຂງທັງໝົດ, dosageformsandreconstitutions ສານປະກອບ.
C2B7 ເມື່ອມີການດັດແກ້ເພີ່ມເຕີມແມ່ນໄດ້ຮ້ອງຂໍໃນລະຫວ່າງຫຼັກສູດການທົບທວນ, anannotatedversionoftherevisedlabelmayberrequested, ແລະຄວນຈະຖືກຈັດໃສ່ໃນພາກສ່ວນນີ້.
1.3.3. PackageInsert (ຂໍ້ມູນຄົນເຈັບທີ່ຮູ້ຈັກPIL)
C2B7AcopyofthePatientInformationLeaflet (PIL) istobeplaced ພາກນີ້.
1.4. ບົດສະຫຼຸບພາກພື້ນ
1.4.1. ແບບຟອມຂໍ້ມູນຊີວະພາບທຽບເທົ່າ (BTIF)
1.4.2. ສັງລວມຂໍ້ມູນຄຸນນະພາບ (ຕໍ່າ)
1.5. Electronic Review Documents
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Electronic versions of applications are encouraged either in searchable Portable Document Format (PDF). ເອກະສານອີເລັກໂທຣນິກນີ້ຄວນຈະຖືກບັນທຶກໄວ້ໃນ CD-ROM. All electronic media submitted to support the drug regulatory document should be placed in this section
1.6. Samples
· A sample of the product in the same packaging intended for commercial purposes should be submitted along with the application. Please note that mock-up packaging may be used when the final product packaging is not available.
ໂມດູນ 2: ເອກະສານເຕັກນິກທົ່ວໄປ (CTD) Summaries
ໂມດູນ 2 includes the following 7 sections. For multisource (ທົ່ວໄປ) pharmaceutical products, ໂມດູນ 2.4-2.7 are not usually needed.
2.1 CTD Table of Contents (ໂມດູນ 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries
2.7 Clinical Summary
2.1 CTD Table of Contents (ໂມດູນ 2-5)
The table of contents for Module 2 ກັບ 5 should be provided.
2.2 CTD Introduction
The introduction should include proprietary name, non-proprietary name or common name of the drug substance, company name, ຮູບແບບປະລິມານຢາ(s), ມີຄວາມເຂັ້ມແຂງ(s), ເສັ້ນທາງການບໍລິຫານ, ແລະການສະເຫນີແນະ(s). ມັນຄວນຈະອະທິບາຍໂດຍຫຍໍ້ກ່ຽວກັບເນື້ອໃນ softheModules 2 ກັບ 5 withappropriatecross-referencestothem.
2.3 Quality Overall Summary
The Quality Overall Summary (QOS) is a summary that follows the scope and the outline of the
Body of Data in Module 3. TheQOS ປະກອບຂອງ APIsection (2.3.ສ), anFPPsection (2.3.ປ), ເອກະສານຊ້ອນທ້າຍ (2.3.ກ) ແລະຂໍ້ມູນພາກພື້ນ (2.3.ຣ). TheQOS ບໍ່ຄວນລວມເອົາຂໍ້ມູນ, dataorjustification ທີ່ບໍ່ໄດ້ລວມຢູ່ໃນໂມດູນແລ້ວ 3 orinotherpartsoftheCTD.
TheQOS-PDTemplate ຄວນຈະສໍາເລັດປະຕິບັດຕາມຄໍາແນະນໍາໃນສ່ວນນີ້.
ອ້າງອີງICHM4Q (R1).
2.3. S Drug Substance
For a drug product containing more than one drug substance, theinformationinmodule2.3.S.1to2.3.S.7 should besubmittedforeachdrugsubstance, clearly identifying the substance name and manufacturer in the title of each module.
2.3. S.1 General Information (ຊື່, manufacturer)
Include information from Module 3.2.S.1
2.3. S.2 Manufacture (ຊື່, ທີ່ຢູ່ທາງດ້ານຮ່າງກາຍ, i.e., site)
Include information from Module 3.2.S.2
Information on the manufacturer,
• Provide the name, address and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing.
• A brief description of the manufacturing process (ລວມທັງ, ຍົກຕົວຢ່າງ, reference to starting materials, critical steps, and reprocessing) and the controls that are intended to result in the routine and consistent production of material(s) of appropriate quality; this could be presented as a flow diagram.
• A flow diagram, as provided in 3.2.S.2.2;
• A description of the Source and Starting Material and raw materials of biological origin used in the manufacture of the API, as described in 3.2.S.2.3;
• Highlight critical process intermediates, as described in 3.2.S.2.4;
• A description of process validation and/or evaluation, as described in 3.2.S.2.5.
2.3. S.3 Characterisation (ຊື່, manufacturer)
A summary of the interpretation of evidence of structure and isomerism, ອະທິບາຍ
3.2.S.3.1, should be included.
A tabulated summary of the data provided in 3.2.S.3.2, with graphical representation, where appropriate should be included.
2.3. S.4 Control of Drug Substance (ຊື່, manufacturer)
A brief summary of the justification of the specification(s), the analytical procedures, ແລະການກວດສອບຄວນຈະຖືກລວມເອົາ.
ຂໍ້ມູນຈໍາເພາະຈາກ 3.2.S.4.1 ຄວນຖືກຈັດໃຫ້.
Atabulatedsummaryofthebatchanalysesfrom3.2.S.4.4, ການນໍາສະເຫນີຮູບພາບທີ່ເຫມາະສົມ, should be provided.
2.3. S.5ReferenceStandardsorMaterials (ຊື່, manufacturer)
ຂໍ້ມູນຈາກ 3.2.S.5 (ການນໍາສະເຫນີຕາຕະລາງ, ບ່ອນທີ່ເຫມາະສົມ) should be included.
2.3. S.6ContainerClosureSystem (ຊື່, manufacturer)
ຄຳອະທິບາຍຫຍໍ້ແລະການສົນທະນາຂອງຂໍ້ມູນ, ຈາກ 3.2.S.6 ຄວນຖືກລວມເຂົ້າ.
2.3. S.7 ຄວາມໝັ້ນຄົງ (ຊື່, manufacturer)
ພາກສ່ວນນີ້ຄວນປະກອບມີບົດສະຫຼຸບຂອງການສຶກສາທີ່ດໍາເນີນ (ເງື່ອນໄຂ, ຊຸດ, ຂັ້ນຕອນການວິເຄາະ) ແລະການສົນທະນາໂດຍຫຍໍ້ທີ່ມີຜົນໄດ້ຮັບແລະຂໍ້ສະຫຼຸບ, ເງື່ອນໄຂການເກັບຮັກສາສະເຫນີ, ທົດສອບຄືນໃຫມ່ຂອງຊີວິດ, ທີ່ກ່ຽວຂ້ອງ, ອະທິບາຍ 3.2. S.7.1.
Thepost-approvalstabilityprotocol, asdescribedin3.2.S.7.2, should be included.
ສະຫຼຸບສັງລວມຄວາມອາດສາມາດໄດ້ຜົນມາຈາກ 3.2.S.7.3, ການນໍາສະເຫນີຮູບພາບທີ່ເຫມາະສົມ, should be provided.
2.3. PFinished PharmaceuticalProduct
2.3. P.1 ຄໍາອະທິບາຍແລະອົງປະກອບຂອງຜະລິດຕະພັນຢາ (ຊື່, ຮູບແບບປະລິມານຢາ) ຂໍ້ມູນຈາກ 3.2.P.1 ຄວນໃຫ້.
ອົງປະກອບຈາກ 3.2.P.1 ຄວນໄດ້ຮັບການສະຫນອງ.
2.3. P.2 ການພັດທະນາຢາ (ຊື່, ຮູບແບບປະລິມານຢາ)
ການສົນທະນາຂອງຂໍ້ມູນແລະຂໍ້ມູນຈາກ 3.2.P.2 ຄວນຖືກນໍາສະເຫນີ.
ສະຫຼຸບສັງລວມຂອງອົງປະກອບຂອງຮູບແບບການນໍາໃຊ້ການທົດລອງທາງດ້ານຄລີນິກແລະການນໍາສະເຫນີຂອງ dissolutionprofile ຄວນໄດ້ຮັບການສະຫນອງໃຫ້, ທີ່ກ່ຽວຂ້ອງ.
2.3. P.3 ການຜະລິດ (ຊື່, ຮູບແບບປະລິມານຢາ) ຂໍ້ມູນຈາກ 3.2.P.3souldinclude:
E280A2ຂໍ້ມູນກ່ຽວກັບຜູ້ຜະລິດ.
E280A2 ລາຍລະອຽດຫຍໍ້ຂອງຂະບວນການຜະລິດແລະການຄວບຄຸມການຄວບຄຸມແມ່ນໄດ້ຕິດຕັ້ງຢູ່ໃນຕົວກໍານົດເອງແລະສອດຄ່ອງການຜະລິດຜະລິດຕະພັນທີ່ມີຄຸນນະພາບທີ່ເຫມາະສົມ.
• A flow diagram, ສະຫນອງໃຫ້ພາຍໃຕ້ການ 3.2. ປ.3.3.
• A brief description of the process validation and/or evaluation, ອະທິບາຍ 3.2. P.3.5.
2.3. P.4 Control of Excipients (ຊື່, ຮູບແບບປະລິມານຢາ)
A brief summary on the quality of excipients, as described in 3.2.P.4, should be included.
2.3. P.5 Control of Drug Product (ຊື່, ຮູບແບບປະລິມານຢາ)
A brief summary of the justification of the specification(s), a summary of the analytical procedures and validation, and characterisation of impurities should be provided.
ຂໍ້ມູນຈໍາເພາະ(s) from 3.2.P.5.1 should be provided.
A tabulated summary of the batch analyses provided under 3.2.P.5.4, with graphical representation where appropriate should be included.
2.3. P.6 Reference Standards or Materials (ຊື່, ຮູບແບບປະລິມານຢາ)
Information from 3.2.P.6 (ການນໍາສະເຫນີຕາຕະລາງ, ບ່ອນທີ່ເຫມາະສົມ) should be included.
2.3. P.7 Container Closure System (ຊື່, ຮູບແບບປະລິມານຢາ)
A brief description and discussion of the information in 3.2.P.7 should be included.
2.3. P.8 Stability (ຊື່, ຮູບແບບປະລິມານຢາ)
A summary of the studies undertaken (ເງື່ອນໄຂ, ຊຸດ, ຂັ້ນຕອນການວິເຄາະ) ແລະການສົນທະນາໂດຍຫຍໍ້ຂອງຜົນໄດ້ຮັບແລະຂໍ້ສະຫຼຸບຂອງຄວາມຫມັ້ນຄົງຂອງການສຶກສາແລະການວິເຄາະຂໍ້ມູນຄວນຈະຖືກລວມເອົາ. ສະຫຼຸບກ່ຽວກັບສະພາບການການເກັບຮັກສາແລະຊີວິດຊັ້ນວາງ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້, ເງື່ອນໄຂການເກັບຮັກສາແລະຊີວິດໃນຊັ້ນວາງຄວນຖືກເລີ່ມຕົ້ນ.
ສະຫຼຸບສັງລວມຄວາມອາດສາມາດໄດ້ຜົນມາຈາກ 3.2.P.8.3, ການນໍາສະເຫນີຮູບພາບທີ່ເຫມາະສົມ, should be included.
Thepost-approvalstabilityprotocol, asdescribedin3.2.P.8.2, should be provided.
2.3. ເອກະສານຊ້ອນທ້າຍ
2.3. ຂໍ້ມູນພາກພື້ນ
2.4. Non-Clinical Overview
The Nonclinical Overview should provide an integrated overall analysis of the information in the Module 4. ທົ່ວໄປ, TheNonclinicalOverview ບໍ່ຄວນເກີນກວ່າ 30 ໜ້າ.
TheNonclinicalOverview ຄວນຈະຖືກສະແດງຢູ່ໃນລໍາດັບຕໍ່ໄປນີ້:
• Overview of the nonclinical testing strategy
• Pharmacology
• Pharmacokinetics
• Toxicology
• Integrated overview and conclusions
• List of literature references
The Integrated Overview and Conclusions should clearly define the characteristics of the human pharmaceutical as demonstrated by the nonclinical studies and arrive at logical, ຂໍ້ສະຫຼຸບທີ່ມີການໂຕ້ຖຽງກັນດີທີ່ສະຫນັບສະຫນູນຄວາມປອດໄພຂອງຜະລິດຕະພັນສໍາລັບການນໍາໃຊ້ທາງດ້ານການຊ່ວຍ. ການກິນຢາປົວພະຍາດ, ການຢາ, andtoxicology ຜົນການບັນຊີ, ການຄົ້ນພົບທາງຄລີນິກອ່ອນເພຍເພື່ອຄວາມປອດໄພຂອງມະນຸດຂອງການໃຊ້ຢາຄວນປຶກສາຫາລື. (i.e., asapplicabletolabelling).
ICHM4S (R2) ໂມດູນ 2.4 ສະຫນອງຄໍາແນະນໍາສໍາລັບເນື້ອໃນ softheNon-clinicalOverview. Thenon-clinicalinformationinModule 2.4 ແລະໂມດູນ 4 ບໍ່ແມ່ນປົກກະຕິຕ້ອງການແຫຼ່ງຂໍ້ມູນ (ທົ່ວໄປ) ຜະລິດຕະພັນຢາ. ຢ່າງໃດກໍຕາມ, ໃນບາງກໍລະນີ, ມີການປ່ຽນແປງ profile insafetyimpurity, ການປະເມີນຄວາມປອດໄພຄວນຈະຖືກປະຕິບັດ.
2.5 Clinical Overview
The Clinical Overview is intended to provide a critical analysis of the clinical data in the Common Technical Document. ສະພາບລວມທາງດ້ານຄລີນິກຈະຕ້ອງອ້າງອີງຂໍ້ມູນການສະໝັກທີ່ສະໜອງໃຫ້ໂດຍສະຫຼຸບສັງລວມທາງດ້ານຄລີນິກ, theindividualclinicalstudyreports (ICHE3), ແລະບົດລາຍງານອື່ນໆທີ່ກ່ຽວຂ້ອງ; ແຕ່ຕົ້ນຕໍຄວນຈະນໍາສະເຫນີຂໍ້ສະຫຼຸບແລະຂໍ້ສະຫຼຸບແລະຂໍ້ມູນການບົ່ງມະຕິ, ແລະບໍ່ຄວນຂຽນຄືນໃຫ້ເຂົາເຈົ້າ.
ໂດຍສະເພາະ, ສະຫຼຸບສັງລວມທາງດ້ານຄລີນິກຄວນໃຫ້ລາຍລະອຽດລາຍລະອຽດຂອງການສະຫຼຸບຄວາມເປັນຈິງຂອງຂໍ້ມູນທາງດ້ານການຊ່ວຍໃນCTD, ແລະພາບລວມທາງດ້ານຄລີນິກຄວນໃຫ້ຂໍ້ສະຫຼຸບການປຶກສາຫາລືແລະການຕີຄວາມໝາຍຂອງການຄົ້ນຄວ້າເຫຼົ່ານີ້ຮ່ວມກັນກັບຂໍ້ມູນທີ່ກ່ຽວຂ້ອງອື່ນໆ. (ຕົວຢ່າງ:, pertinentanimaldataorproductqualityissueshat ອາດຈະມີຄວາມກ່ຽວຂ້ອງທາງດ້ານການປິ່ນປົວ).
ສະພາບລວມທາງດ້ານຄລີນິກຄວນຈະຖືກສະແດງຢູ່ໃນຄໍາສັ່ງຕໍ່ໄປນີ້:
ຕາຕາລາງ
2.5.1 ເຫດຜົນການພັດທະນາຜະລິດຕະພັນ
2.5.2 ພາບລວມຂອງຊີວະຢາ
2.5.3 ພາບລວມຂອງຄລີນິກຢາ
2.5.4 ພາບລວມຂອງປະສິດທິພາບ
2.5.5 ພາບລວມຂອງຄວາມປອດໄພ
2.5.6 ຜົນປະໂຫຍດແລະຄວາມສ່ຽງສະຫຼຸບ
2.5.7 Literature References
ICH M4E (R1) ໂມດູນ 2.5 ສະຫນອງຄໍາແນະນໍາສໍາລັບເນື້ອໃນSoftheClinicalOverview.
Module 3: Quality
The Quality module follows the structure and illustrative explanations that are outlined in ICH M4Q (R1). Text is only duplicated from document in cases where emphasis is desired.
3.1 ຕາຕາລາງ (ໂມດູນ 3)
The table of contents should give the location of each study report in Module 3
3.2. S Body of Data – Drug Substance
The following information may be submitted as information for the API as applicable:
-
ທາງເລືອກ 1 – Confirmation of API prequalification document
-
ທາງເລືອກ 2- A Certificate of Suitability of European Pharmacopeia (CEP)
-
ທາງເລືອກ 3 – Active Pharmaceutical Ingredient Master File (APIMF) procedure
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ທາງເລືອກ 4 – Full Details in the Product Dossier
For a drug product containing more than one drug substance, the information should be submitted for each drug substance.
Where reference is made to a CEP, the applicant must provide a letter of access from the CEP holder. The letter of access should be provided in Module 1.2.16. Evidence of WHO Prequalification should also be provided under this section when applicable.
The applicant should clearly indicate at the beginning of the API section (in the PD and in the QOS-PD) how the information on the API for each API manufacturer is being submitted. The API information submitted by the applicant or FPP manufacturer should include the following according to the options used.
ທາງເລືອກ 1: Confirmation of API prequalification document.
A complete copy of the Confirmation of API prequalification document should be provided in Module 1, together with the duly filled out authorization box in the name of the FPP manufacturer or applicant.
The applicant should supply the following information in the dossier, with data summarized in the QOS-PD.
– 3.2. S.1.3 ຄຸນສົມບັດທົ່ວໄປE28093discussionsonanya ເພີ່ມເຕີມສາມາດນໍາໃຊ້ໄດ້ທາງກາຍະພາບທາງເຄມີແລະທີ່ກ່ຽວຂ້ອງອື່ນໆAPIpropertiestharenotcontrolledbytheAPImanufacturerE28099sspecifications, e.g. ການລະລາຍ ແລະ ໂພລິມະຊັບທີ່ສອດຄ້ອງກັບແນວທາງໃນຂໍ້ນີ້.
– 3.2. S.2E28093if thesterility oftheFPPis baseduponthesterilemanufacture oftheAPIthendataonthesterilizationprocesstogether withfullvalidationdata should beprovided.
– 3.2. S.3.1Elucidation ofstructureandother characteristicsE28093studiestoidentifypolymorphsandparticlesized distribution, ບ່ອນທີ່ສາມາດນໍາໃຊ້, ອີງຕາມການຊີ້ນໍາໃນພາກນີ້.
– 3.2.S.4.1SpecificationE28093thespecificationsoftheFPPmanufacturerincludingalltestsandlimitsoftheAPImanufacturerE28099sspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099sspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099specificationsspecificationsandanyadditionaltestsandacceptancecriteriathatarenotcontrolledbytheAPImanufacturerE28099spo Specifications.
– 3.2. S.4.22F3.2.S.4.3ຂັ້ນຕອນການວິເຄາະແລະການກວດສອບE28093anymethodsedbytheFPPmanufacturerinadditiontothoseintheAPImanufacturerE28099specifications.
– 3.2. S.4.4BatchanalysisE28093ໄດ້ຜົນຈາກສອງຊຸດນັກບິນນ້ອຍສຸດ, ສະແດງໃຫ້ເຫັນການປະຕິບັດຕາມ FPP ຜູ້ຜະລິດE28099sAPIspecifications.
– 3.2. S.5ReferencestandardsormaterialsE28093informationontheFPPmanufacturerE28099sreferencestandards.
– 3.2.S.7 Stability – data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified API.
■ Option 2: Certificate of Suitability of the European Pharmacopoeia (CEP)
A complete copy of the CEP (including any annexes) should be provided in Module 1. The declaration of access for the CEP should be duly filled out by the CEP holder on behalf of the FPP manufacturer or applicant to the WHO Prequalification of Medicines Programmed who refers to the CEP.
In addition, a written commitment should be included that the applicant will inform NAFDAC in the event that the CEP is withdrawn. It should also be acknowledged by the applicant that withdrawal of the CEP will require additional consideration of the API data requirements to support the PD. The written commitment should accompany the copy of the CEP in Module 1.
Together with the CEP, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.
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3.2. S.1.3 General properties – discussions on any additional applicable physicochemical and other relevant properties of the API that are not controlled by the CEP and Ph.Eur. Monograph, e.g. ການລະລາຍ ແລະ ໂພລິມະຊັບທີ່ສອດຄ້ອງກັບແນວທາງໃນຂໍ້ນີ້.
-
3.2. S.3.1 Elucidation of structure and other characteristics – studies to identify polymorphs (except where the CEP specifies a polymorphic form) and particle size distribution, ບ່ອນທີ່ສາມາດນໍາໃຊ້, ອີງຕາມການຊີ້ນໍາໃນພາກນີ້.
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3.2. S.4.1SpecificationE28093thespecificationsoftheFPPmanufacturerincludingalltestsandlimitsoftheCEPandPh.Eur. MonographandanyadditionaltestsandcceptancecriteriathatarenotcontrolledintheCEPandPh.Eur. Monograph, ເຊັ່ນ: ໂພລີມໍຟຊາຍ ແລະ 2 ການແຜ່ກະຈາຍອະນຸພາກ.
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3.2. S.4.22F3.2. S.4.3 ຂັ້ນຕອນການວິເຄາະແລະການກວດສອບE28093ສໍາລັບການanymethodsed bytheFPPmanufacturerinadditiontothoseintheCEPandPh.Eur. Monograph.
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3.2. S.4.4BatchanalysisE28093ໄດ້ຜົນຈາກສອງຊຸດນັກບິນນ້ອຍສຸດ, ສະແດງໃຫ້ເຫັນການປະຕິບັດຕາມ FPP ຜູ້ຜະລິດE28099sAPIspecifications.
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3.2. S.5ReferencestandardsormaterialsE28093informationontheFPPmanufacturerE28099sreferencestandards.
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3.2.S.6ລະບົບການປິດຕູ້ຄອນເທນເນີE28093ສະເພາະລວມທັງລາຍລະອຽດການລະບຸການກໍານົດການຫຸ້ມຫໍ່ຫຼັກ ຍົກເວັ້ນບ່ອນທີ່CEPspecifiesacontainer-closuresystemandtheapplicantdeclarestheintenttousethesamecontainer-closuresystem.
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3.2.S.7 Stability – except where the CEP specifies a retest period that is the same as or longer than that proposed by the applicant, and storage conditions are the same or at a higher temperature and humidity than those proposed by the applicant.
In the case of sterile APIs, data on the process for sterilization of the API including validation data should be included in the PD.
ທາງເລືອກ 3: Active pharmaceutical ingredient master file (APIMF) procedure
Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer
In such cases, the Open part (ຂໍ້ມູນທີ່ບໍ່ແມ່ນຊັບສິນ) needs to be included in its entirety in the PD as an annex to 3.2.S. In addition, the applicant or FPP manufacturer should complete the following sections in the PD and QOS-PD in full according to the guidance provided unless otherwise indicated in the respective sections:
General information S.1.1–S.1.3
Manufacture S.2
ຜູ້ຜະລິດ(s) S.2.1
Description of manufacturing process and process controls S.2.2
Controls of critical steps and intermediates S.2.4 Elucidation of structure and other characteristics S.3.1
Impurities S.3.2
Control of the API S.4.1–S.4.5
Reference standards or materials S.5
Container-closure system S.6
Stability S.7.1–S.7.3
It is the responsibility of the applicant to ensure that the complete APIMF (i.e.. ທັງຜູ້ສະຫມັກE28099sOpenpartandtheAPImanufacturerE28099srestrictedpart) issupplied toNAFDAC ໂດຍກົງໂດຍAPImanufacturerand that the applicantthasaccesstotherelevantin information intheAPIMF ກ່ຽວກັບການຜະລິດປະຈຸບັນຂອງAPI.
Acopyoftheletterofaccess ຄວນຖືກຈັດໃຫ້ຢູ່ໃນPDModule 1. APIMFholders ສາມາດນໍາໃຊ້ການແນະນໍາທີ່ສະຫນອງໃຫ້ສໍາລັບທາງເລືອກE2809CFulldetailsinthePDE2809D forpreparationoftherelevantsectionsoftheOpenandRestrictedpartsoftheirAPIMFs.
ການອ້າງອິງຄວນຈະຖືກສ້າງຂື້ນtotheAPIMFguidelinesinWHOTechnicalReportSeries, No. 948, ເອກະສານຊ້ອນທ້າຍ 4 (4).
ທາງເລືອກ 4: Full details in the PD
Information on the 3.2.S Active pharmaceutical ingredient sections, ລວມທັງລາຍລະອຽດຂອງເຄມີສາດ, manufacturing process, ການຄວບຄຸມຄຸນນະພາບໃນລະຫວ່າງການຜະລິດແລະຂະບວນການກວດສອບ API, ຄວນຈະຖືກສົ່ງເຂົ້າມາໃນ PDasoutlines ຕໍ່ໄປນີ້ຕາມລໍາດັບຂອງຂໍ້ແນະນໍາ. TheQOS-PD ຄວນຈະສໍາເລັດການປະຕິບັດຕາມຂັ້ນຕອນ 3.1 ຂໍ້ແນະນໍາເຫຼົ່ານີ້.
3.2. S.1 ຂໍ້ມູນທົ່ວໄປ (ຊື່, manufacturer)
3.2. S.1.1 ນາມສະກຸນ (ຊື່, manufacturer)
ຂໍ້ມູນກ່ຽວກັບບັນຊີຂອງສານເສບຕິດຢາຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້. ຕົວຢ່າງ:
E280A2RecommendedInternationalNon-proprietaryName (INN);
E280A2 ຊື່ຫຍໍ້ທີ່ກ່ຽວຂ້ອງ;
E280A2 ຊື່ທາງເຄມີ(s);
E280A2 ລະຫັດບໍລິສັດຫ້ອງທົດລອງ;
E280A2ຊື່ອື່ນທີ່ບໍ່ແມ່ນຊັບສິນ(s), ຕົວຢ່າງ:, ຊື່ແຫ່ງຊາດ, United States AdoptedName (ອາເມລິກາ), ຊື່ຍີ່ປຸ່ນທີ່ຍອມຮັບ (ມັງກອນ); ຊື່ທີ່ອະນຸມັດຈາກອັງກິດ (ຫ້າມ), ແລະການບໍລິການ Abstracts ເຄມີ (CAS) ໝາຍເລກທະບຽນ.
ຊື່ທາງເຄມີຄວນຈະສອດຄ່ອງກັນກັບທີ່ປາກົດຢູ່ໃນວັນນະຄະດີວິທະຍາສາດແລະທີ່ປາກົດຢູ່ໃນຜະລິດຕະພັນການປ້າຍຊື່ຂໍ້ມູນ (e.g. ສະຫຼຸບສັງລວມລັກສະນະຂອງຜະລິດຕະພັນ (SmPC) ແລະpackageleaflet, ຍັງຮູ້ຈັກເປັນເອກະສານຂໍ້ມູນຄົນເຈັບ (PIL)).
ຊື່ໃດນຶ່ງທີ່ມີຊື່ທີ່ມັກຄວນຖືກລະບຸໄວ້.
3.2. S.1.2 ໂຄງສ້າງ (ຊື່, manufacturer)
ສູດໂຄງສ້າງ, ລວມທັງການກ່ຽວຂ້ອງກັບສະເຕີຣິໂອເຄມີ, ສູດໂມເລກຸນ, ແລະ ຄວນສະໜອງໃຫ້ມວນສານໂມເລກຸນ.
ຂໍ້ມູນນີ້ຄວນຈະສອດຄ່ອງກັບການສະຫນອງໃຫ້ 3.2. S.1.1. ສໍາລັບAPIsexistingassaltsthemolecularmassofthefreebaseoracidshouldalsobeprovided.
3.2. S.1.3 ຄຸນສົມບັດທົ່ວໄປ (ຊື່, manufacturer)
ໂຄງສ້າງ, ສູດໂມເລກຸນ, ນ້ ຳ ໜັກ ໂມເລກຸນແລະສູດໂຄງສ້າງຖືກ ກຳ ນົດ. Thechiralcentresifanyareidentified.
ຂໍ້ມູນນີ້ສາມາດນໍາໃຊ້ໃນການພັດທະນາສະເພາະ, ໃຫ້ຂໍ້ມູນ FPPsandinthetesting forrelease andstability purposes.
ຄຸນສົມບັດທາງກາຍະພາບ ແລະເຄມີຂອງ API ຄວນພິຈາລະນາ, ລວມທັງການອະທິບາຍທາງດ້ານຮ່າງກາຍ, solubilities incommonsolvents (e.g. ນ້ໍາ, ເຫຼົ້າ, dichloromethaneandacetone), quantitativeaqueouspHsolubilityprofile (e.g. pH1.2E280936.8, dose2Fsolubilityvolume), polymorphism, pHandpKavalues, ultraviolet (UV) ການດູດຊຶມສູງສຸດແລະການດູດຊຶມ molarab, ຈຸດ melting, ດັດຊະນີສະທ້ອນແສງ (ນ້ຳລາຍ), hygroscopicity andpartitioncoefficient (seetable ໃນQOS-PD). ບັນຊີລາຍຊື່ນີ້ບໍ່ໄດ້ຕັ້ງໃຈເຮັດຢ່າງເຄັ່ງຄັດແຕ່ໃຫ້ຂໍ້ບົ່ງຊີ້ເຖິງປະເພດຂອງຂໍ້ມູນລາຍລະອຽດທີ່ອາດຈະລວມເອົາ.
ບາງສ່ວນຂອງຄຸນສົມບັດທີ່ກ່ຽວຂ້ອງທີ່ສຸດທີ່ຈະພິຈາລະນາສໍາລັບ APIs ໄດ້ປຶກສາຫາລືຂ້າງລຸ່ມນີ້ລາຍລະອຽດເພີ່ມເຕີມ.
Physical description
The physical description should include appearance, ສະຖານະການສີ. ຮູບແບບແຂງຄວນຖືກລະບຸວ່າເປັນກ້ອນຫີນເປັນຮູບຊົງກົມ (ເບິ່ງ3.2.S.3.1ຂໍ້ມູນເພີ່ມເຕີມກ່ຽວກັບAPIsolidforms).
Solubilities and quantitative aqueous pH solubility profile
The following should be provided for all options for the submission of API data.
Thesolubilitiesinanumber ofcommonsolvents ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ (e.g. ນ້ໍາ, ເຫຼົ້າ, dichloromethaneandacetone).
Thesolubilities overthephysiologicalpHrange (pH1.2E280936.8) inseveralbufferedmedia ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ໃນmg2Fml. ຖ້າຂໍ້ມູນນີ້ບໍ່ສາມາດໃຊ້ໄດ້ (e.g. ຈາກການອ້າງອີງວັນນະຄະດີ), ມັນຄວນຈະຖືກສ້າງຂື້ນໃນເຮືອນ.
Forsolidoraldosageforms, thedose2Fsolubilityvolumes ຄວນຖືກຈັດໃຫ້ຖືກກຳນົດຕາມສູດ:
ປະລິມານຢາທີ່ໃຫຍ່ທີ່ສຸດ (ມກ)
Dose/solubility volume =
The minimum concentration of the drug (mg2Fml) *
* ທີ່ສອດຄ້ອງກັນກັບລະດັບການລະລາຍຕໍ່າສຸດທີ່ກຳນົດຢູ່ເໜືອລະດັບຄວາມສູງທາງສະລີລະວິທະຍາ (pH1.2E280936.8) ແລະອຸນຫະພູມ (37 C2B1 0.5 C2B0C).
ອີງຕາມລະບົບການຈັດປະເພດ Biopharmaceutics (BCS), ລະລາຍສູງ (ຫຼືລະລາຍນ້ຳສູງ) APIsarethosewithadose2FsolubilityvolumeofE289A4 250 ມລ.
ຍົກຕົວຢ່າງ, compoundAhasasits ການລະລາຍຕໍ່າສຸດ 37 C2B10.5C2B0C, 1.0 mg2FmlatpH 6.8 ແລະສາມາດໃຊ້ໄດ້ໃນ 100 ມກ, 200 mgand 400 ຄວາມເຂັ້ມແຂງ mg. API ນີ້ຈະບໍ່ຖືກພິຈາລະນາ BCS ສູງທີ່ລະລາຍ APIasitsdose2F solubilityvolumeisgreaterthan 250 ມລ (400 mg2F1.0mg2Fml3D 400 ມລ).
Polymorphism
As recommended in ICH’s CTD-Q Questions and answers/location issues document (5) the following list explains where specific data should be located in the PD:
■ The polymorphic form(s) present in the proposed API should be listed in section 3.2. S.1.3.
■ The description of manufacturing process and process controls (3.2.S.2.2) should indicate which polymorphic form is manufactured, ທີ່ກ່ຽວຂ້ອງ.
■ The literature references or studies performed to identify the potential polymorphic forms of the API, including the study results, should be provided in section 3.2. S.3.1.
■ If a polymorphic form is to be defined or limited (e.g. for APIs that are not BCS highly soluble and/or where polymorphism has been identified as an issue), details should be included in
3.2.S.4.1– 3.2. S.4.5.
ຂໍ້ມູນເພີ່ມເຕີມແມ່ນລວມເອົາຂໍ້ກໍານົດຂໍ້ກໍານົດການແນະນໍາ.
Particle size distribution
As recommended in ICH’s CTD-Q Questions and answers/location issues document (5), ການສຶກສາໄດ້ຖືກປະຕິບັດເພື່ອກໍານົດການແຜ່ກະຈາຍອະນຸພາກຂອງ API ຄວນຖືກຈັດໃຫ້ຢູ່ໃນພາກ 3.2.S.3.1 (ອ້າງເຖິງພາກສ່ວນຂອງຂໍ້ແນະນໍາເຫຼົ່ານີ້ສໍາລັບຂໍ້ມູນເພີ່ມເຕີມ).
Information from the literature
Supportive data and results from specific studies or published literature can be included within or attached to this section.
ເອກະສານອ້າງອີງICHGuidelines: Q6AandQ6B
3.2. S.2 ການຜະລິດ (ຊື່, manufacturer)
3.2. S.2.1 ຜູ້ຜະລິດ(s) (ຊື່, manufacturer)
ຊື່, ທີ່ຢູ່, ແລະຄວາມຮັບຜິດຊອບຂອງຜູ້ຜະລິດ, including contractors, ແລະແຕ່ລະສະຖານທີ່ການຜະລິດທີ່ສະເຫນີຫຼືສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດແລະການທົດສອບຄວນໄດ້ຮັບການສະຫນອງໃຫ້.
ສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດ, ການຫຸ້ມຫໍ່, ການຕິດສະຫຼາກ, ການທົດສອບແລະການເກັບຮັກສາຂອງ API ຄວນຖືກບັນລຸໄດ້. ຖ້າບໍລິສັດມີຄວາມຮັບຜິດຊອບສະເພາະຂັ້ນຕອນສະເພາະ (e.g. milling ຂອງ API) ນີ້ຄວນຈະຊີ້ບອກຢ່າງຈະແຈ້ງ.
ບັນຊີລາຍຊື່ຜູ້ຜະລິດຫຼືບໍລິສັດຄວນລະບຸທີ່ຢູ່ທີ່ຢູ່ຂອງການຜະລິດຫຼືສະຖານທີ່ການຜະລິດ(s) ມີສ່ວນຮ່ວມ (ລວມທັງຕັນ(s) andunits(s)), ແທນທີ່ຈະເປັນຫ້ອງການບໍລິຫານ. ເບີໂທລະສັບ(s), ເບີແຟັກ(s) ທີ່ຢູ່ອີເມວວິນຍານ (ນີ້ແມ່ນ) should be provided.
ການຜະລິດການອະນຸຍາດທີ່ຖືກຕ້ອງຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບການຜະລິດ APIs. ຖ້າມີ, ໃບຢັ້ງຢືນການປະຕິບັດຕາມກັບ GMP ຄວນຈະໄດ້ຮັບການສະຫນອງໃນ PDinModule 1.
3.2. S.2.2Descriptionofmanufacturingprocess andprocesscontrols (ຊື່, ຜູ້ຜະລິດ)
Thedescription oftheAPImanufacturingprocessrepresnts the applicantE28099s commitment forthemanufacture oftheAPI. Information should be provided to adequately describe the manufacturing process and process controls. ຍົກຕົວຢ່າງ:
A flow diagram of the synthetic process(ນີ້ແມ່ນ) should be provided that includes molecular formulas, weights, yield ranges, chemical structures of starting materials, intermediates, reagents and API reflecting stereochemistry, and identifies operating conditions and solvents.
A sequential procedural narrative of the manufacturing process should be submitted. The narrative should include, ຍົກຕົວຢ່າງ, quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, process controls, equipment and operating conditions (e.g. temperature, pressure, pH, and time).
Alternative processes should be explained and described with the same level of detail as the primary process. Reprocessing ຂັ້ນຕອນຄວນຈະຖືກລະບຸແລະຍຸຕິທໍາ. ຂໍ້ມູນໃດໆທີ່ຈະສະຫນັບສະຫນູນການສະຫນັບສະຫນູນນີ້ຄວນຈະເປັນເອກະສານອ້າງອີງ doorfiledin3.2.S.2.5.
ບ່ອນທີ່APIMFprocedureised, ການອ້າງອິງຂ້າມພາກສ່ວນທີ່ຈຳກັດຂອງAPIMF ອາດຈະຖືກລະບຸໄວ້ສຳລັບຂໍ້ມູນລັບ. ໃນນີ້, ຖ້າຫາກວ່າຂໍ້ມູນລະອຽດຖືກນໍາສະເຫນີຢູ່ໃນສ່ວນຈໍາກັດ, ຂໍ້ມູນທີ່ໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບພາກສ່ວນນີ້ຂອງPD ໄດ້ລວມທັງຕາຕະລາງ (ລວມທັງໂຄງສ້າງໂມເລກຸນ ແລະທາດລະລາຍ ແລະທາດລະລາຍ) ແລະຫຍໍ້ກ່ຽວກັບຂະບວນການຜະລິດ, ດ້ວຍການເນັ້ນໜັກເປັນພິເສດໃນຂັ້ນຕອນສຸດທ້າຍ, ລວມທັງຂັ້ນຕອນການຊໍາລະລ້າງ. ຢ່າງໃດກໍຕາມ, forsterileAPIs, ຂໍ້ມູນຄວາມຖືກຕ້ອງເຕັມທີ່ກ່ຽວກັບຂະບວນການເຮັດເປັນໝັນຄວນຈະໄດ້ຮັບການສະໜອງໃຫ້ໃນພາກເປີດ (ໃນກໍລະນີທີ່ບໍ່ມີການເຮັດໝັນຕື່ມອີກຂອງຜະລິດຕະພັນສຸດທ້າຍ).
ຄວາມຕ້ອງການຕໍ່ໄປນີ້ແມ່ນໃຊ້ກັບສີ່ຂັ້ນຕອນຂອງການຍື່ນສະເຫນີຂໍ້ມູນ API, ບ່ອນໃດທີ່ລາຍລະອຽດມີສະໜອງໃຫ້ໄດ້.
AsdiscussedinICHQ7andWHOTechnicalReportSeries, No. 957, ເອກະສານຊ້ອນທ້າຍ 2, ຈຸດທີ່ເອພີເອກະສານການເລີ່ມຕົ້ນແມ່ນນໍາສະເຫນີໃນຂະບວນການການຜະລິດແມ່ນຈຸດເລີ່ມຕົ້ນສໍາລັບການນໍາໃຊ້ຂອງຂໍ້ກໍານົດ GMPrequirements. TheAPIstartingmaterialitself needstobeproposedanditschoicejustified bythemanufacturerandacceptedassuchbyassessors. ວັດສະດຸເລີ່ມຕົ້ນ API ຄວນຖືກສະເໜີໃຫ້ເຂົ້າບັນຊີຄວາມຊັບຊ້ອນຂອງໂມເລກຸນ, ຄວາມໃກ້ຊິດຂອງ API ເລີ່ມຕົ້ນວັດສະດຸໄປຫາ API ສຸດທ້າຍ, ຄວາມພ້ອມຂອງ API ເລີ່ມຕົ້ນວັດສະດຸເປັນການຄ້າທາງເຄມີແລະການຄວບຄຸມຄຸນນະພາບສະຖານທີ່ API ເລີ່ມຕົ້ນວັດສະດຸ. This justification should be documented in the dossier and be available for review by NAFDAC GMP inspectors.
In situations where the API starting material is a complex molecule and only a minimal number of synthetic steps from the final API, a further molecule called the starting material for synthesis should be proposed and its choice justified by the applicant. The starting material for synthesis defines the starting point in the manufacturing process for an API to be described in an application. The applicant should propose and justify which substances should be considered as starting materials for synthesis (see section 3.2.S.2.3 for further guidance). In the case where the precursor to the API is obtained by fermentation, or is of plant or animal origin, such a molecule can be considered the API starting material regardless of complexity.
A one-step synthesis may be accepted in exceptional cases, ຍົກຕົວຢ່າງ, where the API starting material is covered by a CEP, or where the API starting material is an API accepted through the APIMF or API prequalification procedure within the WHO Prequalification of Medicines Programmed, or when the structure of the API is so simple that a one-step synthesis can be justified, e.g. ethambutol or ethionamide.
In addition to the detailed description of the manufacturing process as per ICH M4Q, the recovery of materials, ຖ້າມີ, should be described in detail with the step in which they are introduced into the process. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times of mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.
Where there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.
All solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; ຢ່າງໃດກໍຕາມ, their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7.
Where polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.
Where particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described.
Justification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.
It is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to NAFDAC according to the requirements of the NAFDAC variation guidelines.
3.2. S.2.3 Control of Materials (ຊື່, manufacturer)
Materials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. ຂໍ້ມູນສະແດງໃຫ້ເຫັນວ່າອຸປະກອນການໄດ້ຮັບມາດຕະຖານທີ່ເຫມາະສົມສໍາລັບການນໍາໃຊ້ຂອງເຂົາເຈົ້າຄວນຈະສະຫນອງໃຫ້, ທີ່ເຫມາະສົມ (details in
3.2.A.2). ບ່ອນທີ່APIMFprocedureised, ຂ້າມການອ້າງອີງເຖິງພາກສ່ວນທີ່ຈຳກັດຂອງAPIMFis ພິຈາລະນາວ່າມີຄວາມພຽງພໍສຳລັບພາກສ່ວນນີ້.
ຄວາມຕ້ອງການຕໍ່ໄປນີ້ແມ່ນໃຊ້ກັບສີ່ຂັ້ນຕອນຂອງການຍື່ນສະເຫນີຂໍ້ມູນ API, ບ່ອນໃດທີ່ລາຍລະອຽດມີສະໜອງໃຫ້ໄດ້.
ວັດສະດຸເລີ່ມຕົ້ນ API ຄວນຈະມີລັກສະນະຄົບຖ້ວນ ແລະ ເໝາະ ສົມກັບການສະ ເໜີ ແລະຖືກແກ້ໄຂ, ລວມທັງ, ພໍ່ຂອງຂ້ອຍ, ການຄວບຄຸມ, ວິເຄາະ, ເນື້ອໃນ impurity ແລະຄຸນລັກສະນະທີ່ສໍາຄັນອື່ນໆຂອງວັດສະດຸ. ForeachAPIstartingmaterial, ຊື່ແລະທີ່ຢູ່ຂອງໂຮງງານຜະລິດ(s) ຂອງຜູ້ຜະລິດ(s) ຄວນຊີ້ບອກ. ລາຍລະອຽດຫຍໍ້ຂອງການກະກຽມຂອງ API ການເລີ່ມຕົ້ນອຸປະກອນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ສໍາລັບຜູ້ຜະລິດ, ລວມທັງສານລະລາຍ, catalystsandreagentsused. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.
As indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. ທົ່ວໄປ, the starting material for synthesis described in the PD should:
ເປັນ) be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the race mate of a single enantiomer API, are not considered final intermediates;
b) be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable);
c) have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;
d) be incorporated as a significant structural fragment into the structure of the API.
Copies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.
Thecarry-overofimpuritiesofthestartingmaterials forsynthesisintothefinalAPI ຄວນພິຈາລະນາ ແລະ ປຶກສາຫາລື.
Aletterofattestation ຄວນຈະໄດ້ຮັບການຢັ້ງຢືນວ່າAPI ແລະອຸປະກອນການເລີ່ມຕົ້ນແລະຜະລິດຕະພັນທີ່ຖືກນໍາໃຊ້ເພື່ອການຜະລິດຂອງAPIare ໂດຍບໍ່ມີຄວາມສ່ຽງຕໍ່ການແຜ່ກະຈາຍຂອງສັດປີກແລະພະຍາດທາງດ້ານການອັກເສບ..
ເມື່ອມີໃຫ້CEP ສະແດງໃຫ້ເຫັນການປະຕິບັດຕາມຂໍ້ສະເຫນີແນະໂດຍ Sonmissiblespongiformencephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.
ເອກະສານອ້າງອີງ: ICHQ6A.
3.2. S.2.4Controlsofcriticalstepsandintermediates (ຊື່, manufacturer)
ບາດກ້າວສຳຄັນ: ເງື່ອນໄຂການຍອມຮັບ (withjustification ລວມທັງຂໍ້ມູນການທົດລອງ) ປະຕິບັດຢ່າງເຂັ້ມງວດໃນຂັ້ນຕອນsidentifiedin3.2.S.2.2ຂອງຂະບວນການຜະລິດການຜະລິດເພື່ອຄວາມໝັ້ນໃຈວ່າຂະບວນການຄວບຄຸມຄວນຈະໄດ້ຮັບການສະໜອງໃຫ້..
ຕົວກາງ: Information on the quality and control of intermediates isolated during the process should be provided.
ບ່ອນທີ່APIMFprocedureised, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant.
The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.
The critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral center or resulting in a major chemical transformation; steps having an impact on solid-state properties and homogeneity of the API that may be relevant for use in solid dosage forms.
Specifications for isolated intermediates should be provided and should include tests and acceptance criteria for identity, purity and assay, ບ່ອນທີ່ສາມາດນໍາໃຊ້.
ເອກະສານອ້າງອີງ: ICHQ6A.
3.2. S.2.5 Process validation and/or evaluation (ຊື່, manufacturer)
Process validation and/or evaluation studies for aseptic processing and sterilization should be included.
ບ່ອນທີ່APIMFprocedureised, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.
The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.
It is expected that the manufacturing processes for all APIs are properly controlled. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).
3.2. S.2.6 Manufacturing process development (ຊື່, manufacturer)
ຄໍາບັນຍາຍແລະການສົນທະນາຄວນຈະໄດ້ຮັບການສະຫນອງຂອງການປ່ຽນແປງທີ່ສໍາຄັນທີ່ໄດ້ເຮັດກັບຂະບວນການຜະລິດແລະ2Formanufacturingsite oftheAPIusedin producingcomparativebioavailability orbiowaiver, ຂະຫນາດຂຶ້ນ, ນັກບິນ, ແລະ, ຖ້າມີ, ຂະໜາດການຜະລິດ.
ການອ້າງອິງຄວນຈະເຮັດກັບພາກສ່ວນ APIdataprovidedin 3.2. S.4.4.
ບ່ອນທີ່APIMFprocedureised, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.
3.2. S.3 ລັກສະນະ (ຊື່, manufacturer)
3.2. S.3.1Elucidation ofstructure ແລະລັກສະນະອື່ນໆ (ຊື່, manufacturer) ການຢືນຢັນໂຄງສ້າງໂດຍອີງໃສ່, e.g. syntheticroute ແລະspectralanalyses ຄວນໃຫ້. ຂໍ້ມູນຂ່າວສານທີ່ມີອໍານາດສໍາລັບການ forisomerism, ການລະບຸຕົວຂອງສະເຕີຣິເຄມີສາດ, orthepotential forformingpolymorphsshouldalsobe ລວມມີ.
Elucidation of structure
The PD should include quality assurance (QA) ໃບຢັ້ງຢືນການສໍາເນົາ softhespectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure).
For APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
For APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each of the proposed manufacturer(s) ດໍາເນີນການພ້ອມກັນກັບມາດຕະຖານການຮັບຮູ້ຢ່າງເປັນທາງການ. Seesection3.2.S.5fordetailsonacceptablereferencestandardsormaterials.
Isomerism/stereochemistry
When an API is chiral, ມັນຄວນຈະຖືກລະບຸໄວ້ບໍ່ວ່າຈະເປັນສະເຕີຣອຍໄອໂຊມີໂຊຣາມິກຂອງສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄອໂຊມີສະເຕີຣອຍໄດ້ນຳໃຊ້ໃນການສຶກສາຊີວະພາບປຽບທຽບ, ແລະຂໍ້ມູນຄວນຈະຖືກມອບໃຫ້ stereoisomer ຂອງ API ທີ່ຖືກນໍາໃຊ້ໃນ FPP.
ບ່ອນທີ່ມີທ່າແຮງສໍາລັບ stereoisomerismexists, ການສົນທະນາຄວນຈະຖືກລວມເອົາເຖິງຄວາມເປັນໄປໄດ້ຂອງ isomers ທີ່ສາມາດເປັນຜົນມາຈາກຂະບວນການຜະລິດແລະຂັ້ນຕອນຂອງບ່ອນທີ່chirality ໄດ້ຖືກນໍາສະເຫນີ. ໂດຍວິທີທາງການຂອງອົງປະກອບຂອງໄອໂຊມິກຂອງAPItotha ຂອງ APIinthecomparator ຄວນໄດ້ຮັບການສ້າງຕັ້ງຂຶ້ນ. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, ທີ່ເຫມາະສົມ. The API specification should include a test to ensure isomeric identity and purity.
The potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.
When a single enantiomer of the API is claimed for non-pharmacopoeia APIs, unequivocal proof of absolute configuration of asymmetric centers should be provided, such as determined by X-ray of a single crystal.
If, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.
Polymorphism
Many APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.
Polymorphic forms of the same chemical compound differ in internal solid-state structure and, ເພາະສະນັ້ນຈຶ່ງ, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. The unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.
Applicants intending to register products with NAFDAC and API manufacturers are expected to have adequate knowledge about the polymorphism of the APIs used and/or produced. Information on polymorphism can come from the scientific literature, ສິດທິບັດ, compendia or other references to determine if polymorphism is a concern, e.g. for APIs that are not BCS highly soluble. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.
A number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.
Decision tree 4 of ICH Q6A can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. ຮູບແບບວິທີການຄວບຄຸມໂພລີໂມຟິກຄວນຖືກສະແດງໂດຍສະເພາະສໍາລັບຮູບແບບທີ່ຕ້ອງການ.
Polymorphismcanalsoincludessolvation orhydrationproducts (ເປັນທີ່ຮູ້ຈັກກັນວ່າ aspseudopolymorphs). IftheAPIisusedinasolvatedform, ຂໍ້ມູນດັ່ງຕໍ່ໄປນີ້ຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້:
E296A0Specificationsforthesolvent-freeAPIin3.2.S.2.4, ifthatcompoundisasyntheticprecursor; E296A0Specifications forthesolvatedAPI ຮວມເຖິງການຈຳກັດຄວາມເໝາະສົມຂອງອັດຕາສ່ວນນ້ຳໜັກຂອງAPItosolvent (ກັບຂໍ້ມູນເພື່ອສະຫນັບສະຫນູນຂອບເຂດຈໍາກັດທີ່ສະເຫນີ); E296A0 ລາຍລະອຽດຂອງວິທີການນໍາໃຊ້ເພື່ອpreparethesolvatein 3.2. S.2.2.
Particle size distribution
For APIs that are not BCS highly soluble contained in solid FPPs, orliquidFPPscontainingundissolvedAPI, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g. delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.
If particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch (ນີ້ແມ່ນ) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch (ນີ້ແມ່ນ) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:
▪ d10 not more than (NMT) 10% of total volume less than X µm;
▪ d50 XX µm–XXX µm;
▪ D90 not less than (NLT) 90% of total volume less than XXXX µm.
Other controls on particle size distribution can be considered acceptable, if scientifically justified.
ເອກະສານອ້າງອີງ: ICHQ6A.
3.2. S.3.2 Impurities (ຊື່, manufacturer)
Information on impurities should be provided.
Details on the principles for the control of impurities (e.g. reporting, identification and qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines (10–12). Additional information elaborating on some of the elements discussed in the ICH guidelines is outlined below.
Regardless of whether a pharmacopoeia standard is claimed, a discussion should be provided of the potential and actual impurities arising from the synthesis, manufacture or degradation of the API. This should cover starting materials, by-products, intermediates, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeia APIs should not be limited to the impurities specified in the API monograph.
The tables in the QOS-PD template should be used to summarize the information on the APIrelated and process-related impurities. In the QOSPD, thetermE2809CoriginE2809Dreferstohow and wheretheimpurity wasintroduction (e.g. E2809CSyntheticintermediatefromຂັ້ນຕອນ 4 ofthesynthesisE2809DorE2809CPທ່າແຮງໂດຍຜະລິດຕະພັນ ການຈັດລຽງຕາມຂັ້ນຕອນ 6 ofthesisE2809D). ມັນຄວນຈະໄດ້ຮັບການຊີ້ບອກເຖິງຄວາມບໍ່ບໍລິສຸດແມ່ນametaboliteຂອງ API.
TheICHthresholds ສໍາລັບການລາຍງານ, ການລະບຸຕົວຕົນ (ໃຊ້ເພື່ອກໍານົດຂອບເຂດສໍາລັບຄວາມບໍ່ສະອາດສ່ວນບຸກຄົນ) ແລະຄຸນວຸດທິແມ່ນຖືກກໍານົດໂດຍພື້ນຖານຂອງຄວາມສາມາດເປີດເຜີຍຕໍ່ກັບຄວາມບໍລິສຸດ, e.g. ໂດຍປະລິມານສູງສຸດປະຈໍາວັນ (MDD) ຂອງ API. ສໍາລັບAPIsavailableinmultipledosageformsandstrengthshavingdifferentMDDvalues, itisimperative thatthethresholdsandcorrespondingcontrolsforeachofthepresentations beconsidered toensurehattherisksposedbyimpuritieshaveenaddressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.
It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. ຢ່າງໃດກໍຕາມ, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, which has subsequently undergone several chemical modification reactions, would generally fall within the scope of the ICH impurity guidelines, whereas an API whose sole chemical step was the formation of a salt from a fermentation product generally would not. It is understood that there is some latitude for these types of APIs.
Identification of impurities
It is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. ຍິ່ງໄປກວ່ານັ້ນ, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendia monograph. As a result, each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% ຫຼື 1.0 mg per day intake (whichever is lower) for APIs having an MDD ≤ 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendia monograph, which could potentially be higher than the applicable ICH limit.
Qualification of impurities
The ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:
The limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.
Levels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.
AspecifiedimpuritypresentintheexistingAPIisconsideredqualifiediftheamountoftheimpurityintheexistingAPIreflectsthelevelsobservedintheinnovatororprequalifiedFPP.
Basis for setting the acceptance criteria
The basis for setting the acceptance criteria for the impurities should be provided. ນີ້ຖືກສ້າງຕັ້ງຂຶ້ນໂດຍພິຈາລະນາການກໍານົດຕົວຕົນແລະເງື່ອນໄຂເງື່ອນໄຂສໍາລັບຄວາມບໍ່ສະອາດທີ່ກ່ຽວຂ້ອງກັບ API (e.g. starting materials, by-products, intermediates, chiralimpurities ຜະລິດຕະພັນການເຊື່ອມໂຊມ) ແລະຂໍ້ຈຳກັດຄວາມເຂັ້ມຂຸ້ນສຳລັບຄວາມບໍ່ສະອາດທີ່ກ່ຽວຂ້ອງກັບຂະບວນການ (e.g. residualsolvents) ອີງຕາມຂໍ້ແນະນຳICH (e.g. Q3A, Q3C).
ລະດັບທີ່ມີຄຸນວຸດທິຄວນຈະຖືກພິຈາລະນາເປັນຂອບເຂດຈໍາກັດສູງສຸດ. ຢ່າງໃດກໍຕາມ, ຂອບເຂດຈໍາກັດທີ່ພິຈາລະນາຢ່າງກວ້າງຂວາງກວ່າຄວາມສາມາດໃນການດໍາເນີນການຜະລິດຕົວຈິງແມ່ນທໍ້ຖອຍໃຈໂດຍທົ່ວໄປ. ເຫດຜົນນີ້, the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.
If there are identified impurities specified in an official compendia monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. “Impurities D, E and F listed in The International Pharmacopoeia (Ph.Int.) Monograph are not potential impurities from the proposed route of synthesis used by manufacturer X”). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendia monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeia method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.
ICH class II solvent(s) ໃຊ້ກ່ອນຂັ້ນຕອນການຜະລິດຂັ້ນຕອນການຜະລິດອາດຈະຖືກຍົກເວັ້ນຈາກລະບົບການຄວບຄຸມໃນAPI ຂໍ້ມູນສະເພາະທີ່ເໝາະສົມແມ່ນສະໜອງໃຫ້. ການຍື່ນສະເຫນີຜົນໄດ້ສະແດງໃຫ້ເຫັນຫນ້ອຍກວ່າ 10% ຂອງ ICHQ3Climit (ທາງເລືອກ I) ofthesolvent(s) inthreeconsecutiveproduction-scalebatchesorsixconsecutivepilot-scalebatchesoftheAPIorasuitable intermediatewould beconsidered to acceptablejustification. The Laststepsolvents ນໍາໃຊ້ຂະບວນການທີ່ຄວນຈະປົກຄອງຢ່າງເປັນປົກກະຕິໃນ API ສຸດທ້າຍ.
Forguidanceonacceptableresidualsolvent limititsrefertoICHQ3C. ຂອບເຂດຈໍາກັດສໍາລັບ residuesoftrimethylamine (ຊາ) ຄືກັນ 320 ppmonthebasisofICHQ3CoptionIor 3.2 mg2Fdayonthebsisof permitted dailyexposure (PDE).
ການບໍ່ມີທີ່ຮູ້ຈັກ, ການສ້າງຕັ້ງເປັນສານພິດສູງ (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. Genotoxic and carcinogenic impurities in drug substances and products, recommended approaches) or by providing experimental safety data or published data in peer-reviewed journals.
Residues of metal catalysts used in the manufacturing process and determined to be present in batches of API are to be controlled in specifications. This requirement does not apply to metals that are deliberate components of the pharmaceutical substance (such as a counter ion of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). ຄູ່ມືການກໍານົດຂອບເຂດຈໍາກັດສໍາລັບ residuesofmetalcatalystsormetalreagents (EMEA2FCHMP2FSWP2F44462F2000) ຫຼືວິທີການທຽບເທົ່າສາມາດຖືກນໍາໃຊ້ເພື່ອແກ້ໄຂບັນຫານີ້. ຕາມກົດລະບຽບ, ບໍ່ນໍາໃຊ້ກັບ extraneousmetalcontaminants ທີ່ຢູ່ ເຫມາະສົມກວ່າໂດຍ GMP, ການປະຕິບັດການແຈກຢາຍທີ່ດີ (GDP) ຄຸນນະພາບທີ່ກ່ຽວຂ້ອງກັນຢ່າງອື່ນແມ່ນໄດ້ມາຈາກການຜະລິດອຸປະກອນການຜະລິດ ແລະ ສິ່ງແວດລ້ອມ..
ເອກະສານອ້າງອີງ: ICHQ6A, Q3A, Q3C.
3.2. S.4ControloftheAPI (ຊື່, manufacturer)
3.2. S.4.1 ຂໍ້ມູນຈໍາເພາະ (ຊື່, manufacturer)
ຂໍ້ມູນຈໍາເພາະສໍາລັບ API ຄວນໄດ້ຮັບການສະຫນອງໃຫ້.
AsdefinedinICHE28099sQ6Aguideline (6), ສະເພາະ:
E28098E28098Alistoftests, ຂັ້ນຕອນການວິເຄາະ ແລະເງື່ອນໄຂການຍອມຮັບທີ່ເໝາະສົມ, ຈໍານວນຈໍາກັດ, ຊ່ວງ, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. ‘Conformance to specifications’ means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.’’
Copies of the API specifications, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.
The FPP manufacturer’s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).
▪ The standard declared by the applicant could be an officially recognized compendia standard (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard.
▪ The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.
▪ For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, and Ph.Eur. Ph.Int., USP or in-house) and the version (e.g. code number/version/date) should be provided for version control purposes.
In cases where there is more than one API manufacturer, the FPP manufacturer’s API specifications should be one single compiled set of specifications that is identical for each manufacturer. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method for a single parameter with the statement “for API from manufacturer A” (e.g. in the case of residual solvents).
Any non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.
The ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.
ເອກະສານອ້າງອີງ: ICHQ6A, Q3A, Q3C and officially recognized pharmacopoeias.
3.2. S.4.2 Analytical procedures (ຊື່, manufacturer)
ຂັ້ນຕອນການວິເຄາະແມ່ນໃຊ້ເພື່ອທົດສອບ API ຄວນໃຫ້.
Copysofthein-houseanalytical procedures ນໍາໃຊ້ເພື່ອຜະລິດການທົດສອບຜົນໄດ້ຮັບສະຫນອງໃຫ້ PD, aswellasthoseproposed forroutinetestingoftheAPIbytheFPPmanufacturer, should be provided. ເວັ້ນເສຍແຕ່ວ່າມີການດັດແກ້ການດັດແກ້ບໍ່ຈໍາເປັນຂອງ toprovided copyes of officiallyrecognized compendiaanalyticalprocedures.
ຕາຕະລາງສໍາລັບການສະຫຼຸບຈໍານວນຂອງຂັ້ນຕອນການວິເຄາະທີ່ແຕກຕ່າງກັນແລະຂໍ້ມູນທີ່ຖືກຕ້ອງ (e.g. HPLCassay2Fimpuritymethods, gaschromatography (GC) ວິທີການ) ສາມາດຄົ້ນພົບໄດ້ໃນ 2.3.RR Regionalinformationsection oftheQOS-PD (i.e.. 2.3.R.2). ຕາຕະລາງເຫຼົ່ານີ້ບໍ່ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບຂັ້ນຕອນການວິເຄາະໃນຄົວເຮືອນsoftheFPP ຜູ້ຜະລິດສໍາລັບການກໍານົດຂອງສານລະລາຍໃນບ່ອນຢູ່ບ່ອນນັ້ນ., ການກວດສອບແລະຄວາມບໍລິສຸດຂອງ API, insection2.3.S.4.2oftheQOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendia methods need not be summarized unless modifications have been made.
Although HPLC is normally considered the method of choice for determining API-related impurities, other chromatographic methods such as GC and thin-layer chromatography (TLC) can also be used if appropriately validated. For determination of related substances, reference standards should normally be available for each of the identified impurities, particularly those known to be toxic and the concentration of the impurities should be quantified against their own reference standards. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), ຈາກແຫຼ່ງການຄ້າ sorpreparedin-house. ຖືວ່າຍອມຮັບໄດ້ໃນການນຳໃຊ້ APIasanexternal ມາດຕະຖານເພື່ອປະເມີນລະດັບຄວາມບໍລິສຸດ, ສະໜອງໃຫ້ໄດ້ຕາມຄວາມຮັບຜິດຊອບຂອງສານສະກັດຈາກທໍ່ລະບາຍນ້ຳສະອາດຢ່າງພຽງພໍທີ່ໃກ້ຄຽງກັບ API, i.e.. ລະຫວ່າງ 80 ແລະ 120%. ໃນກໍລະນີທີ່ມີຄວາມຮັບຜິດຊອບຢູ່ນອກຂອບເຂດນີ້ມັນອາດຈະຍອມຮັບໄດ້ເພື່ອໃຊ້ API, ສະຫນອງການແກ້ໄຂປັດໄຈນໍາໃຊ້. ຂໍ້ມູນການສະຫນັບສະຫນູນການຄິດໄລ່ຂອງການແກ້ໄຂປັດໄຈຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ foranin-housemethod. Unspecified impurities maybebequantifiedusingasolution oftheAPIasthereferencestandarddataconcentrationcorrespondingtothelimited for individualunspecified impurities (e.g.
0.10%). ThetestforrelatedsinthePh.Int. Monographforlamivudineservesasatypical ຕົວຢ່າງ.
ການທົດສອບຄວາມເໝາະສົມຂອງລະບົບ (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. ຢ່າງໃດກໍຕາມ, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. Section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).
ເອກະສານອ້າງອີງ: ICH Q2, WHO Technical Report Series, No. 943, ເອກະສານຊ້ອນທ້າຍ 3.
3.2. S.4.3 Validation of analytical procedures (ຊື່, manufacturer)
Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided.
Copies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, aswellasthoseproposed forroutinetestingoftheAPIbytheFPPmanufacturer.
Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC methods) ສາມາດຄົ້ນພົບໄດ້ໃນ 2.3.RR Regionalinformationsection oftheQOS-PD (i.e.. 2.3.R.2). ຕາຕະລາງເຫຼົ່ານີ້ບໍ່ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບຂໍ້ມູນການກວດສອບຄວາມຖືກຕ້ອງຂອງຂັ້ນຕອນການວິເຄາະSoftheFPP ຜູ້ຜະລິດສໍາລັບການກໍານົດຂອງ residualsolvents, ການກວດສອບແລະຄວາມບໍລິສຸດຂອງ API, insection2.3.S.4.3oftheQOSPD. ຂໍ້ມູນການຮັບຮອງຄວາມຖືກຕ້ອງສໍາລັບວິທີການອື່ນໆທີ່ຖືກນໍາໃຊ້ເພື່ອສ້າງຕັ້ງການປະເມີນຄວາມບໍລິສຸດແລະຄວາມບໍລິສຸດ PDcanbesummarizedin2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.
ໄດ້ຮັບການຍອມຮັບໂດຍອົງການປົກຄອງແລະຮ້ານຂາຍຢາດ້ວຍຕົນເອງ, ການຢັ້ງຢືນຂອງcompendiamethodscanbenecessary. Thecompendiamethodsas ຈັດພີມມາແມ່ນຖືກຕ້ອງຕາມປົກກະຕິໂດຍອີງໃສ່APIoranFPP ທີ່ມາຈາກຜູ້ຜະລິດສະເພາະ. ແຫຼ່ງທີ່ແຕກຕ່າງຂອງSofthesameAPIorFPPສາມາດບັນຈຸຄວາມບໍລິສຸດແລະ2ການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນທີ່ບໍ່ໄດ້ພິຈາລະນາໃນລະຫວ່າງການພັດທະນາຂອງthemonograph. ເພາະສະນັ້ນ, the monograph and compendia method should be demonstrated as suitable to control the impurity profile of the API from the intended source(s).
In general verification is not necessary for compendia API assay methods. ຢ່າງໃດກໍຕາມ, specificity of a specific compendia assay method should be demonstrated if there are any potential impurities that are not specified in the compendia monograph. If an officially recognized compendia method is used to control API-related impurities that are not specified in the monograph, full validation of the method is expected with respect to those impurities.
If an officially recognized compendia standard is claimed and an in-house method is used in lieu of the compendia method (e.g. for assay or for specified impurities), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For impurity methods the sample analyzed should be the API spiked with impurities at concentrations equivalent to their specification limits.
ເອກະສານອ້າງອີງ: ICH Q2.
3.2. S.4.4 Batch analyses (ຊື່, manufacturer)
Description of batches and results of batch analyses should be provided.
The information provided should include batch number, batch size, date and production site of relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and clinical data (if relevant), stability, ນັກບິນ, scale up and, ຖ້າມີ, production-scale batches.
These data are used to establish the specifications and evaluate consistency in API quality.
Analytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(ນີ້ແມ່ນ) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer’s test results should be summarized in the QOS-PD.
The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. A discussion and justification should be provided for any incomplete analyses (e.g. results not tested according to the proposed specification).
ເອກະສານອ້າງອີງ: ICHQ6A, Q3A, Q3C).
3.2. S.4.5 Justification of specification (ຊື່, manufacturer)
Justification for the API specification should be provided.
A discussion should be provided on the inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendia standard(s). If the officially recognized compendia methods have been modified or replaced a discussion of the modifications or replacement method(s) should be included.
The justification for certain tests, ຂັ້ນຕອນການວິເຄາະແລະການຍອມຮັບມາດຕະການມີການສົນທະນາພາກສ່ວນອື່ນໆsofthePD (e.g. forimpuritiesorparticlesized distribution) ແລະບໍ່ຈໍາເປັນຕ້ອງເຮັດຊ້ຳຢູ່ບ່ອນນີ້, ເຖິງແມ່ນວ່າການອ້າງອິງຂ້າມຄວນຈະໃຫ້.
ເອກະສານອ້າງອີງ: ICHQ6A, Q3A, Q3C, ແລະຮັບຮູ້ຢ່າງເປັນທາງການຢາປົວພະຍາດ.
3.2. S.5Referencestandardsormaterials (ຊື່, manufacturer)
ຂໍ້ມູນກ່ຽວກັບການສະຫນອງມາດຕະຖານການສະຫນອງການເອກະສານການນໍາໃຊ້ສໍາລັບການທົດສອບຂອງ API ຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້.
ຂໍ້ມູນຄວນຈະໄດ້ຮັບການສະຫນອງໃຫ້ໂດຍສະນັ້ນມາດຕະຖານ(s) ການນໍາໃຊ້ຜະລິດຕະພັນ PD, aswellasthosetobeused bytheFPPmanufacturerinroutineAPIandFPPtesting.
ແຫຼ່ງຂໍ້ມູນ(s) ຂອງເອກະສານມາດຕະຖານການດູດຊືມທີ່ນໍາໃຊ້ໃນການທົດສອບຂອງ API ຄວນໄດ້ຮັບການສະຫນອງໃຫ້ (e.g. ທີ່ໃຊ້ສໍາລັບການລະບຸຕົວຕົນ, purityandassaytests). These could be classified as primary or secondary reference standards.
A suitable primary reference standard should be obtained from an officially recognized pharmacopoeia source (e.g. BP, JP, and Ph.Eur. Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeia standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeia sources do not need further structural elucidation.
Otherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary reference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).
A secondary (or in-house) ມາດຕະຖານການອ້າງອິງສາມາດນຳໃຊ້ໄດ້ໂດຍການສ້າງລະບົບການອ້າງອີງມາດຕະຖານທີ່ເໝາະສົມ, e.g. ໂດຍສະໜອງການສຳເນົາເອກະສານທີ່ອ້າງອີງຈາກຊັ້ນປະຖົມ ແລະ ຊັ້ນສອງ ມາດຕະຖານການດຳເນີນການວິເຄາະ ແລະ ການຢັ້ງຢືນ, ລວມທັງ asassay ກໍານົດຕໍ່ກັບມາດຕະຖານການອ້າງອິງເບື້ອງຕົ້ນ. Assecondaryreferencestandardisoftencharacterized and evaluated foritsintended purpose with ຂັ້ນຕອນການເພີ່ມເຕີມອື່ນໆກ່ວາການດໍາເນີນການກວດສອບປົກກະຕິ. (e.g. ifadditionalsolventsareusedduringthead ຂັ້ນຕອນການເຮັດໃຫ້ບໍລິສຸດແບບດັ້ງເດີມ tharenotused forroutinepurposes).
ມາດຕະຖານການອ້າງອິງຄວນຈະຖືກຕັ້ງໄວ້ຕາມປົກກະຕິສໍາລັບການສະເພາະ impurities. ເອກະສານອ້າງອີງ 3.2.S.4.2 foradditionalguidance.
ເອກະສານອ້າງອີງ: ICHQ6A, WHO Technical Report Series, No. 943, ເອກະສານຊ້ອນທ້າຍ 3.
3.2. S.6 ລະບົບປິດຕູ້ຄອນເທນເນີ (ຊື່, manufacturer)
ລາຍລະອຽດຂອງລະບົບການປິດຕູ້ຄອນເທນເນີ(s) should be provided, ລວມທັງຕົວຕົນຂອງວັດສະດຸຂອງການກໍ່ສ້າງ, ອົງປະກອບການຫຸ້ມຫໍ່ຕົ້ນຕໍ, ແລະສະເພາະຂອງເຂົາເຈົ້າ. ຂໍ້ມູນຈໍາເພາະຄວນປະກອບມີຄໍາອະທິບາຍແລະການກໍານົດ (ແລະວິພາກວິຈານການຖອນຕົວ, ບ່ອນທີ່ເຫມາະສົມ). ວິທີທີ່ບໍ່ໄດ້ອ້າງອີງ (ຢືນຢັນ) should be included, ບ່ອນທີ່ເຫມາະສົມ.
ອົງປະກອບການຫຸ້ມຫໍ່ສຳຮອງທີ່ເຮັດວຽກບໍ່ໄດ້ (e.g. ເຫຼົ່ານັ້ນບໍ່ໄດ້ສະຫນອງການປົກປ້ອງເພີ່ມເຕີມ), ຄວນໃຫ້ຄຳອະທິບາຍຫຍໍ້ໆເທົ່ານັ້ນ. ອົງປະກອບການຫຸ້ມຫໍ່ທີ່ມີປະໂຫຍດຂັ້ນສອງ, ຂໍ້ມູນເພີ່ມເຕີມຄວນໄດ້ຮັບການສະຫນອງໃຫ້.
ຄວາມເໝາະສົມຄວນປຶກສາຫາລືດ້ວຍກັນ, ຍົກຕົວຢ່າງ, ວັດສະດຸທາງເລືອກ, ການປົກປ້ອງຈາກຄວາມຊຸ່ມຊື້ນແລະແສງສະຫວ່າງ, ຄວາມເຂົ້າກັນໄດ້ຂອງວັດສະດຸຂອງການກໍ່ສ້າງກັບ API, ລວມທັງການສະຫນອງການບັນຈຸແລະການຊັກ, ແລະ2ດ້ານຄວາມປອດໄພຂອງວັດສະດຸກໍ່ສ້າງ.
ການ WHO Guidelines on packaging for pharmaceutical products and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs.
Primary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR).
Copies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the container, regardless of whether relabeling is conducted at any stage during the API distribution process.
2. S.7 ຄວາມໝັ້ນຄົງ (ຊື່, manufacturer)
3.2. S.7.1 Stability summary and conclusions (ຊື່, manufacturer)
The types of studies conducted, protocols used, ແລະມັນຄວນຈະຖືກສະຫຼຸບ. ບົດສະຫຼຸບຄວນລວມເອົາຜົນໄດ້ຮັບ, ຍົກຕົວຢ່າງ, ຈາກການເສື່ອມໂຊມຂອງການສຶກສາແລະສະພາບຄວາມເຄັ່ງຕຶງ, aswellas conclusions withrespecttostorageconditionsandretestdateors-ຊີວິດ, ທີ່ເຫມາະສົມ.
The WHO guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.
AsoutlinedintheWHOstabilityguidelines, ຈຸດປະສົງຂອງຄວາມຫມັ້ນຄົງການທົດສອບ: E2809Cprovidedence of how thequalityofanAPIorFPPvaries withtime undertheinfluence ofvarietyofenvironmentalfactors ອຸນຫະພູມ, humidity and light.”
The tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. ເງື່ອນໄຂ, testing parameters, conclusions and commitments).
Stress Testing
As outlined in the ICH Q1A guidance document, stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used.
The nature of the stress testing will depend on the individual API and the type of FPP involved.
Stress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2, as well as, “A typical set of studies of the degradation paths of an active pharmaceutical ingredient”, in: WHO Technical Report Series, No. 929, ເອກະສານຊ້ອນທ້າຍ 5, Table A1.
The objective of stress testing is not to completely degrade the API but to cause degradation to occur to a small extent, typically 10–30% loss of API by assay when compared with non-degraded API. This target is chosen so that some degradation occurs, but not enough to generate secondary products. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.
ThetablesintheQOS-PDtemplate ຄວນຖືກນໍາມາໃຊ້ເພື່ອສະຫຼຸບກ່ຽວກັບການທົດສອບຄວາມເຄັ່ງຕຶງ ແລະຄວນລວມເອົາເງື່ອນໄຂການປິ່ນປົວ (e.g. ອຸນຫະພູມ, ຄວາມຊຸ່ມຊື່ນ, ຄວາມເຂັ້ມຂຸ້ນຂອງການແກ້ໄຂແລະໄລຍະເວລາ) ແລະການສັງເກດການສໍາລັບຕົວກໍານົດການທົດສອບທີ່ແຕກຕ່າງກັນ (e.g. ວິເຄາະ, ຜະລິດຕະພັນການເຊື່ອມໂຊມ). ການສົນທະນາຂອງຜົນໄດ້ຮັບຄວນຈະເນັ້ນໃຫ້ເຫັນເຖິງຄວາມສົມດຸນຂອງມະຫາຊົນ.
ການທົດສອບຄວາມຄົງທີ່ຂອງຮູບພາບຄວນເປັນສ່ວນລວມຂອງການທົດສອບຄວາມກົດດັນ. ເງື່ອນໄຂມາດຕະຖານໄດ້ອະທິບາຍdinICHQ1B (22). IfE2809CprotectfromlightE2809Disstatedinone ໄດ້ຮັບການຍອມຮັບຢ່າງເປັນທາງການທາງຢາສໍາລັບAPI, itissufficienttostateE2809CprotectfromlightE2809Donlabelling, inlieuofphotostabilitystudies ເມື່ອລະບົບການປິດຕູ້ຄອນເທນເນີສະແດງໃຫ້ເຫັນການປ້ອງກັນແສງສະຫວ່າງ.
When available it is acceptable to provide the relevant data published in the scientific literature (ລວມທັງ, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.
Accelerated and long-term testing
Available information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature.
The source of the information should be identified.
The required long-term storage conditions for APIs is 30 ºC ± 2 ºC/75% ± 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the Nigerian environmental conditions (i.e.. Zone IVB). Alternative conditions should be supported with appropriate evidence, which may include literature references or in-house studies, demonstrating that storage at 30 ºC is inappropriate for the API. For APIs intended for storage in a refrigerator and those intended for storage in a freezer, refer to the WHO stability guidelines in the WHO Technical Report Series, No.
953, ເອກະສານຊ້ອນທ້າຍ 2. APIs intended for storage below −20 °C should be treated on a case-by-case basis.
To establish the retest period, ຂໍ້ມູນຄວນຈະໄດ້ຮັບການສະຫນອງບໍ່ຫນ້ອຍກ່ວາສາມຊຸດຂະຫນາດນ້ອຍສຸດຂອງນັກບິນ. The batches ຄວນໄດ້ຮັບການຜະລິດໂດຍthesamesynthesisrouteasproductionbatches ແລະໃຊ້ວິທີການຜະລິດແລະຂັ້ນຕອນການຜະລິດທີ່ simulates thefinalprocesstobeused forproduction batches. ໂຄງການການທົດສອບຄວາມຫມັ້ນຄົງຄວນຈະສະຫຼຸບແລະຜົນການທົດສອບຄວາມຫມັ້ນຄົງຄວນຈະສະຫຼຸບໂດຍຫຍໍ້ໃນ QOS-PD.
ຂໍ້ມູນກ່ຽວກັບຄວາມສາມາດການສຶກສາຄວນຈະລວມທັງລາຍລະອຽດສະພາບການເກັບຮັກສາ, ໝາຍເລກຊຸດ, batch size, ລະບົບປິດຕູ້ຄອນເທນເນີແລະສໍາເລັດ (ແລະສະເຫນີ) ຊ່ວງເວລາທົດສອບ. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. ຂອບເຂດຂອງການວິເຄາະຜົນໄດ້ຮັບທີ່ກ່ຽວຂ້ອງຢູ່ບ່ອນໃດບ່ອນຫນຶ່ງແລະແນວໂນ້ມທີ່ໄດ້ຖືກສັງເກດເຫັນຄວນຈະຖືກລວມເອົາ. For quantitative tests (e.g. ແຕ່ລະບຸກຄົນ ແລະທັງໝົດການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນ), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.
The minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.
Table 1 Minimum data required at the time of submitting the dossier
Storage
(ºC)
|
temperature Relative humidity (%) Minimum time
period
(ເດືອນ)
|
Accelerated 40 C2B1 2 75 C2B1 5 6
Intermediate –a –a
Long-term 30 C2B1 2 65 C2B1 5 ຫຼື 75 C2B1 5 6
ເປັນWhere long-term conditions are 30 ºC ± 2 ºC/65% ± 5% RH or 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition.
Refer to WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2 for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.
Proposed storage statement and retest period
A storage statement should be established for display on the label, ອີງໃສ່ການປະເມີນຄວາມສາມາດຂອງ API. ຄູ່ມືດ້ານຄວາມໝັ້ນຄົງຂອງອົງການອະນາໄມໂລກ ລວມມີຈຳນວນທີ່ແນະນຳໃຫ້ໃຊ້ໃນຂັ້ນຕອນການເກັບຮັກສາທີ່ຄວນຈະຖືກນຳໃຊ້ເມື່ອໄດ້ຮັບການສະໜັບສະໜູນໂດຍການສຶກສາຄວາມເປັນໄປໄດ້..
ໄລຍະເວລາການສອບເສັງຄວນໄດ້ຮັບຂໍ້ມູນຈາກຂໍ້ມູນຄວາມເປັນໄປໄດ້ແລະຄວນຈະຖືກສະແດງຢູ່ໃນປ້າຍຄອນເທນເນີ.
ຫຼັງຈາກນີ້ ໄລຍະທົດລອງທົດລອງຂອງ API ໄດ້ຖືກຕັ້ງໄວ້ເພື່ອນຳໃຊ້ໃນການຜະລິດຂອງ FanFPP ສາມາດທົດສອບໄດ້ແລ້ວ., ຖ້າຫາກວ່າບໍ່ສອດຄ່ອງກັບສະເພາະ, ສາມາດນຳໃຊ້ໄດ້ທັນທີ (e.g. ພາຍໃນ 30 ວັນ). ຖ້າຫາກວ່າການທົດສອບແລະພົບເຫັນວ່າສອດຄ່ອງ, The batchdoesnotreceiveanaditional ໄລຍະເວລາທີ່ສອດຄ້ອງກັນກັບໄລຍະເວລາທີ່ຖືກສ້າງຕັ້ງຂື້ນສໍາລັບໄລຍະເວລາທົດສອບໃຫມ່. ຢ່າງໃດກໍຕາມ, anAPIbatchcanbereted ໄດ້ຫຼາຍຄັ້ງແລະສ່ວນທີ່ແຕກຕ່າງກັນຂອງ thebatchusedaftereachretest, aslongasit ສືບຕໍ່ປະຕິບັດຕາມຂໍ້ກໍານົດສະເພາະ. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period.
Limited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, the proposed retest period could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 ເດືອນ).
ເອກະສານອ້າງອີງ: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2.
3.2. S.7.2 Post-approval stability protocol and stability commitment (ຊື່, ຜູ້ຜະລິດ)
The post-approval stability protocol and stability commitment should be provided.
Primary stability study commitment
When the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.
Commitment stability studies
The long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) ຄວນເປັນການລວມເອົາ.
Thestabilityprotocolforthecommitmentbatches should beprovided and should include, ແຕ່ບໍ່ຈໍາກັດ, ຕົວກໍານົດການດັ່ງຕໍ່ໄປນີ້:
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ຈຳນວນຊຸດ(ນີ້ແມ່ນ) ແລະຂະຫນາດທີ່ແຕກຕ່າງກັນ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້;
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ທາງດ້ານຮ່າງກາຍທີ່ກ່ຽວຂ້ອງ, ເຄມີ, ວິທີການທົດສອບ microbiological ແລະຊີວະສາດ;
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ເງື່ອນໄຂການຍອມຮັບ;
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ອ້າງອິງວິທີການທົດສອບ;
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ລາຍລະອຽດຂອງລະບົບປິດຕູ້ຄອນເທນເນີ(s);
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ຄວາມຖີ່ຂອງການທົດສອບ;
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ລາຍລະອຽດຂອງເງື່ອນໄຂການເກັບຮັກສາ (ເງື່ອນໄຂມາດຕະຖານສໍາລັບການທົດສອບໄລຍະຍາວທີ່ອະທິບາຍບົດແນະນໍາເຫຼົ່ານີ້ແລະສອດຄ່ອງກັບ APIlabelling, ຄວນໃຊ້); EF82A7ພາຣາມິເຕີທີ່ໃຊ້ໄດ້ອື່ນໆສະເພາະຂອງ API.
Ongoing stability studies
The stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.
At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.
Refer to section 2.1.11 of WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2, for further information on ongoing stability studies.
Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.
ເອກະສານອ້າງອີງ: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2.
3.2. S.7.3 Stability data (ຊື່, manufacturer)
Results of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.
The actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. ແຕ່ລະບຸກຄົນ ແລະທັງໝົດການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນ) it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”.
ເອກະສານອ້າງອີງ: ICH Q1A, Q1B, Q1D, Q1E, Q2 WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2.
3.2. P Drug product (or finished pharmaceutical product (FPP))
3.2. P.1 Description and composition of the FPP (ຊື່, ຮູບແບບປະລິມານຢາ)
A description of the FPP and its composition should be provided. The information provided should include, ຍົກຕົວຢ່າງ:
Description of the dosage form
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The description of the FPP should include the physical description, ຄວາມເຂັ້ມແຂງທີ່ມີຢູ່, ກົນໄກການປົດປ່ອຍ (e.g. ແກ້ໄຂທັນທີ (delayedorextended)), ເຊັ່ນດຽວກັນກັບຄຸນລັກສະນະທີ່ແຕກຕ່າງກັນໄດ້, e.g.
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E2809CTheproposedXYZ50-mgtablets ສາມາດໃຊ້ໄດ້ເປັນສີຂາວ, ຮູບໄຂ່, ເມັດເຄືອບເງົາ, debossed ກັບE2809850E28099ononesideandabreak-lineontheotherside.
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TheproposedXYZ100-mgtabletsare available asyellow, ຮອບ, ເມັດເຄືອບເງົາ, debossed with ‘100’ on one side and plain on the other side.”
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Composition, i.e.. listofallcomponentsofthedosageform, ແລະ theiramountonaperunitbassis (ລວມທັງຄ່າຈ້າງ, ຖ້າມີ), ການທໍາງານຂອງອົງປະກອບ, ແລະອ້າງອີງເຖິງມາດຕະຖານຄຸນນະພາບຂອງພວກເຂົາ (e.g. compendiamonographsormanufacturerE28099sspecifications).
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The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable.
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All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. “1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride”). All overages should be clearly indicated (e.g. “contains 2% overage of the API to compensate for manufacturing losses”).
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The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) ແລະ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້, their grades (e.g. “microcrystalline cellulose NF (PH 102)") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).
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The function of each component (e.g. diluent or filler, binder, disintegrate, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated.
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The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring, blends or imprinting inks). This information (excluding the solvents) istobelisted ໃນຂໍ້ມູນຜະລິດຕະພັນ (e.g. ສະຫຼຸບຄຸນລັກສະນະຜະລິດຕະພັນ, labelling andpackageleaflet).
ລາຍລະອຽດກ່ຽວກັບການປັບປຸງແຕ່ງຕັ້ງ(s)
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ForFPPs ສະ ຫນອງ ໃຫ້ ກັບ reconstitutiondiluent(s) ທີ່ເປັນການຄ້າທີ່ມີຢູ່ຫຼືວ່າ Thavebeenassed ແລະພິຈາລະນາຍອມຮັບໄດ້ໃນການເຊື່ອມຕໍ່ກັບຜະລິດຕະພັນອື່ນ dossier ກັບ NAFDAC, ຄຳອະທິບາຍຫຍໍ້ຂອງຮ່າງລັດຖະທຳມະນູນ(s) should be provided.
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ForFPPs ສະ ຫນອງ ໃຫ້ ກັບ reconstitutiondiluent(s) ທີ່ບໍ່ແມ່ນທາງການຄ້າມີໃຫ້ນຳໃຊ້ ຫຼືບໍ່ມີການປະເມີນ ແລະພິຈາລະນາຍອມຮັບໄດ້ໃນການເຊື່ອມຕໍ່ກັບຜະລິດຕະພັນອື່ນທີ່ເຮັດກັບ NAFDAC, ຂໍ້ມູນຂ່າວສານ(s) ຄວນຈະຖືກຈັດໃຫ້ແຍກຕ່າງຫາກ FPPportion (E2809C3.2.PE2809D), ທີ່ເຫມາະສົມ.
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ປະເພດຂອງຕູ້ຄອນເທນເນີແລະການປິດທີ່ນໍາໃຊ້ສໍາລັບຮູບແບບການປະກອບແລະການປັບໂຄງສ້າງໃຫມ່, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້
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The container-closure used for the FPP (ແລະການປະກອບການດັດແກ້ລັດຖະທໍາມະນູນ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້) should be briefly described, with further details provided under 3.2.P.7
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Container-closure system, e.g. “The product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminum foil unit dose blisters (in packages of 100s) (cards of 5 × 2, 10 cards per package).” Reference documents: ICHQ6A (6).
3.2. P.2 Pharmaceutical development (ຊື່, ຮູບແບບປະລິມານຢາ)
The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.
Pharmaceutical development information should include, ພໍ່ຂອງຂ້ອຍ:
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the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, ຍົກຕົວຢ່າງ, the route of administration, ຮູບແບບປະລິມານຢາ, bioavailability, strength and stability;
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identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;
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discussion of the potential CQAs of the API(s), excipients ແລະລະບົບປິດຕູ້ຄອນເທນເນີ(s) ລວມທັງການເລືອກປະເພດ, gradeandamounttodeliverd ຜະລິດຕະພັນຂອງຄຸນນະພາບທີ່ຕ້ອງການ;
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ການສົນທະນາກ່ຽວກັບເງື່ອນໄຂການຄັດເລືອກສໍາລັບຂະບວນການຜະລິດແລະຍຸດທະສາດການຄວບຄຸມທີ່ຕ້ອງການເພື່ອການຜະລິດການຄ້າການປະຊຸມ QTPPinaconsistent. ຄຸນນະສົມບັດເຫຼົ່ານີ້ຄວນຈະໄດ້ຮັບການພິຈາລະນາເປັນສ່ວນຫນຶ່ງຂອງການພັດທະນາຜະລິດຕະພັນການນໍາໃຊ້ຫຼັກການຂອງການຄຸ້ມຄອງການຄຸ້ມຄອງຕະຫຼອດຊີວິດຕະຫຼອດຊີວິດຂອງຜະລິດຕະພັນ. (ICQ8).
ການປຶກສາຫາລືກ່ຽວກັບການພັດທະນາການຢາເພີ່ມເຕີມສະເພາະບັນຫາສະເພາະການພັດທະນາຂອງ FDC ການອ້າງອິງຄວນຈະເຮັດການຜ່າຕັດ 6.3.2 of WHO Technical Report Series, No. 929, ເອກະສານຊ້ອນທ້າຍ 5 (21).
ເອກະສານອ້າງອີງ: ICHQ6A, Q8, ຄໍາຖາມທີ 9, Q10.
3.2. P.2.1ComponentsoftheFPP (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.2.1.1 ສ່ວນປະກອບຢາທີ່ໃຊ້ໄດ້ (ຊື່, ຮູບແບບປະລິມານຢາ)
ຄວາມເຂົ້າກັນໄດ້ຂອງAPIwithexcipientslistedin3.2.P.1 ຄວນປຶກສາຫາລື. Additionally, ຄຸນລັກສະນະທາງກາຍະພາບທາງເຄມີ (e.g. ນ້ໍາ, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed.
For FDCs, the compatibility of APIs with each other should be discussed.
Physicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.
Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for registration of fixed-dose combination medicinal products (WHO Technical Report Series, No. 929, ເອກະສານຊ້ອນທ້າຍ 5, 2005). In addition to visual examination, chromatographic results (ວິເຄາະ, purity) are required to demonstrate API–API and API–excipient compatibility. ທົ່ວໄປ, API–excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product.
3.2. P.2.1.2 Excipients (ຊື່, ຮູບແບບປະລິມານຢາ)
The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.
When choosing excipients those with a compendia monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list and the Handbook of pharmaceutical excipients. Use of excipients in concentrations outside established ranges is discouraged and generally requires justification. In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azocolourants as listed in the EMA Guideline CPMP/463/00. Other guidance such as the WHO Guidelines on development of paediatric medicines: points to consider in formulation (32) may provide useful general guidance in this regard.
Ranges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch).
Where antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.
Antimicrobial preservatives are discussed in 3.2. P.2.5.
3.2. P.2.2 Finished pharmaceutical product (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.2.2.1 Formulation development (ຊື່, ຮູບແບບປະລິມານຢາ)
A brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e.. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.
An established multisource product is one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (ເປັນ). In addition, a product quality review should be provided as outlined in Appendix 2.
The requirements for bioequivalence studies should be taken into consideration, ຍົກຕົວຢ່າງ, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, ເອກະສານຊ້ອນທ້າຍ 7) should be consulted.
Product scoring may be recommended or required, ຍົກຕົວຢ່າງ, when scoring is specified in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.
If the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e.. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for other situations) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an illustrative example, the number of units (i.e.. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) ຫຼື 10 quarters for quadrisect tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions can be demonstrated on a one-time basis and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling andpackageleaflet) should reflect the presence of a score.
If splitting of a tablet is intended for preparation of a paediatric dose a demonstration of content uniformity of tablet fragments may be required.
Where relevant, labelling should state that the score line is only to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses.
In vitro dissolution or drug release
A discussion should be included as to how the development of the formulation relates to development of the dissolution method(s) and the generation of the dissolution profile.
The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) should be provided. Data should also be submitted to demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters. Use of a single point test or a dissolution range should be justified based on the solubility and/ or biopharmaceutical classification of the API.
For slower dissolving immediate-release products (e.g. Q = 80% in 90 ນາທີ), a second time point may be warranted (e.g. Q = 60% in 45 ນາທີ).
Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro–in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.
For extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally, the acceptance range at each intermediate test point should not exceed 25% or ± 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.
3.2. P.2.2.2 Overages (ຊື່, ຮູບແບບປະລິມານຢາ)
Any overages in the formulation(s) described in 3.2.P.1 should be justified.
Justification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).
Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.
3.2. P.2.2.3 Physicochemical and biological properties (ຊື່, ຮູບແບບປະລິມານຢາ)
Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.
3.2. P.2.3 Manufacturing process development (ຊື່, ຮູບແບບປະລິມານຢາ)
The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.
Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.
Differences between the manufacturing processes (ນີ້ແມ່ນ) used to produce comparative bioavailability or biowaiver batches and the process described in
3.2.P.3.3 that can influence the performance of the product should be discussed.
For products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.
The rationale for choosing the particular pharmaceutical product (e.g.
ແບບຟອມຢາ, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture).
The scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (CPP), controls and robustness with respect to the QTPP and CQA of the product should be included (ICQ8).
3.2. P.2.4 Container-closure system (ຊື່, ຮູບແບບປະລິມານຢາ)
The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (ການຂົນສົ່ງ) and use of the FPP should be discussed. This discussion should consider, e.g. ວັດສະດຸທາງເລືອກ, ການປົກປ້ອງຈາກຄວາມຊຸ່ມຊື້ນແລະແສງສະຫວ່າງ, compatibility of the materials of construction with the dosage form (ລວມທັງການສະຫນອງການບັນຈຸແລະການຊັກ) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).
Testing requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, ລວມທັງ, ຍົກຕົວຢ່າງ, ດັ່ງຕໍ່ໄປນີ້: – glass containers:
– plastic containers:
– rubber/elastomeric closures:
Table 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.
Table 2: One-time studies to establish the suitability of the container-closure system contact materials
Solid Products
|
Oral Liquid and Topical Products
|
Sterile Products
(including ophthalmics)
|
|
Description of any additional × treatmentsເປັນ
|
×
|
× (sterilization dehydrogenation components)
|
ແລະ
|
|
|
of
|
the
|
|
|
Extraction studies –
|
×
|
×
|
|
|
|
|
Interaction studies –
(migration/sorption)
|
×
|
×
|
|
|
|
|
Moisture permeability ×
(uptake)
|
× (usually loss)
|
×
(usually loss)
|
|
|
|
|
Light transmission ×b
|
×
|
×
|
|
|
|
|
|
|
|
|
|
|
|
|
× Information should be submitted. – Information does not need to be submitted. ເປັນE.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials. bNot required if product has been shown to be photostable.
For solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (ຍົກຕົວຢ່າງ (EU) No. 10/2011 (40)) can be considered acceptable.
The suitability of the container-closure system used for the storage, transportation (ການຂົນສົ່ງ) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed.
A device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.
In accordance with the Ph.Int. General chapter Liquid preparations for oral use:
‘‘Each dose from a multi-dose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.’’
For a device accompanying a multi-dose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose.
A sample of the device should be provided with Module 1.
3.2. P.2.5 Microbiological attributes (ຊື່, ຮູບແບບປະລິມານຢາ)
Where appropriate, the microbiological attributes of the dosage form should be discussed, ລວມທັງ, ຍົກຕົວຢ່າງ, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.
Where an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.
AsoutlinedintheWHOstabilityguidelines (WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2, 2009), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelflife acceptance criteria for preservative content.
3.2. P.2.6 Compatibility (ຊື່, ຮູບແບບປະລິມານຢາ)
The compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling.
Where a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.
Where sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, ວິເຄາະ, levels of individual and total degradation products, sub visible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. ຢ່າງໃດກໍຕາມ, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.
Studies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e.. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).
3.2. P.3 ການຜະລິດ (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.3.1 Manufacturer(s) (ຊື່, ຮູບແບບປະລິມານຢາ)
ຊື່, ທີ່ຢູ່, ແລະຄວາມຮັບຜິດຊອບຂອງຜູ້ຜະລິດ, including contractors, ແລະແຕ່ລະສະຖານທີ່ການຜະລິດທີ່ສະເຫນີຫຼືສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດແລະການທົດສອບຄວນໄດ້ຮັບການສະຫນອງໃຫ້.
ສິ່ງອໍານວຍຄວາມສະດວກທີ່ກ່ຽວຂ້ອງກັບການຜະລິດ, ການຫຸ້ມຫໍ່, labelling and testing should be listed. ຖ້າບໍລິສັດມີຄວາມຮັບຜິດຊອບສະເພາະຂັ້ນຕອນສະເພາະ (e.g. manufacturing of an intermediate), ນີ້ຄວນຈະຊີ້ບອກຢ່າງຈະແຈ້ງ (WHO good distribution practices for pharmaceutical products).
The list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) ມີສ່ວນຮ່ວມ (ລວມທັງຕັນ(s) and unit(s)), ແທນທີ່ຈະເປັນຫ້ອງການບໍລິຫານ.
For a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, ເພາະສະນັ້ນຈຶ່ງ, the mixture does not fall under the definition of an API. The only exceptions are in the cases where the API cannot exist on its own. ເຊັ່ນດຽວກັນ, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacture of the final product. Sites for such manufacturing steps should be listed in this section.
A valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (ໂມດູນ 1, 1.2.2).
For each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (ໂມດູນ 1, 1.2.2).
Justification for any differences to the product in the country or countries issuing the WHOtype certificate(s)
When there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.
Regulatory situation in other countries
A listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (ໂມດູນ 1, 1.2.2).
ເອກະສານອ້າງອີງ: WHO Technical Report Series, No. 961, ເອກະສານຊ້ອນທ້າຍ 3 and No. 957, ເອກະສານຊ້ອນທ້າຍ 5
3.2. P.3.2 Batch formula (ຊື່, ຮູບແບບປະລິມານຢາ)
A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, ລວມທັງຄ່າຈ້າງ, ແລະອ້າງອີງເຖິງມາດຕະຖານຄຸນນະພາບຂອງພວກເຂົາ.
The tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.
All components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. “1 kg of active ingredient base = 1.075 kg active ingredient hydrochloride”). All overages should be clearly indicated (e.g. “Contains 5 kg (corresponding to 2%) overage of the API to compensate for manufacturing losses”).
The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) ແລະ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້, their grades (e.g. “Microcrystalline cellulose NF (PH 102)") and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified).
3.2. P.3.3 Description of manufacturing process and process controls (ຊື່, ຮູບແບບປະລິມານຢາ) A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.
A narrative description of the manufacturing process, including packaging that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, ທີ່ກ່ຽວຂ້ອງ.
Steps in the process should have the appropriate process parameters identified, such as time, temperature, or ph. associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.
The maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 ວັນ. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.
Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.ປ.3.3).
The information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.
For the manufacture of sterile products, the class (e.g. ກ, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.
ເອກະສານອ້າງອີງ: ICQ8, ຄໍາຖາມທີ 9, Q10.
3.2. P.3.4 Controls of critical steps and intermediates (ຊື່, ຮູບແບບປະລິມານຢາ)
ບາດກ້າວສຳຄັນ: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.
ຕົວກາງ: Information on the quality and control of intermediates isolated during the process should be provided.
Examples of applicable in-process controls include:
-
Granulations: moisture (limits expressed as a range), blend uniformity (e.g. low-dose tablets), bulk and tapped densities and particle size distribution;
-
Solid oral products: average weight, weight variation, hardness, thickness, friability, and disintegration checked periodically throughout compression, weight gain during coating;
-
Semi-solids: viscosity, homogeneity, pH;
-
Transdermal dosage forms: assay of API–adhesive mixture, weight per area of coated patch without backing;
-
Metered dose inhalers: fill weight or volume, leak testing, valve delivery;
-
Dry powder inhalers: assay of API–excipient blend, moisture, weight variation of individually contained doses such as capsules or blisters;
-
Liquids: pH, specific gravity, clarity of solutions;
-
Parenterals: appearance, clarity, fill volume or weight, pH, filter integrity tests, particulate matter, leak testing of ampoules, prefiltration and/or pre-sterilization bioburden testing.
ເອກະສານອ້າງອີງ: ICH Q2, Q6A, Q8, ຄໍາຖາມທີ 9, Q10, WHO Technical Report Series, No. 929, ເອກະສານຊ້ອນທ້າຍ 5.
3.2. P.3.5 Process validation and/or evaluation (ຊື່, ຮູບແບບປະລິມານຢາ)
Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling).
Viral safety evaluation should be provided in 3.2A.2, if necessary.
For products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.
The following information should be provided for all other products:
1. a copy of the process validation protocol, specific to this FPP, described below;
2. a commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the NAFDAC inspection team;
3. if the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. ແລະ 2. above.
One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. ດັ່ງນັ້ນຈຶ່ງ, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analyzed statistically to verify the “normality” of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendia specifications.
ເຊັ່ນດຽວກັນ, extensive sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. ດັ່ງນັ້ນຈຶ່ງ, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.
Where ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.
The process validation protocol should include, ແຕ່ບໍ່ຈໍາກັດ, ດັ່ງຕໍ່ໄປນີ້:
-
A reference to the current master production document;
-
A discussion of the critical equipment;
-
The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;
-
Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);
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The testing parameters and acceptance criteria including in process and release specifications and comparative dissolution profiles of validation batches against the batch(ນີ້ແມ່ນ) used in the bioavailability or biowaiver studies;
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The analytical procedures or a reference to appropriate section(s) of the dossier;
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The methods for recording and evaluating results; – the proposed timeframe for completion of the protocol.
The manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate inprocess controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:
-
Washing, treatment, sterilization and dehydrogenation of containers, closures and equipment;
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Filtration of solutions;
-
Lyophilization process;
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Leaker test of filled and sealed ampoules; – final inspection of the product; – sterilization cycle.
The sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. ເພາະສະນັ້ນ, scientific justification for selecting any other method of sterilization should be provided.
The sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as the safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 °C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.
Any filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.
For the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current NAFDAC or WHO GMP guidelines for details.
ເອກະສານອ້າງອີງ: ICQ8, ຄໍາຖາມທີ 9, Q10, WHO Technical Report Series, No. 961, ເອກະສານຊ້ອນທ້າຍ 3.
3.2. P.4 Control of excipients (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.4.1 Specifications (ຊື່, ຮູບແບບປະລິມານຢາ)
The specifications for excipients should be provided.
The specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers).
If the standard claimed for an excipient is an officially recognized compendia standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendia monograph.
If the standard claimed for an excipient is a non-compendia standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendia monograph, a copy of the specification for the excipient should be provided.
For products submitted to NAFDAC for registration, only excipients with an officially recognized pharmacopoeia monograph should be used. Exceptions may be justified.
For excipients of natural origin, microbial limit testing should be included in the specifications. Skiptesting is acceptable if justified (submission of acceptable results of five production batches).
For oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.
The colours permitted for use are limited to those listed in the “Japanese pharmaceutical excipients”, the European Union (EU) “List of permitted food colours”, and the FDA “Inactive ingredient guide”. For proprietary mixtures, the supplier’s product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer’s specifications for the product, including identification testing.
For flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations).
Information that is considered confidential may be submitted directly to the NAFDAC by the supplier who should make reference in the cover letter to the specific related product.
Other certifications of at-risk components may be required on a case-by-case basis.
If additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.
ເອກະສານອ້າງອີງ: ICHQ6A.
3.2. P.4.2 Analytical procedures (ຊື່, ຮູບແບບປະລິມານຢາ)
The analytical procedures used for testing the excipients should be provided, ບ່ອນທີ່ເຫມາະສົມ.
Copies of analytical procedures from officially recognized compendia monographs do not need to be submitted.
Reference document: ICH Q2.
3.2. P.4.3 Validation of analytical procedures (ຊື່, ຮູບແບບປະລິມານຢາ)
Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, ບ່ອນທີ່ເຫມາະສົມ.
Copies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate.
Reference document: ICH Q2.
3.2. P.4.4 Justification of specifications (ຊື່, ຮູບແບບປະລິມານຢາ)
Justification for the proposed excipient specifications should be provided, ບ່ອນທີ່ເຫມາະສົມ.
A discussion of the tests that are supplementary to those appearing in the officially recognized compendia monograph should be provided.
3.2. P.4.5 Excipients of human or animal origin (ຊື່, ຮູບແບບປະລິມານຢາ)
For excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, specifications, description of the testing performed, and viral safety data) (ລາຍລະອຽດໃນ3.2.A.2).
The following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice.
For excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies.
Materials of animal origin should be avoided whenever possible.
When available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1.
ເອກະສານອ້າງອີງ: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908, ເອກະສານຊ້ອນທ້າຍ 1.
3.2. P.4.6 Novel excipients (ຊື່, ຮູບແບບປະລິມານຢາ)
For excipient(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).
Novel excipients are not accepted by NAFDAC. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.
3.2. P.5 Control of FPP (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.5.1 Specification(s) (ຊື່, ຮູບແບບປະລິມານຢາ)
The specification(s) for the FPP should be provided.
AsdefinedinICHE28099sQ6Aguideline, ສະເພາະ:
‘‘a list of tests, ຂັ້ນຕອນການວິເຄາະ ແລະເງື່ອນໄຂການຍອມຮັບທີ່ເໝາະສົມ, ຈໍານວນຈໍາກັດ, ຊ່ວງ, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.’’
A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e.. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.
The specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods).
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The standard declared by the applicant could be an officially recognized compendia standard (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard.
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The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes.
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For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur. Ph.Int., USP, in-house) and the version (e.g. code number/version/ date) should be provided for version control purposes.
ICH’s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, ພໍ່ຂອງຂ້ອຍ, tests for appearance, ການລະບຸຕົວຕົນ, ວິເຄາະ, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, ແລະ, ນຳໃຊ້ໄດ້, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests.
The following information provides guidance on specific tests that are not addressed by ICH’s Q6A guideline:
▪ fixed-dose combination FPPs (FDC-FPPs):
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Analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,
-
Acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards,
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A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit,
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For the API(s) present at ≥ 5 mg and ≥ 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing;
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Modified-release products: a meaningful API release method;
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Inhalation and nasal products: consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss;
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Suppositories: uniformity of dosage units, ຈຸດ melting;
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Transdermal dosage forms: peel or shear force, mean weight per unit area and dissolution. Unless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is ± 5% of the label claim (i.e.. 95.0–105.0%).
For products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. ຖ້າບໍ່ດັ່ງນັ້ນ, the test for mass uniformity may be applied.
Skip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, ພໍ່ຂອງຂ້ອຍ, the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. In addition, for stability indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.
Any differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.
ເອກະສານອ້າງອີງ: ICH Q3B, Q3C, Q6A.
3.2. P.5.2 Analytical procedures (ຊື່, ຮູບແບບປະລິມານຢາ)
The analytical procedures used for testing the FPP should be provided.
Copies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.
Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) ສາມາດຄົ້ນພົບໄດ້ໃນ 2.3.RR Regionalinformationsection oftheQOS-PD (i.e.. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.
Refer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.
Reference document: ICH Q2 (16).
3.2. P.5.3 Validation of analytical procedures (ຊື່, ຮູບແບບປະລິມານຢາ)
Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided.
Copies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.
ຕາຕະລາງສໍາລັບການສະຫຼຸບຈໍານວນຂອງຂັ້ນຕອນການວິເຄາະທີ່ແຕກຕ່າງກັນແລະຂໍ້ມູນທີ່ຖືກຕ້ອງ (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOSPD (i.e.. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.
ໄດ້ຮັບການຍອມຮັບໂດຍອົງການປົກຄອງແລະຮ້ານຂາຍຢາດ້ວຍຕົນເອງ, ການຢັ້ງຢືນຂອງcompendiamethodscanbenecessary. Thecompendiamethodsas ຈັດພີມມາແມ່ນຖືກຕ້ອງຕາມປົກກະຕິໂດຍອີງໃສ່APIoranFPP ທີ່ມາຈາກຜູ້ຜະລິດສະເພາະ. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. ເພາະສະນັ້ນ, the monograph and compendia method(s) should be demonstrated suitable for the control of the proposed FPP.
For officially recognized compendia FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendia method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.
If an officially recognized compendia standard is claimed and an in-house method is used in lieu of the compendia method (e.g. for assay or for related compounds), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analyzed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.
Reference document: ICH Q2.
3.2. P.5.4 Batch analyses (ຊື່, ຮູບແບບປະລິມານຢາ)
A description of batches and results of batch analyses should be provided.
Information on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, ນັກບິນ, scale-up and, ຖ້າມີ, production-scale batches).
Analytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated[1] FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 ຫຼື 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
The results should include those of tests on the batch (ນີ້ແມ່ນ) used in the comparative bioavailability or biowaiver studies. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.
The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The discussion should include ranges of analytical results, ທີ່ກ່ຽວຂ້ອງ. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms” (e.g. “levels of degradation product A ranged from 0.2 ກັບ 0.4 %"). Dissolution results should be expressed, ພໍ່ຂອງຂ້ອຍ, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.
A discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification).
ເອກະສານອ້າງອີງ: ICH Q3B, Q3C, Q6A.
3.2. P.5.5 Characterization of impurities (ຊື່, ຮູບແບບປະລິມານຢາ)
Information on the characterization of impurities should be provided, if not previously provided in “3.2.S.3.2 Impurities”.
A discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (e.g. residual solvents in the manufacturing process for the FPP).
ເອກະສານອ້າງອີງ: ICH Q3B, Q3C, Q6A.
3.2. P.5.6 Justification of specification(s) (ຊື່, ຮູບແບບປະລິມານຢາ)
Justification for the proposed FPP specification(s) should be provided.
A discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendia standard(s). If the officially recognized compendia methods have been modified or replaced, a discussion should be included.
The justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, ເຖິງແມ່ນວ່າການອ້າງອິງຂ້າມຄວນຈະໃຫ້.
ICH Q6A should be consulted for the development of specifications for FPPs.
3.2. P.6 Reference standards or materials (ຊື່, ຮູບແບບປະລິມານຢາ)
Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in “3.2.S.5 Reference standards or materials”.
See section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.
ເອກະສານອ້າງອີງ: ICHQ6A (6), WHO Technical Report Series, No. 943, ເອກະສານຊ້ອນທ້າຍ 3.
3.2. P.7 Container-closure system (ຊື່, ຮູບແບບປະລິມານຢາ)
A description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. ຂໍ້ມູນຈໍາເພາະຄວນປະກອບມີຄໍາອະທິບາຍແລະການກໍານົດ (and critical dimensions, with drawings where appropriate). ວິທີທີ່ບໍ່ໄດ້ອ້າງອີງ (ຢືນຢັນ) should be included, ບ່ອນທີ່ເຫມາະສົມ.
ອົງປະກອບການຫຸ້ມຫໍ່ສຳຮອງທີ່ເຮັດວຽກບໍ່ໄດ້ (e.g. those that neither provide additional protection nor serve to deliver the product), ຄວນໃຫ້ຄຳອະທິບາຍຫຍໍ້ໆເທົ່ານັ້ນ. ອົງປະກອບການຫຸ້ມຫໍ່ທີ່ມີປະໂຫຍດຂັ້ນສອງ, ຂໍ້ມູນເພີ່ມເຕີມຄວນໄດ້ຮັບການສະຫນອງໃຫ້.
Suitability information should be located in 3.2.P.2.
The WHO Guidelines on packaging for pharmaceutical products (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.
Descriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:
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In direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler);
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Used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension;
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Used as a protective barrier to help ensure stability or sterility; ▪ necessary to ensure FPP quality during storage and shipping.
Primary packaging components are those that are in direct contact with the API or FPP.
The specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thickness or area weight.
Information to establish the suitability (e.g. qualification) of the container closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).
3.2. P.8 Stability (ຊື່, ຮູບແບບປະລິມານຢາ)
3.2. P.8.1 Stability summary and conclusions (ຊື່, ຮູບແບບປະລິມານຢາ)
The types of studies conducted, protocols used, ແລະມັນຄວນຈະຖືກສະຫຼຸບ. The summary should include, ຍົກຕົວຢ່າງ, conclusions with respect to storage conditions and shelf-life, ແລະ, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້, in-use storage conditions and shelf-life.
The WHO stability guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (19) should be consulted for recommendations on the core stability
data package required for the prequalification of APIs and FPPs.
AsoutlinedintheWHOstabilityguidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product related factors that influence the quality of the API or FPP, ຍົກຕົວຢ່າງ, interaction of API with excipients, container-closure systems and packaging materials.
Stress testing
AsoutlinedintheWHOstabilityguidelines, photo stability testing should be conducted on at least one primary batch of the FPP if appropriate. If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze–thaw studies for liquid products).
Accelerated, intermediate (if necessary) and long-term testing
Stability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2, ເອກະສານຊ້ອນທ້າຍ 1 (7) for information on climatic zones. Effective as of September 2011, the required longterm storage conditions for the WHO Prequalification of Medicines Programmed are 30 ºC ± 2 ºC/75% ± 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.
Other storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below −20 °C should be treated on a case-by-case basis.
Table 3: Minimum data required at the time of submitting the dossier (in the general case)
Storage Temperature
(ºC)
|
Relative Humidity
(%)
|
Minimum Time Period
(ເດືອນ)
|
Accelerated 40 C2B1 2
|
75 C2B1 5
|
6
|
Intermediate
|
N/A
|
N/A
|
Long-term 30 C2B1 2
|
75 C2B1 5
|
6
|
ເປັນWhere long-term conditions are 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2 (19) for further information regarding the storage conditions.
To establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 ຫຼື 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
The stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.
For sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, sub visible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.
Any in-use period and associated storage conditions should be justified with experimental data, ຍົກຕົວຢ່າງ, after opening, reconstitution and/or dilution of any sterile and/or multidose products or after first opening of FPPs packed in bulk multidose containers (e.g. bottles of 1000s). ຖ້າໃຊ້ໄດ້, the inuse period and storage conditions should be stated in the product information.
The information on the stability studies should include details such as
-
storage conditions;
-
ມີຄວາມເຂັ້ມແຂງ;
-
ໝາຍເລກຊຸດ, including the API batch number(s) and manufacturer(s);
-
batch size;
-
a container-closure system including orientation (e.g. erect, inverted, on-side) ບ່ອນທີ່ສາມາດນໍາໃຊ້;
-
completed (ແລະສະເຫນີ) ຊ່ວງເວລາທົດສອບ.
The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The discussion should include ranges of analytical results and any trends that were observed. For quantitative tests (e.g. ແຕ່ລະບຸກຄົນ ແລະທັງໝົດການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນ) actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, ພໍ່ຂອງຂ້ອຍ, as both the average and range of individual results.
Applicants should consult ICH’s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 ເດືອນ).
Proposed storage statement and shelf-life
The proposed storage statement and shelf-life (and in-use storage conditions and in-use period, ຖ້າຫາກວ່າສາມາດນໍາໃຊ້) for the FPP should be provided.
The recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines.
ເອກະສານອ້າງອີງ: WHO Technical Report Series, No. 953, ເອກະສານຊ້ອນທ້າຍ 2, ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q3B, Q6A.
3.2. P.8.2 Post-approval stability protocol and stability commitment (ຊື່, ຮູບແບບປະລິມານຢາ)
The post-approval stability protocol and stability commitment should be provided.
Primary stability study commitment
When the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.
Commitment stability studies
The long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) ຄວນເປັນການລວມເອົາ.
Ongoing stability studies
As described in the WHO stability guidelines, an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, if relevant, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.
Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.
Reference document: ICH Q1A.
3.2. P.8.3 Stability data (ຊື່, ຮູບແບບປະລິມານຢາ)
Results of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, and narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.
Information on characterization of impurities is located in 3.2. P.5.5.
The actual stability results and reports used to support the proposed shelf-life should be provided in the PD. For quantitative tests (e.g. ແຕ່ລະບຸກຄົນ ແລະທັງໝົດການເຊື່ອມໂຊມຂອງຜະລິດຕະພັນ), actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”.
Dissolution results should be expressed, ພໍ່ຂອງຂ້ອຍ, as both the average and range of individual results.
ເອກະສານອ້າງອີງ: ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q2.
3.2. A Appendices
3.2. A.1 Facilities and equipment
Not applicable (i.e.. not a biotech product).
3.2. A.2 Adventitious agent’s safety evaluation
3.2. A.3 Novel excipients
Novel excipients are not accepted.
3.2. R Regional information
3.2. R.1 Production documentation
3.2. R.1.1 Executed production documents
A minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 ຫຼື 50 000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
Forsolidoraldosageforms, pilot scale is generally, ພໍ່ຂອງຂ້ອຍ, one-tenth that of full production scale or 100 000 tablets or capsules, whichever is the larger.
Copies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.
If not included in the executed batch records through sufficient in process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the bio batch should involve testing to an extent greater than that required in routine quality control.
English translations of executed records should be provided where relevant.
3.2.R.1.2 Master production documents
Copies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site.
The details in the master production documents should include, ແຕ່ບໍ່ຈໍາກັດ, ດັ່ງຕໍ່ໄປນີ້:
■ master formula;
■ dispensing, processing and packaging sections with relevant material and operational details;
■ relevant calculations (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis);
■ identification of all equipment by, ພໍ່ຂອງຂ້ອຍ, type and working capacity (including make, model and equipment number, where possible);
■ process parameters (e.g. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed ( expressed as target and range));
■ list of in-process tests (e.g. appearance, pH, ວິເຄາະ, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications;
■ sampling plan with regard to the:
– steps at which sampling should be done (e.g. drying, lubrication and compression),
– number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),
– frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);
■ precautions necessary to ensure product quality (e.g. temperature and humidity control and maximum holding times);
■ for sterile products, reference to standard operating procedures ( SOPs) in appropriate sections and a list of all relevant SOPs at the end of the document;
■ theoretical and actual yield;
■ compliance with the GMP requirements.
Reference document: WHO Technical Report Series, No. 961.
3.2. R.2 Analytical procedures and validation information
The tables presented in section 2.3.R.2 in the QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3,
2.3.S.4.4 (c),
2.3. S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant.
4.3 Literature references
References to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate.
ໂມດູນ 4: Non-clinical Summaries
This module is not normally needed for multisource (ທົ່ວໄປ) pharmaceutical products. It deals with the toxicity testing intended to justify the stability and safety of the product. The module is included for completeness to indicate the appropriate format and placement of the nonclinical data.
Refer to ICH M4S (R2) for additional detail on the organization of Module 4 and for ICH references on study design and data content.
4.1 ຕາຕາລາງ (ໂມດູນ 4)
4.2 Study Reports
The study reports should be presented in the following order:
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)
4.2.2.2 Absorption
4.2.2.3 Distribution 4.2.2.4 Metabolism
4 2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity (in order by species, by route)
4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations)
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo (supportive toxicokinetics evaluations)
4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)
4.2.3.4.1 Long-term studies (in order by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)
4.2.3.4.2 Short- or medium-term studies (including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)
4.2.3.4.3 Other studies
4.2.3.5 Reproductive and Developmental Toxicity
4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including maternal function
4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated.
4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (ຖ້າມີ)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
4.3 Literature References
ໂມດູນ 5: Clinical Summaries
For multisource (ທົ່ວໄປ) pharmaceutical products, only Module 5.3.1 Reports of Biopharmaceutical Studies would normally be needed. ຢ່າງໃດກໍຕາມ, all parts of the module are included for completeness to indicate the appropriate format and placement of the nonclinical data.
ICH E3 provides guidance on the organisation of clinical study reports, other clinical data, and references within a Common Technical Document (CTD).
ໂມດູນ 5 provides the recommended organization for the placement of clinical study reports and related information to simplify preparation and review of dossiers and to ensure completeness. The placement of a report should be determined by the primary objective of the study. Each study report should appear in only one section. Where there are multiple objectives, the study should be cross-referenced in the various sections. An explanation such as “not applicable” or “no study conducted” should be provided when no report or information is available for a section or subsection.
Refer to ICH M4E (R2) for additional detail on the organization of Module 5 and for additional ICH references on study design and data content.
5.1 ຕາຕາລາງ (ໂມດູນ 5)
A Table of Contents for study reports should be provided.
5.2 Tabular Listing of Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Bio-pharmaceutic Studies
Bioavailability (BA) studies evaluate the rate and extent of release of the active substance from the medicinal product. Comparative BA or bioequivalence (BE) studies may use Pharmacokinetic (PK), Pharmacodynamic (PD), clinical or in vitro dissolution endpoints, and may be either single dose or multiple doses. When the primary purpose of a study is to assess the PK of a drug, but also includes BA information, the study report should be submitted in Section 5.3.1, and referenced in Sections 5.3.1.1 and/or 5.3.1.2.
5.3.1.1 Bioavailability (BA) Study Reports
BA studies in this section should include
• studies comparing the release and systemic availability of a drug substance from a solid oral dosage form to the systemic availability of the drug substance given intravenously or as an oral liquid dosage form
• dosage form proportionality studies, ແລະ
• food-effect studies.
5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports
Studies in this section compare the rate and extent of release of the drug substance from similar drug products (ຕົວຢ່າງ:, tablet to tablet, tablet to capsule). Comparative BA or BE studies may include comparisons between
• the drug product used in clinical studies supporting effectiveness and the to-be-marketed drug product,
• the drug product used in clinical studies supporting effectiveness and the drug product used in stability batches, ແລະ
• similar drug products from different manufacturers.
5.3.1.3 In vitro-In vivo Correlation Study Reports
In vitro dissolution studies that provide BA information, including studies used in seeking to correlate in vitro data with in vivo correlations, should be placed in this section. Reports of in vitro dissolution tests used for batch quality control and/or batch release should be placed in the Quality section (ໂມດູນ 3) of the CTD.
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
Bioanalytical and/or analytical methods for biopharmaceutics studies or in vitro dissolution studies should ordinarily be provided in individual study reports. Where a method is used in multiple studies, the method and its validation should be included once in Section 5.3.1.4 and referenced in the appropriate individual study reports.
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies References
5.3.5.3 Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses
5.3.5.4 Other Clinical Study Reports
5.3.6 Reports of Post-marketing Experience
For products that are currently marketed, reports that summarize marketing experience (including all significant safety observations) should be included.
5.3.7 Case Report Forms and Individual Patient Listings (when submitted)
Case report forms and individual patient data listings that are described as appendices in the ICH or WHO clinical study report guideline should be placed in this section when submitted in the same order as the clinical study reports and indexed by study.
5.4 Literature References
Copies of referenced documents, including important published articles, official meeting minutes, or other regulatory guidance or advice should be provided here. This includes copies of all references cited in the Clinical Overview, and copies of important references cited in the Clinical Summary or in the individual technical reports that were provided in Module 5, Only one copy of each reference should he provided. Copies of references that are not included here should be immediately available on request.
ເອກະສານຊ້ອນທ້າຍ 1
Recommendations for conducting and assessing comparative dissolution profiles
The dissolution measurements of the two FPPs (e.g. test and reference (ຕົວປຽບທຽບ) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (ຕົວປຽບທຽບ) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) ນາທີ). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f2 must be calculated. For extended release FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2, 3, 5 ແລະ 8 hours for a 12-hour release and additional test intervals for longer duration of release.
Studies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. International Pharmacopoeia buffers are recommended; other pharmacopoeia buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.
If both the test and reference (ຕົວປຽບທຽບ) products show more than 85% dissolution in 15 ນາທີ, the profiles are considered similar (no calculations required). ຖ້າບໍ່ດັ່ງນັ້ນ:
▪ Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (f2):
f2 = 50 LOG {[1+1/n ∑nt=1 (ຣt−Tt) 2] −0.5 × 100}
where Rt and Tt are the mean per cent API dissolved in reference (ຕົວປຽບທຽບ) and test product, ຕາມລໍາດັບ, at each time-point. An f2 value between 50 ແລະ 100 suggests that the two dissolution profiles are similar.
▪ A maximum of one time-point should be considered after 85% dissolution of the reference (ຕົວປຽບທຽບ) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.
▪ At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.
▪ When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 medium.
▪ When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.
▪ Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.
REFERENCES:
ICH Common Technical Document References (http://www.ich.org)
1. ICH M4 – Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (2016)
2. ICH M4E(R2) – Common Technical Document for the Registration of Pharmaceuticals for Human Use: Efficacy (2016)
3. ICH M4Q(R1) – Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality (2002)
4. ICHM4S(R2) – Common Technical Document for the Registration of Pharmaceuticals for Human
Use: Safety (2002)
ICH Quality Guidelines
1. ICH Q1A(R2) – Stability Testing of New Drug Substances and Products (2003)
2. ICH Q1B Stability Testing: Photo stability Testing of New Drug Substances and Products (1996)
3. ICH Q1D – Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products (2002)
4. ICH Q1E – Evaluation for Stability Data (2003)
5. ICH Q2(R1) – Validation of Analytical Procedures: Text and Methodology (2005) [combines the previous Q2A and Q2B Guidelines]
6. ICH Q3A(R2) – Impurities in New Drug Substances (2006)
7. ICH Q3B(R2) – Impurities in New Drug Products (2206)
8. ICH Q3C(R6) – Impurities: Guideline For Residual Solvents Q3C(2016)
9. ICH Q5A, Q5B, Q5C, Q5D Quality of Biological Products [not needed for multisource (ທົ່ວໄປ) pharmaceutical products]
10. ICHQ6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999)
11. ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological
Products (1999) [not needed for multisource (ທົ່ວໄປ) pharmaceutical products]
World Health Organization Guidelines
1. Guidelines on packaging for pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2002
( WHO Technical Report Series, No. 902), ເອກະສານຊ້ອນທ້າຍ 9
2. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva,
World Health Organization, 2009 (WHO Technical Report Series, No. 953), ເອກະສານຊ້ອນທ້າຍ 2. [Together with
2015 update table Stability Conditions for WHO Member States by Region]
3. Guideline on submission of documentation for a multisource (ທົ່ວໄປ) finished pharmaceutical product (FPP): quality part, In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2012 (WHO Technical Report Series, No. 970), ເອກະສານຊ້ອນທ້າຍ 4
4. Multisource (ທົ່ວໄປ) pharmaceutical products: guidelines on registration requirements to establish interchangeability, In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. . World Health Organization, 2015 (WHO Technical Report Series, No. 992), ເອກະສານຊ້ອນທ້າຍ 7.
5. Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (ທົ່ວໄປ) products In WHO Expert Committee on Specifications for
Pharmaceutical Preparations: Forty-ninth report. World Health Organization, (WHO Technical
Report Series, No. 992), ເອກະສານຊ້ອນທ້າຍ 8 2015
6. Guidance for organizations performing in vivo bioequivalence studies (revision), In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fiftieth report.
7. WHO Technical Report Series, No. 996, ເອກະສານຊ້ອນທ້າຍ 9, 2016
World Health Organization Templates
Quality Templates
1. Quality overall summary – product dossier (QOS-PD)
2. Quality information summary (ຕໍ່າ)
Bioequivalence Template
1. Bioequivalence trail information form (BTIF)
2. Biowaiver Application Form (BAF)
3. Make reference to WHO guideline for bioavailability and bioequivalence studies and the WHO
Template on Bio waiver]
Labelling Templates
1. Patient information leaflet – Template
2. Summary Product Characteristics (SmPC) Template
3. Labelling Template
ANNEX A: PRODUCT LABELLING GUIDANCE
The Guidance and templates for product labelling shall be based on the NAFDAC Labelling Template guidance for the Package Leaflet,
ໂມດູນ 1.3.1 ສະຫຼຸບສັງລວມລັກສະນະຂອງຜະລິດຕະພັນ (SmPC)
The format of the SmPC document is to be consistent with the NAFDAC SmPC Template. The information should be provided in English language.
Refer to NAFDAC SmPC Guidance
Use NAFDAC SmPC Template
ໂມດູນ 1.3.2 Patient Information Leaflet
The format of the PIL is to be consistent with the NAFDAC PIL template. The information should be provided in the English Language
Refer to NAFDAC PIL Guidance
Use NAFDAC PIL Template
ໂມດູນ 1.3.3 Container Labelling (Inner and Outer Labels)
The primary and secondary packaging must include the following information in a legible, understandable and indelible manner. The information should be provided in English.
The Container Labelling is to be consistent with the WHO template.
Refer to NAFDAC Label Guidance
ANNEX B: TEMPLATES
Refer to NAFDAC Templates found at
Quality Overall Summary – product dossier (QOS-PD)
Quality information Summary (ຕໍ່າ)
ANNEX C: MANAGEMENT OF APPLICATIONS AND STANDARD OPERATING PROCEDURES
For pharmaceutical products that have been prequalified by the World Health Organization, registration will be via the Collaborative Procedure for the Accelerated Registration of WHO Prequalified medicines and vaccines.
As for other products, including those for specific or neglected tropical diseases, a complete application will be required.
1.4 GENERAL POLICIES ON APPLICATIONS
A separate application is required for each product. For purposes of clarification, one application could be submitted for products containing the same active ingredients and the same strength made by the same manufacturer at the same manufacturing site, to the same specifications and dosage form, but differing only in packing or pack sizes. On the other hand, separate applications shall be submitted for products that contain the same active ingredient(s) but of different salts, different strength, dosage form and proprietary or brand name.
1.4.1 Classes of Applications
Applications shall be classified into three (3)
• New Applications
• Renewal of applications (i.e., registration)
• Variation of Applications ( i.e., of a registered product )
1.4.2 New Applications
Applications for the registration of a pharmaceutical product either submitted to the Director General NAFDAC and copy the Director Registration and Regulatory Affairs Directorate for the granting of market authorization. In addition to the dossier submitted, the applicant shall provide:
ຂ້າພະເຈົ້າ. A site master file of the plant in which the product was manufactured. (submitted in Module 3)
ii. For NCEs and innovator products the pharmacovigilance plan shall be submitted. (Submitted in Module 1.2.8 (PSURs).
1.4.3 Applications for Renewal of Registration
Applications for renewal of registration shall be made at least 3 months before the expiry of existing registration and shall follow the “Guidelines for the Renewal of Marketing Authorisation Licence for a
Pharmaceutical Product”
1.4.4 Application for Variation of a registered product
Applications for variation to a registered product shall be made according to requirements “NAFDAC
Variation Guidelines”
1.5 SUBMISSION OF APPLICATION
Applications for the registration of products for market authorization shall be made to NAFDAC. For products meant for marketing authorization in a specific country, the application shall be sent to the Head of the NMRA in that country.
1.6 APPLICATION FEES
Application fees shall be paid for each application submitted. -This shall be as per the approved NAFDAC tariff.
Others may be charged by various country MRAs as their legislation requires.
1.8 TIMELINES
Complete applications for expedited registration (Locally manufactured and Priority Medicines only), Post Approval Variation and Renewal of registration will be processed within 90 working days of receiving the applications. Complete new applications will be processed within 12 months of receipt of the application. The applicant will be required to provide any requested additional data within 6 ເດືອນ.
In case additional time is required, a formal request must be submitted.
1.9 WITHDRAWAL OF AN APPLICATION
When the applicant fails to submit written responses to queries within 6 months from the date of their issuance, it will be deemed that the applicant has withdrawn the application or if the queries have been reissued for a second time and the applicant provides unsatisfactory responses, the product will be disqualified and the application will be rejected. The applicant will be required to apply afresh.
1.10 VALIDITY OF REGISTRATION
The registration of a pharmaceutical product shall be valid for five (5) years unless otherwise suspended or revoked by NAFDAC, or withdrawn by applicant.
1.11 APPEALS
Any person aggrieved by a decision in relation to any application for marketing authorization of a pharmaceutical product may within two (2) months from the date of notice of the decision, make representations in writing to NAFDAC and submit additional data to support the appeal.
Documentation in support of the manufacturer’s request to appeal a regulatory decision is placed in Module 1.1.5 of the CTD.
1.1.5 of the CTD.
Quality Templates
Bioequivalence Template
2. Biowaiver Application Form ( BAF )
Labelling Templates
3. NAFDAC Label Template
Administrative Templates
[1] The term “complicated FPP” includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under “complicated FPP” include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin.
ຂັ້ນຕອນຕໍ່ໄປ?
The foregoing ໃຫ້ພຽງແຕ່ສະພາບລວມແລະບໍ່ໄດ້ຢູ່ໃນວິທີການໃດປະກອບໃຫ້ຄໍາແນະນໍາທາງດ້ານກົດຫມາຍ. ຜູ້ອ່ານຈຶ່ງໃຫ້ຄໍາແນະນໍາທີ່ຈະໄດ້ຮັບການຊີ້ນໍາເປັນມືອາຊີບສະເພາະໃດຫນຶ່ງ.
ກ່ຽວກັບ LEX ຈິດຕະນາການ LLP
Lex ຈິດຕະນາການ LLP, ທຸລະກິດແລະບໍລິສັດກົດຫມາຍວ່າດ້ວຍການຄ້າໃນໄນຈີເລຍ, ແມ່ນປ່ອງຢ້ຽມສໍາລັບຜູ້ຜະລິດ, ຜູ້ສົ່ງອອກ, ແລະຈໍາຫນ່າຍສະບຽງອາຫານແລະຢາເສບຕິດກໍານົດລະບຽບຜະລິດຕະພັນກໍາລັງຊອກຫາອະນຸຍາດໃນໄນຈີເລຍແລະກໍາລັງຊອກຫາການເຂົ້າເຖິງຕະຫຼາດຂອງໄນຈີເຣຍ. ພວກເຮົາແມ່ນຮ້ານຫນຶ່ງຢຸດສໍາລັບ ປະຕິບັດຕາມຢ່າງລະອຽດກົດຫມາຍບໍລິການໃນໄນຈີເລຍ. ພວກເຮົາໃຫ້ລູກຄ້າມີ ຄຳ ແນະ ນຳ ດ້ານກົດ ໝາຍ ຜ່ານທຸກໆບາດກ້າວຂອງຂະບວນການຄ້າແລະນອກ ເໜືອ ຈາກ.
ເພື່ອຮຽນຮູ້ເພີ່ມເຕີມກ່ຽວກັບອາຫານທີ່ Lex ຈິດຕະນາການ LLP ຂອງ & ຢາ (F&D) ຝ່າຍຊ່ວຍເຫລືອດ້ານແລະວິທີການທີ່ພວກເຮົາສາມາດສະເຫນີໃຫ້ຜູ້ແທນເຂົ້າຮ່ວມທ່ານໃນໄນຈີເລຍ, ກະລຸນາສົ່ງອີເມວຫາ: lexartifexllp@lexartifexllp.com; ໂທ +234.803.979.5959.
