上海cmc培訓(xùn)commonandchallengingcmcqueriesfromregulatoryauthorities-資料下載頁
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【正文】 ation assay and either an invitro cytogeic assay in mammalian cells or an invitro mouse lymphoma tk assay (with colony sizing). (US) GM: AAPSCPA 6/10 29 Agency Questions GTI ? Health authority identified 2 structural alerts (α, β unsaturated ketones) in impurity. ? The maximum dose of XXX supported is 11 mg/day such that RRT does not exceed 60 μg/day. ? The 800 mg dose of XXX in the proposed DDI study would result in 4,320 μg/day of RRT . (US) GM: AAPSCPA 6/10 30 Agency Questions GTI ? Ensure that alkyl tosylate will not be produced at the end of the synthesis and if necessary eliminate or limit to the TTC (France) ? Please provide a certificate supported by your own or literature data which is to confirm that the possible allilebromide impurity of the active pound cannot be considered genotoxic in vivo (Hungary) GM: AAPSCPA 6/10 31 Agency Questions GTI ? Submit a discussion on the potential genotoxic structures that may occur during the manufacturing process and the carryover to the final API. (Spain) ? Evidence must be submitted that shows that the synthesis of XXX mesylate salt does not yield any potentially genotoxic alkyl mesilates (. methyl mesilates, ethyl mesilates). Where applicable, the content of any alkyl mesilates in the active ingredient must be specified and tested (Germany) GM: AAPSCPA 6/10 32 Agency Questions GTI ? Certify that the active substance is in pliance with CPMP/SWP/8199/02, EMEA/CHMP/QWP/251344/2021 Guideline on the Limits of Genotoxic Impurities. (Hungary) ? Methanesulfonic acid, methanol, and ethanol are used in the manufacture of the starting material. Please provide a justification for not testing ining RM or drug substance for the presence of genotoxic methyl and ethyl methanesulfonate. (US) GM: AAPSCPA 6/10 33 Agency Questions GTI ? Ethyl methanesulfonate and isopropyl methanesulfonate are genotoxic impurities and should be adequately specified and controlled in the drug substance. Validated analytical procedure should be provided. ? In the new synthesis of the starting material “benzyl hydrazine salt” hydrazine is used which is a genotoxic impurity and should be specified and controlled either in the starting material or in the drug substance. Validated analytical procedure should be provided. (US) GM: AAPSCPA 6/10 34 Approaches to control of GTI ? Controlling Genotoxic impurities both during clinical phase and marketed phase is critical ? Developing methods for controlling the GTIs at the early stages of development is quite challenging for a number of reasons (analytical, robustness etc.,) ? Having a clearly defined strategy is important to proactively be prepared to meet the global regulatory requirement GM: AAPSCPA 6/10 35 Conclusion ? Prepare CMC regulatory filings that will ? Ensure pliance with regulatory guidelines ? Ensure ments from internal reviews are addressed ? If clarity is requested/needed by internal reviews then it is quite likely the Health Authorities would ask for it too! ? Ensure deviations from regulatory guidelines are justified and get Agency concurrence ahead of time ? Respond to Agency queries promptly Helps with smooth progression towards approval GM: AAPSCPA 6/10 36 Acknowledgements ? Meg Casais ? Steve Colgan (Pfizer) ? Jeffrey Ding ? Paul Dradransky ? Chaaya Ganorkar ? Carol Thomas
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