上海CMC培训 Common and Challenging CMC Queries from Regulatory Authorities.ppt

1、1,Common and Challenging CMC Queries from Regulatory Authorities,Ganapathy Mohan, Ph.D Merck Sharp and Dohme Corp., AAPS/CPA CMC Workshop endorsed by SHFDA Quality, Regulatory, Scientific requirements and Strategies Shanghai, China, PRC 28 -29 June 2010,GM: AAPS-CPA 6/10,2,Discussion Topics,Type of

2、filings Why do Health Authorities raise questions? Areas of questions Examples of queries from Health Authorities How do we prepare to address these? Conclusions,GM: AAPS-CPA 6/10,3,Typical Filing Types,Clinical/Development Phase -IND/CTA/IMPD Registration-NDA/WMA Post- approval filings -Varied base

3、d on the change,GM: AAPS-CPA 6/10,4,Reasons for regulatory queries,Clarity of justifications/data interpretations Missing data/information Challenging the assumptions/projections eg: shelf-life calculations Setting specifications Overall control strategies Assurance that Quality, Identity, Strength

4、and Purity are met,All geared towards achieving PATIENT SAFETY,GM: AAPS-CPA 6/10,5,Some of the common areas of queries,Stability Related Impurities/Degradation Specifications Genotoxic Impurities Validation/Qualifications Shelf-life projections Dissolution- BA/BE adequacy,GM: AAPS-CPA 6/10,6,Origin

5、of questions,GM: AAPS-CPA 6/10,7,Typical range of agency questions,Conformation to the guidance Potential impurities that could be formed based on the presented synthetic route Screening of raw materials/reagents used Limits used and justification Stability protocols/shelf-life projections Process v

6、alidations Phase of development,8,Development Phase Questions,GM: AAPS-CPA 6/10,9,General Topics Early Phase,General questions relating to PGIs are increasing at very early stages in development Phase I: Germany: The sponsor should clarify the origin of media fills and demonstrate compliance with th

7、e TSE-Guidelines if necessary Phase II: France: Concerning the final product - the diluted solution must be used immediately although its physicochemical stability was shown during 24h at a temperature not exceeding +25C,GM: AAPS-CPA 6/10,10,General Topics - CTA,Phase II: Czech: The final product sp

8、ecifications include a pharmacopoeia limit for sub-visible particles set only for the filtered product. The amount of particles in the non-filtered product is only listed for information which is not acceptable. We ask for modification of the limit so that even the non-filtered solution conforms to

9、the requirements of the USP Inhalation: Czech: the designated starting material contributes a significant portion of the drug substance structure and is only two synthetic steps away from the final product. Accordingly, you should justify why XXX should be considered a “starting material” rather tha

10、n an “intermediate” in the scheme to form the drug substance,GM: AAPS-CPA 6/10,11,General Topics Phase III,Hungary: Specifications of starter substances used for agent synthesis (with special regard to the starter substance Compound XX that could contain genotoxic contamination Peru: The health Auth

11、orities are requesting inclusion of average weight of the tablet in COA for the investigational medicinal product SFDA: DS manufacture technique: There are 7 chiral centers in the DS. Step X is critical for chiral reaction of the final product, where the high stereo-specificity Diels-Alder cyclizati

12、on reaction happens. Please additionally describe the principle and quality control methods of this chemical reaction in this step, as well as the controllability of the stereo-specific structure SFDA: Please explain why only 9-epimer and 6-epimer were studied, may other epimers be produced, is it n

13、ecessary to control them, and can other potential isomers be detected in this chromatographic conditions?,GM: AAPS-CPA 6/10,12,General Topics Phase III,SFDA: There are several chiral centers in the DS, so it is suggested to adopt multiple means like X-ray single crystal diffraction and describe the

14、absolute structure of this product in combination of the process. Please provide the detailed research materials of the crystal form study and describe the batch consistency of this products crystal form Sweden: Unless otherwise justified, either a “conforms to reference standard” specification shou

15、ld be set or a discriminating specification should be introduced, allowing for an evaluation of any trend in the impurity profile between batches and of any degradation upon storage,GM: AAPS-CPA 6/10,13,General Topics Phase III,Caps: US: Provide a summary of qualitative results on purification attem

16、pts made to reduce the residual levels of XXX and reduced XXX in the product Caps: US: Please discuss your residual solvent specifications in the context of ICH Q3C Caps: Spain: the proposed limit of NMT 0.10% for individual unknown impurities of groups A and B is not compliant with the ICH limits f

17、or a daily dose of more than 2g/day. Additionally, no unknown impurities above 0.05% have been observed in all recent batches reported. Therefore, the Company should consider the feasibility of a restriction on this limit Czech: We require submission of results of compatibility/stability of the medi

18、cinal product after dissolution in infusion bags at room temperature,GM: AAPS-CPA 6/10,14,General Topics - Registration,MDI: EMA: Analytical methods used during the in-process control should be specified and validated, if applicable MDI: EMA: Add a lower acceptance criterion to the specification for

19、 the throat and mouthpiece adaptor stage grouping, since the mass of drugs deposited on this stage grouping is substantial and it should be consistent Suspension: Japan: Taking into account that the mean particle size of the DS is 3.0 to 5.5 micron please provide an explanantion of the particle size

20、 distribution of particles _10 micron and explain that the formulation change does not affect the uniformity of the DS Some MOW/ROW countries requesting seemingly unnecessary information/data, such as Chromatograms from each time point for every batch on stability,GM: AAPS-CPA 6/10,15,General Topics

21、: post-approval,MOW/ROW countries insisting on CTD formatted responses/renewal information for legacy products not yet converted from “old” format to CTD Keeping in-line/legacy products up to todays standards (impurities, degs, stability studies/ and requirements, “original” signatures required on d

22、ocumentation, etc., Many MOW/ROW countries have increasing requirements for legacy products that may not be available (level of detail, technical information) Very short deadlines within MOW/ROW countries for responding to Health Authority questions,GM: AAPS-CPA 6/10,16,Stability,CTA: Recently some

23、EU countries have asked for the stability data supporting any shelf-life extension to be submitted in advance of CT material use (Spain in particular) WMA: Additional site specific stability requested by many MOW/ROW countries beyond that included in MOW/ROW Dossier (eg: full shelf-life data on full

24、 scale batches from the commercial site) Post- approval: In-use studies being requested (eg: dermatological products with pumping mechanisms, liquids with droppers or spoonula devices, etc.,),GM: AAPS-CPA 6/10,17,Stability Clinical Trial Applications,The proposed shelf-life of the DP must not exceed

25、 the maximum time of available data The proposed 30 months shelf life will only be approved following submission of data for 18 months Provide chromatograms Provide additional data (supportive studies, stability at longer times) 24 months stability data at 25C/60%RH was submitted to support 36 month

26、s at 15-25C; provide accelerated stability results The proposed impurity levels are not justified,GM: AAPS-CPA 6/10,18,Stability Published Information,For EU marketing Applications* 2 Major objections from 3.2S.7 (13 total MOs) Lack of identification/investigation of degradation products 4 Major obj

27、ections from 3.2.S.8 (19 total MOs) Data regarding the stability of the drug product and not plausible/not reliable Issues around color development not fully justified Significant decrease in the assay values at accelerated conditions 32% of the concerns regarded lack of data submitted by the applic

28、ant to substantiate the proposed shelf-life of the drug product JJ Borg et al; J Pharm Pharmaceutic Sci 12(2) 181-198, 2009. (52 marketing authorization applications evaluated),GM: AAPS-CPA 6/10,19,API: Clinical Trial Applications,Requirement to supply additional CoAs for DS in some EU and MOW/ROW c

29、ountries Method validation information/data being requested at earlier stages of development than previously seen in some EU and MOW/ROW countries ICH impurity requirements sometimes requested at very early stages of development (eg: Phase I) within the EU, particularly Spain and Portugal also Czech

30、 Republic,GM: AAPS-CPA 6/10,20,API: Marketing Applications,Increasing level of detail being requested by many MOW/ROW Health Authorities (overall) EU: Will not accept cross-referrals to existing DS information within approved MAs if DS being used for line extensions, etc., - EMA have required all ex

31、isting information be included in a full MAA in CTD format or have agreed to a post-approval commitment to do so Exceedingly large amount of detail requested by South Korea for the PAI, beyond WMA/ “full” dossier content,GM: AAPS-CPA 6/10,21,Drug Product: Clinical Trial Applications,Additional requi

32、rements to supply CoAs for DP in some EU and MOW/ROW countries Method validation information/data being requested at earlier stages of development than previously seen in some EU and MOW/ROW countries Challenges to the impurity specifications at earlier stages of development (EU and Canada) Confirm

33、porcine-free excipients/dry product for Middle East countries (in particular) US: DP tests should include a test for reconstitution time with suitable limit,GM: AAPS-CPA 6/10,22,Drug Product: Marketing Applications,Increasing level of detail being requested by MOW/ROW health Authorities (overall) EM

34、A: Discriminatory Dissolution Method must be utilized Confirm porcine-free excipients/drug product for Middle East countries (in particular) Site specific stability, full scale at the commercial site being requested by many MOW/ROW countries MOW/ROW requests for full PV information, not summary repo

35、rt(s) Spain: The applicant is reminded that in Europe the assay specification at release is 95-105% unless otherwise justified,GM: AAPS-CPA 6/10,23,Drug Product: post-approval changes,For Sterile products: FDA requesting addition of Sterility and Bacterial Endotoxin testing at additional intervals f

36、or post-approval Stability Protocols; FDA has also been requesting CCI to potentially replace sterility testing Question relating to confirmation of porcine-free excipients/drug product for Middle East countries (in particular) MOW/ROW requests for accelerated data for refrigerated products (40/60 o

37、r even 40/75),GM: AAPS-CPA 6/10,24,Drug Product: post-approval changes,Asia-Pacific countries: Requests for very specific analytical test results and details, eg: copies of notebook pages showing plant water quality (eg: results of Purified Water tested on the day of DP batching) Asia-Pacific countr

38、ies questioning compendial testing requests to provide copies of internal SOPs/procedures and copies of the applicable compendial pages,GM: AAPS-CPA 6/10,25,General Topics IV formulations,Phase 1b: Germany A request for information on any non-compendial sterilization methods used for preparing the v

39、ials and stoppers A request to describe the suitability of the analytical methods with validation summary and confirm the compliance to the ICH guideline Phase II: France: The evaluation of the pharmaceutical data to provide data quality on the comparability of the product manufactured starting from

40、 the sites: A to another site B. Indeed, these two sites are proposed in the IMPD to realize the operations of purification Phase III: US: The identification test in the DP specification based only on HPLC retention time is inadequate (ICH Q6A) Registration: Japan: Purity test of the drug product (d

41、egradation product): Please establish a section on system repeatability for the system suitability test in accordance with JP,GM: AAPS-CPA 6/10,26,Process Validation (PV),CTA: Additional sterile PV questions/data requested for sterile products at very early stage in development beyond the sterile PV

42、 data provided in CTA (Phase I) WMA: DS PV data requested for non-sterile DS processes (MOW/ROW countries),27,Genotoxic Impurities,GM: AAPS-CPA 6/10,28,Agency Questions - GTI,Provide information on the actual level of the potential genotoxic degradant, (Epoxide Degradate) in the clinical drug substa

43、nce batch. You should either limit the amount of this impurity such that the daily dose of the impurity would be not more than 1.5 g/day or demonstrate that it is negative when tested directly with in-vitro genotoxicity assays (i.e., an in-vitro bacterial reverse mutation assay and either an in-vitr

44、o cytogenetic assay in mammalian cells or an in-vitro mouse lymphoma tk assay (with colony sizing). (US),GM: AAPS-CPA 6/10,29,Agency Questions - GTI,- Health authority identified 2 structural alerts (, unsaturated ketones) in impurity. - The maximum dose of XXX supported is 11 mg/day such that RRT 1

45、.05 does not exceed 60g/day. - The 800mg dose of XXX in the proposed DDI study would result in 4,320g/day of RRT 1.05. (US),GM: AAPS-CPA 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)

46、Please provide a certificate supported by your own or literature data which is to confirm that the possible allile-bromide impurity of the active compound cannot be considered genotoxic in vivo (Hungary),GM: AAPS-CPA 6/10,31,Agency Questions - GTI,Submit a discussion on the potential genotoxic struc

47、tures that may occur during the manufacturing process and the carry-over 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 (e.g. methyl mesilates, ethyl mesilates). Where applicable, the co

48、ntent of any alkyl mesilates in the active ingredient must be specified and tested (Germany),GM: AAPS-CPA 6/10,32,Agency Questions - GTI,Certify that the active substance is in compliance with CPMP/SWP/8199/02, EMEA/CHMP/QWP/251344/2006 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 incoming RM or