Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle Management FDA s Perspective

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1 Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle Management FDA s Perspective Susan Rosencrance, Ph.D. Director, Office of Lifecycle Drug Products Office of Pharmaceutical Quality/CDER/FDA November 16, 2016 Symposium Session AAPS 2016

2 Drug Product Lifecycle Management OPQ s Role 2

3 OPQ Focused on Drug Product Quality Strategically organized to streamline regulatory processes and focus on product quality Integrates functional areas for more informed decision making Emphasizes a lifecycle approach to drug quality using knowledge management 3 3

OPQ Immediate Office Director: Michael Kopcha Deputy Director: Lawrence Yu Office of Program and Regulatory Operations Director: Giuseppe Randazzo Office of Policy for Pharmaceutical Quality

4 OPQ Immediate Office Director: Michael Kopcha Deputy Director: Lawrence Yu Office of Program and Regulatory Operations Director: Giuseppe Randazzo Office of Policy for Pharmaceutical Quality Director: Ashley Boam Office of Biotech Products Director: Steven Kozlowski Office of New Drug Products Director: Sarah Pope Miksinski Office of Lifecycle Drug Products Director: Susan Rosencrance Office of Process and Facilities Director: Robert Iser Office of Surveillance Acting Director: Sarah Pope Miksinski Office of Testing and Research Director: Lucinda Buhse

5 OPQ s Lifecycle Management Approach The Office of Lifecycle Drug Products (OLDP) generally leads the quality assessment of post-approval changes for generic and brand products and serves as the centralized home office*; inter-office collaborations occur where appropriate The Office of Process and Facilities (OPF) plays a key role in evaluating the need for inspection of manufacturing sites and makes the final site recommendation; performs a quality assessment of microbiological aspects; provides a quality assessment when complex manufacturing technologies/processes are involved. * After the NDA transitions from the Office of New Drug Products (ONDP). 5 5

6 Why OLDP? Centralizing the long-term lifecycle management function within a single OPQ sub-office has a number of benefits: Provides a uniform, consistent approach to postapproval changes (ANDA success story); promotes parity in the regulatory oversight of brand and generic drug products Provides a home-office that makes it easily manageable for all stakeholders (note: transition period for NDA supplements) 6 6

7 Why OLDP (cont.)? OPQ s major stakeholders (e.g., Office of New Drugs, Office of Generic Drugs, Industry) know who to contact when questions arise Agency receives approximately 5,000 supplements annually; need a system that can handle highthroughput efficiently; a centralized home office provides the right environment Reference: Susan M. Rosencrance and Geoffrey K. Wu, Advancing pharmaceutical quality oversight during the lifecycle of generic drug products, Journal of Generic Medicines, Oct

8 CMC Enablers or Tools for Drug Product Lifecycle Management 8

9 CMC Enablers or Tools for Drug Product Lifecycle Management The Post-Marketing Phase Supplements I. Comparability Protocols II. Post-Marketing Commitments/ Requirements 9

I. Comparability Protocols The regulations provide for protocols as an optional way to manage post-approval changes [21CFR 314.70(e) and 21 CFR 601.12(e)].

10 I. Comparability Protocols The regulations provide for protocols as an optional way to manage post-approval changes [21CFR (e) and 21 CFR (e)]. A comparability protocol can be used to implement a CMC post-approval change. A Comparability Protocol is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity, strength, quality, purity, and potency of a drug product or a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality). = Agency definition in draft guidance published April

11 I. Comparability Protocols Basic Facts Comparability Protocols can be submitted in original applications (NDAs, ANDAs, BLAs) and in supplements to these applications. Comparability Protocols allow the Agency to review and assess the: 1. Description of one of more proposed post-approval changes; 2. Supporting information including any analyses and risk assessment activities; 3. Plan for implementing the change; and 4. Proposed reduced reporting category for the change, if appropriate. 11

I. Comparability Protocols Basic Facts Agency approval of the

applicant with an agreed-upon plan to implement the change.

product lifecycle management because they enable a proactive approach

12 I. Comparability Protocols Basic Facts Agency approval of the submission containing the comparability protocol provides the applicant with an agreed-upon plan to implement the change. Comparability protocols facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution, and promote continuous improvement. 12

I. Comparability Protocols Comparability Protocols - Chemistry, Manufacturing, and Controls Information

Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research

Drugs and Biologics: Chemistry, Manufacturing, and Controls Information (CDER) Center for Biologics

13 I. Comparability Protocols Comparability Protocols - Chemistry, Manufacturing, and Controls Information Guidance for Industry DRAFT GUIDANCE U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) February 2003 Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information Guidance for Industry DRAFT GUIDANCE U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April

protocols associated with NDAs since 2007 Results show 106 comparability protocols submitted

14 I. The NDA Experience with Comparability Protocols The Agency has significant experience with comparability protocols in NDAs (original submissions and supplements) Survey of comparability protocols associated with NDAs since 2007 Results show 106 comparability protocols submitted in 55 NDAs; all approved % How submitted? 76 72% In an original NDA As a PAS 14

I. Comparability Protocols NDA Experience 2 4% 1 2% 1 2%

Tablets/Capsules Topical Cream/Ointment/Gel/Lotion

15 I. Comparability Protocols NDA Experience 2 4% 1 2% 1 2% 1 1 2% 2% 1 2% Dosage Form Distribution IR Tablets/Capsules/ODT Injections; Solutions/Powder 6 11% 8 14% 24 43% Inhalation; Powder/Solution DR/ER Tablets/Capsules Topical Cream/Ointment/Gel/Lotion Ophthalmic Oral Liquid Oral Suspension 10 18% Suspension Transdermal 15

16 I. Comparability Protocols NDA Experience 10 9% 32 30% 3 2 3% 2% 6 6% 53 50% Change Type Distribution Manufacturing Site Manufacturing Process Container/Closure Components/Composition Specifications Miscellaneous 16

without CP 2 2% 4 4% 13 12% 13 12% 69 65%

17 I. Comparability Protocols NDA Experience 5 5% Reporting Category Distribution without CP 2 2% 4 4% 13 12% 13 12% 69 65% PAS CBE 30 CBE 0 AR Not Specified NA Reduced Reporting Category Distribution with CP 23 22% 16 15% 1 1% 6 6% 6 5% 54 51% Legend NA: CP contains comparability report or changes beyond CP scope Not Specified: Proposed multi reporting categories or subject to regulation changes 17

18 Case Study Example NDA x Solid Oral Tablet S-x (PAS) A comparability protocol for managing postapproval design space changes. Synopsis of Comparability Protocol: Provided for specific design space changes resulting from equipment changes or modifications. Used for changes to multiple design spaces at one time as long as the design spaces did not interact If any proposed change resulted in a change to a CQA (critical quality attribute) acceptance criteria, the proposed change was out of protocol scope. Defined the experiments, testing, acceptance criteria, and regulatory reporting strategy based on the specific proposed change 18

19 Case Study Example (cont.) Synopsis of Comparability Protocol (cont.): Defined the data to be included for the post-approval change Experimental Design and Results (e.g., conditions, in-process control results) Additional testing results from increased sampling plan Product CQA testing results for impacted CQAs Revised design space limits Changes to parameter criticality (if applicable) Stability results/stability commitment Regulatory Filing Strategy: Design Space change for Critical Process Parameter (CPP) CBE-30 Design Space change for non-critical Process Parameter CBE-0 Site addition as part of a change to the Design Space (with inspection history) CBE-0 S-x (PAS) - Approved August

20 I. The ANDA Experience with Comparability Protocols Limited experience with comparability protocols in ANDAs; just getting started with the issuance of the April 2016 draft guidance. Survey results show: 122 comparability protocols submitted in 44 ANDAs 2 comparability protocols submitted in 2 supplements All submitted comparability protocols are under evaluation and none have been approved yet. 20

21 I. Comparability Protocols ANDA Experience 2, 5% 2, 5% 1, 2% 1, 2% 1, 2% Dosage Form Distribution IR Tablets/Capsules/ODT ER/DR Tablets/Capsule 3, 7% 5, 11% 23, 52% Injections ( solutions/powder) Oral liquid Inhalation Sublingual Film Transdermal 6, 14% Ophthalmic Vaginal Ring 21

22 I. Comparability Protocols ANDA Experience 6, 5% 3, 2% 2, 2% Change Type Distribution Container/Closure System (CCS) 17, 14% 17, 14% 27, 22% 11, 9% CCS and Packaging site Drug Substance Source Manufacturing Site (drug product) Manufacturing Site (drug substance) Testing Facility 19, 16% 20, 16% In-Process Test Removal Manufacturing Process Components and Composition 22

23 I. Comparability Protocols ANDA Experience Reporting Category Distribution without CP 1, 1% Reduced Reporting Category Distribution with CP 0, 0% 14, 12% 43, 35% PAS CBE 30 34, 28% 64, 52% CBE 0 AR 64, 52% 24, 20% 23

24 I. Comparability Protocols Points to Consider when submitting a comparability protocol: 1. Firms are expected to employ: Effective use of knowledge and understanding of the product and manufacturing process A robust control strategy Risk management activities over a drug product s lifecycle An effective pharmaceutical quality system 2. Protocols should contain application/product specific information (e.g., specifications, specific routine and non-routine tests) to demonstrate equivalency before and after the proposed change(s). 3. Typically one level downgrade for the reporting category is permitted. 24

25 I. Comparability Protocols Points to Consider when submitting a comparability protocol (cont.): 4. Adding a new drug substance source (i.e., new DMF to the application) is inappropriate for comparability protocols. 5. Changes requiring new clinical or bioequivalence studies/data are inappropriate for comparability protocols. 6. Draft Guidance for Industry Comparability Protocols for Human Drugs and Biologics: CMC Information (April 2016) provides our current thinking. 25

I. Comparability Protocols NDAs vs ANDAs NDAs ANDAs Regardless of application type (NDA or ANDA), the science and associated risks are the same. Same/similar rules apply (e.g., regulations, policies, guidance, guidelines, etc.

26 I. Comparability Protocols NDAs vs ANDAs NDAs ANDAs Regardless of application type (NDA or ANDA), the science and associated risks are the same. Same/similar rules apply (e.g., regulations, policies, guidance, guidelines, etc.) Same documentation and supporting information should be provided, commensurate with the product complexity and associated risks. Long historical practice; protocols have been submitted and reviewed since 2003 Generally the protocols contain good supporting information and are specific Little historical practice as applicants often asked to withdraw protocol; just starting to review protocols Typically too general; lack of information to demonstrate product and process understanding; lack of risk assessment 26

27 CMC Enablers or Tools for Drug Product Lifecycle Management The Post-Marketing Phase Supplements II. Post-Marketing I. Comparability Commitments/ Protocols Requirements 27

28 II. Post-Marketing Commitments/Requirements Under the regulations post-marketing requirements (PMRs) and post-marketing commitments (PMCs) refer to studies and clinical trials conducted after approval. They are agreed upon between the applicant and the Agency and are intended to further refine the safety, efficacy, or optimize use of the drug to ensure consistency and reliability of product quality. The regulations only apply to NDAs/BLAs, and not ANDAs 28

29 II. PMCs vs PMRs The Difference PMCs Studies or clinical trials a sponsor has committed to conduct, but that are not required by a statute or regulation PMRs Required studies and clinical trials under one or more statutes or regulations 29

30 II. When a PMR is Involved The review issue, safety risk, and goal of the study/clinical trial is documented. A timetable for completion is established. There are periodic reports on the status of the study/clinical trial The PMR may occur at the time of approval or after approval if the Agency becomes aware of new safety information. 30

31 Case Study Example PMR for Drug Product x Reason for PMR: The issue of foreign contamination was not permanently resolved at the time of BLA approval. A test/acceptance criteria for particulates was implemented to mitigate the risk for contamination of commercial batches, but alleviation via a specification was not considered a complete solution (i.e., no foreign contamination should be present). The applicant was required to perform a complete evaluation of foreign matter contamination for the intermediate and drug substance to prevent use in drug product manufacturing if contamination was present. 31

32 Case Study Example (cont.) To fulfill the PMR the applicant submitted quarterly reports as required and provided a final summary with all required information on April 30, 2015 On June 1, 2016 the Agency sent a PMR fulfillment letter to the applicant. 32

33 The Importance of Drug Product Lifecycle Management 33

34 The Importance of Drug Product Lifecycle Management OPQ brings new opportunities through its emphasis on a lifecycle approach to drug product quality. 34

35 The Importance of Drug Product Lifecycle Management The new paradigm in OPQ allows for: Clearer identification of product risks for more informed decision making Quickly addressing quality problems Overall efficiency improvements Greater parity in the regulatory oversight and quality assessment of brand and generic drugs Reduced regulatory oversight and increased operational flexibility in the commercial manufacturing phase 35

36 The Importance of Drug Product Lifecycle Management Patients Regulators Industry Everyone Benefits! Good lifecycle management in the postmarketing phase results in a continuous supply of quality drug products 36 36

37 Acknowledgments Geoffrey Wu Hasmukh Patel Hardikkumar Patel* Akshata Nevrekar* Xue Li* * ORISE (Post-doctoral) Fellows 37

Evolution of the CMC Review - ANDAs

Evolution of the CMC Review - ANDAs Susan Rosencrance, Ph.D. Director (Acting), Office of Lifecycle Drug Products Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research October 6,