Evolution of the CMC Review - ANDAs

Transcription

1 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, 2015 PQRI

2 Historical Perspective

3 Historical Perspective 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) Promoted the manufacture of generic drugs less costly versions of brand drugs with no patent protection Established a system of government regulations for generic drugs and authorized the FDA to accept ANDAs A critical option to ensure all Americans have access to healthcare! 3

4 Cheaper does not mean lower quality!!! Same Quality Standards Active ingredient Strength Dosage Form Route of Administration Use of Indication Same Batch Requirements (identity, strength, purity, quality) Bioequivalent Manufactured under cgmp regulations Same CMC (Quality) Review Process Chemistry Manufacturing Quality Control Measures/Testing Labeling Inspection Bioequivalence (rather than animal, clinical, bioavailability studies) Pharmaceutical Equivalence (same patient expectation and experience) 4

5 Generic manufacturers are not required to repeat the costly clinical trials of new drugs and don t pay advertising, marketing, and promotion costs Multiple generic firms are often approved to market a single product, thus creating market competition lower costs 5

6 Past Practices in CMC Review of ANDAs In the past, conventional drug product manufacturing had many uncertainties To ensure product quality, FDA controlled every aspect through testing Quality by Testing (QbT) approach to CMC Review QbT Framework Pharmaceutical Quality = Drug Meeting Regulatory Specifications Excipient Testing Drug Substance Testing Fixed Manufacturing Controls In-process Material Testing End-Product Testing 6

7 Limitations to QbT 1. The review was essentially the same for all dosage forms 2. Little emphasis placed on linking product quality attributes to clinical performance 3. Many problems related to specifications being too rigid Product failing specifications had to be discarded Clinical performance may have been acceptable, but no link to the patient had been established 7

8 Limitations to QbT 4. During CMC Review little to no attention was given to how the formulation or manufacturing process was designed 5. Supplements had to be filed for nearly all changes (specification, process parameter, etc.) Depleted FDA resources Discouraged manufacturing process improvements, innovation, and new technologies 8

9 Time for Change Early 2000s Pharmaceutical quality is redefined FDA s Pharmaceutical Quality for the 21 st Century Initiative ICH Q8, Q9, & Q10 Quality by Design (QbD) Pharmaceutical quality is a product that is free of contamination and reproducible, delivering the therapeutic benefit promised on the label to the consumer. Product Quality Clinical Performance Dr. Janet Woodcock Quality cannot be tested into products; quality can only be built into products. QbT QbD 9

10 The Impact of QbD QbD is a systematic approach to development that begins with predefined objectives, and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8(R2)) Under QbD pharmaceutical quality is assured by understanding and controlling the formulation and manufacturing variables Specifications now established based on product knowledge and process understanding; not based on empirical testing of limited batches 10

11 The Impact of QbD To implement QbD principles and concepts, Question-based Review (QbR) was developed for the CMC review of ANDAs Today it is expected that QbD principles are applied during the development of all generic drug products Across the board agreement that QbD enhanced the quality of generic drugs Still work to be done to realize maximum benefit 11

12 Additional Drivers for Change

13 #1 GDUFA 5-Year Program Implemented on October 1, 2012 FDA committed to reducing the backlog of ANDAs and meeting goal dates 10-month review cycle for 90% ANDAs by GDUFA Year-5 (FY-2017) Challenge: More ANDA receipts than expected GDUFA Year 1 (FY-2013) 28% more GDUFA Year 2 (FY-2014) 50% more 13

14 Big Question (?) How to enhance the efficiency and effectiveness of CMC review while ensuring patients receive quality generics. 14

15 Formalized a Risk Management Approach - Spring 2014 Designed specifically for the CMC review process Risk ranking of the drug product CQAs using a quantitative scoring algorithm; prospectively flags risk and provides a starting point for the review Focuses reviewers and helps allocate resources based on product risk and patient impact Ensures high risk areas receive appropriate scrutiny; streamlines the review of lower risk areas 15

16 Formalized a Block Review Approach - Summer/Fall 2014 Block Review Grouping CMC review assignments to a single team of reviewers Employed when multiple ANDAs reference a single RLD Triggered by 3 of more ANDAs Focuses expertise, accelerating the review process Eliminates the need to relearn Promotes consistent and improved decision making 16

17 Implemented Real-Time Communication Fall 2014/Spring 2015 Found historical communication practice to be inherently inefficient and ineffective as it promoted review cycles (see graph) Recognized the need for real-time communication with industry to achieve timely ANDA approvals of quality generics Maximized the use of Information Requests and T-cons while working with OGD to meet Target Action Dates (TADs) Driving the CMC review process towards a more efficient 1- cycle review system. 17

18 Data from Complete Response Letters in FY-2013 and FY-2014 Approx. 70% Information Requests Prepared by Geoffrey Wu

19 19 Historical Data on Cycles to ANDA Approval (AP or TA) Prepared by Yuexia Li

20 20 The 6-Month Impact of Real-Time Communication Prepared by Glen Smith

21 21 Current Status of Backlog and GDUFA Year-1 (FY-2013) and Year-2 (FY-2014) ANDAs Prepared by Yuexia Li

22 #2 Reorg CDER s Office of Pharmaceutical Quality (OPQ) January 11, 2015 A single unit in CDER dedicated to drug product quality (new drugs, generic drugs, OTC drugs) Strategically organized to align review, inspection, and research functional areas ANDA review is matrixed across OPQ sub-offices, mainly residing in ONDP, OLDP, and OPF 22

23 Reorganization OPS OGD Chemistry and Micro (CMC) OPQ 23

24 OPQ Immediate Office Office of Program and Regulatory Operations Office of Policy for Pharmaceutical Quality Office of Biotech Products Office of New Drug Products Office of Lifecycle Drug Products Office of Testing and Research Office of Surveillance Office of Process and Facilities

25 Moving Forward The Integrated Quality Assessment

26 The Integrated Quality Assessment OPQ is organized based on discipline and expertise to keep pace with the increasing complexity of drug products and manufacturing processes Matrixing the ANDA review across OPQ enhances interactions, communication, and consistency Ensures the same quality standards are applied fairly and consistently to both brand and generic products imparting parity in the regulatory oversight 26

27 The Integrated Quality Assessment Under OPQ a team-based approach is used to perform the quality assessment of an ANDA based on risk management principles Currently the integrated quality assessment approach is being used for ANDAs submitted in GDUFA Year-3 (FY-2015). 27

28 The Integrated Quality Assessment The team consists of: drug substance experts drug product experts process experts facility experts (including ORA investigators) other technical advisors as needed Application Technical Lead (ATL) - oversees the technical content Business Process Manager (BPM) - manages the process 28

29 The Integrated Quality Assessment (IQA) The team produces a single collaborative integrated quality assessment (IQA) that provides a recommendation on ANDA approvability to OGD 29

30 Benefits of the New Paradigm Integrating quality review with inspection means: Informed Decision Making Facility Acceptability Application Approvability 30

31 Benefits of the New Paradigm Knowledge sharing and a comprehensive lifecycle approach to quality is emphasized OPQ organization Matrixing of review across sub-offices Integrated Quality Assessment Knowledge about quality issues gained from review of the brand product can be appropriately applied to the review of the generic product 31

32 Drug Product Lifecycle Phases (Brand and Generic) ONDP Phase 1 - IND NDA snda Knowledge base of quality issues and potential risks established Transition Period: 1 or 3 years OLDP Phase 2 - snda Knowledge base accumulated during NDA post-marketing and lifecycle monitoring phase OLDP Phase 3 ANDA NDA knowledge base guides ANDA pre-marketing quality assessment OLDP Phase 4 sanda Knowledge base accumulates during ANDA post-marketing and lifecycle monitoring phase

33 Conclusion

34 The CMC Review Continuum Quality by Testing (QbT) Quality by Design (QbD) -Risk-based Review -Block Review -Real-Time Comm. Integrated Quality Assessment (IQA) If we aren t moving forward, we re falling behind - Ronald Volpe - 34

35 The Goal is Drug Product Quality The Agency is committed to adapting and changing its organizational structure and processes to best respond to ongoing challenges Increasing drug product complexity New user fee requirements (GDUFA) Increasing globalization of facilities Drug Shortages Drug Recalls 35

36 Thank You! 36