1. Implementation of Quality-by-Design: ONDQA Initiatives Advisory Committee for Pharmaceutical Science October 5, 2006 Chi-wan Chen, Ph.D. Deputy Director Office of New Drug Quality Assessment

2. 2 Outline Implementation of QbD in ONDQA Reorganization Pharmaceutical Quality Assessment System CMC Pilot Program Objectives, goal/status, process, criteria, observation to date, benefits/challenges Public meetings Internal trainings Next steps

3. 3 Reorganization ONDC was reorganized to Office of New Drug Quality Assessment (ONDQA) in November 2005 Objective: To implement PQAS Separation of pre-marketing (INDs/NDAs) from post-marketing (supplements/annual reports) review activities to better utilize limited resources Establishment of Manufacturing Science Branch and recruitment of pharmaceutical scientists, chemical engineers, and industrial pharmacists to complement current review staff

4. 4 Reorganization (cont’d) Pharmaceutical Assessment Lead (PAL) in Pre- Marketing Division Serves as liaison to clinical division Performs an Initial Quality Assessment (IQA), a “big-picture” assessment protocol focusing on critical CMC issues, and a timeline for completing the review PAL in Post-Marketing Division Performs a risk assessment to determine the extent of review needed Where in-depth review is needed, performs an IQA focusing on critical CMC issues

5. 5 Pharmaceutical Quality Assessment System PQAS is ONDQA’s new science- and risk- based approach to CMC review that Emphasizes submissions rich in scientific information demonstrating product knowledge and process understanding Focuses on critical pharmaceutical quality attributes and their relevance to safety and effectiveness Enables FDA to provide regulatory flexibility for specification setting and post-approval changes Facilitates innovation and continuous improvement throughout product lifecycle

6. 6 CMC Pilot Program - Objectives To provide participating firms an opportunity to submit CMC information demonstrating application of quality-by-design (QbD) principles product knowledge and process understanding To enable FDA to evaluate CQOS; new concepts and approaches (e.g., QbD, design space, real-time release) in Q8, Q9, Q10, and PAT Guidance; CMC Agreement; team review To enable FDA to seek public input in developing a guidance on the new PQAS

7. 7 CMC Pilot – Timeline/Goal/Status Program timeline FR Notice re CMC Pilot: July 14, 2005 Deadline to request for participation: March 31, 2006 Deadline to submit NDA or supplement: March 31, 2007 Goal: 12 original NDAs and supplements Status 11 original and supplemental NDAs accepted 4 submitted to date One approved; 3 under reivew Others are to be submitted within a year

8. 8 CMC Pilot - Submission Criteria An expanded Pharmaceutical Development (P.2) More relevant scientific information Demonstrating QbD, product knowledge, and process understanding Identifying critical quality attributes (CQAs) and how they relate to safety and effectiveness Linking material attributes and process parameters (CPPs) to quality attributes Identifying possible sources of variability and how associated risks can be mitigated Describing process controls and quality assurance strategies A comprehensive Quality Overall Summary (CQOS)

9. 9 CMC Pilot - Review Process CMC assessment performed by a team of experienced reviewers with good understanding of the new PQAS, and strong background in pharmaceutical and manufacturing sciences Process managed and overseen by ONDQA IO with PM support Integrated review/inspection team Frequent meetings with applicant before submission, during review, and after approval

10. 10 CMC Pilot - Expanded P.2 All pilot NDAs to date provided more scientific information than typical NDAs regarding Formulation and product development Process understanding and optimization Most demonstrated process reproducibility, but not necessarily process robustness The more relevant scientific information is useful in facilitating CMC review and justifying proposed regulatory flexibility

11. 11 CMC Pilot - Application of QbD All pilot NDAs to date contained some elements of QbD: Critical quality attributes (CQAs) Formulation development Risk assessment; design of experiments Impact of DS/excipient attributes on DP manufacturability and/or CQAs Process development; impact of process parameters on CQAs Design space for critical DS/excipient attributes and CPPs Other observations: Process reproducibility, but not necessarily process robustness, demonstrated Process analyzers used to collect data in development, but not for commercial production

12. 12 CMC Pilot - Design Space Issues raised: How were design space and control space established for each unit operation? Is the design space for each unit operation independent of equipment design and batch size? How does control space relate to design space? How does control space relate to operational ranges in the Master Batch Record?

13. 13 CMC Pilot - Regulatory Flexibility Examples of proposed regulatory flexibility: In-process testing in lieu of end-product testing, e.g., blend uniformity in lieu of content uniformity Real-time release in lieu of end-product testing Annual report for post-approval changes within established design space Degree of flexibility granted would depend on level of knowledge and understanding demonstrated

14. 14 CMC Pilot - Regulatory Agreement (under consideration) An agreement between FDA and applicant on critical CMC issues which could potentially Enable applicant to share QbD information without concerns about regulatory implications Identify CQAs and CPPs, their ranges and interrelationship Describe design space for excipient attributes and process parameters Describe control strategy Describe change control protocols for assessing post- approval changes to CQAs, CPPs, process, equipment, scale, etc., and associated regulatory mechanisms Describe how design space will be reassessed, verified, or redefined

15. 15 CMC Pilot - Benefits Pilot enables industry and FDA to Explore ways to implement Q8, Q9, PAT, and PQAS Pilot enables FDA to Better define what constitutes a QbD-based submission Better establish what constitutes a science-based risk assessment Use experience gained to develop a guidance on QbD and PQAS Good science leads to better quality product, fewer product rejects/recalls, and enhanced public health protection

16. 16 CMC Pilot - Challenges Level of detail in submission demonstrating product knowledge and process understanding Expectations for a QbD-based submission while addressing traditional requirements Providing regulatory flexibility while assuring product quality Industry’s continuous apprehension in sharing information, including failed experiments, with FDA Cultural changes needed in industry and FDA More resources needed initially for industry & FDA

17. 17 CMC Pilot - Summary Pilot Program got off to a good start in meeting its initial goal for industry participation Aspects of QbD were included in Pilot NDAs, and expanded PD is useful CQOS needs further development Scientific approaches to CQAs, CPPs, & design space need further development Regulatory flexibility is being proposed CMC Regulatory Agreement is being explored Program benefits FDA in developing guidance to implement QbD and PQAS Challenges remain for industry and FDA

18. 18 Public Meetings CMC Workshop, October 2005 ACPS, October 2005 CMC-GMP Track, DIA Meeting, June 2006 PDA-FDA Meeting, September 2006 ACPS, October 2006 AAPS Meeting, October 2006 ISPE/PDA Q8/Q9 Workshop, December 2006 FDA Quality Initiatives Workshop, February 2007

19. 19 Internal Trainings Hands-on training through team review NDA Peer Review Forum twice a month ONDQA Focus Groups Biotech; Dissolution; Drug Eluting Devices; Excipients; Fermentation Products; Inhalation Products; Manufacturing Science; Oral Dosage Form Formulation; Quality by Design; Topical Products; Transdermal Delivery System ONDQA Science Forum once a year ONDQA Seminar Series by outside experts Other subject matter trainings on an ad hoc basis

20. 20 Next Steps Sharing of lessons learned with each applicant under CMC Pilot Program Sharing of lessons learned from CMC Pilot Program within FDA and with industry Evaluate need for new guidances on PQAS QbD CQOS CMC Regulatory Agreement