Implementation of Quality-by-Design: ONDQA Initiatives

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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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