Linking Regulatory Commitments to Post Approval Changes Robert Iser

Transcription

1 Linking Regulatory Commitments to Post Approval Changes Robert Iser Senior Scientific Advisor (acting) Office of Process & Facilities / OPQ / CDER IFPAC 2015 Product Lifecycle and QA January 27 th,

2 Definition of Regulatory Commitment (RC) RC has not been defined by FDA or is it already been defined in the regulations? Common use - CMC elements of an application that are subject to reporting, if changed after approval PhRMA White Paper- Regulatory Commitments and Post-approval Change Management A regulatory commitment is a specific description of how a company intends to manufacture and control the drug product that is defined in the dossier, and that is subject to a regulatory action if changed after approval 2

3 Food, Drug and Cosmetic Act Manufacturing Changes FD&C Act 506A Manufacturing Changes Requires validation of all manufacturing changes before distribution of product made with change Major manufacturing change : requires pre-approval before distribution of product Some formulation changes Most changes in specification Changes requiring clinical data to demonstrate equivalence Allows for other types of major changes to be established Other manufacturing change Changes requiring supplemental application Changes not requiring supplemental application Submission of report- shall be submitted by such date as the secretary specifies Annual Report: allowed if the applicant makes more than one manufacturing change during a single year 3

4 Regulations Related to Change Management All changes must be assessed under the Pharmaceutical Quality System (PQS) (21 CFR , , , , ). The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application 21 CFR (a) Prior Approval Supplements (PAS) 21 CFR (b) Changes that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product Changes Being Effected (CBE/CBE-30) 21 CFR (c) Changes. that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency... Annual Report (AR) - 21 CFR (d) Changes that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency must be documented by the applicant in the next annual report Change Protocol- 21 CFR (e) may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect.. 4

5 Examples of FDA Guidance Related to Change Management SUPAC Guidances ( ) Provide both change categories and method of evaluation of the effects of the change Specific to dosage form type Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (7/1/1997) Changes to an Approved NDA or ANDA (4/1/2004) Gives example listing of many changes and related reporting categories CMC Postapproval Manufacturing Changes Reportable in Annual Reports (3/14/ 2014) 5

6 Current FDA Regulatory Approaches & Limitations Risk management concepts are applied, but often assumed that all products within a drug product category have similar risk Much effort in development and less clarity for commercial products Often overly conservative, occasionally overly liberal (e.g., narrow therapeutic index drugs; 10X scale up) Insufficient flexibility to recognize well understood risks to product quality or process Lack of clarity regarding Conditions established and need for reporting could: lead to unnecessary submission of post-approval supplements to FDA for changes that could be managed solely by an applicant s PQS discourage continual improvement in drug manufacturing processes or lead to citations for changes that should have been reported to FDA, upon inspection. 6

7 Why do we need RC? Allow for more effective post-approval change management Focus on high risk areas of the product and process Reduce /or eliminate regulatory focus on well justified or demonstrated low risk areas Promote knowledge rich submission Facilitate innovation and continual improvement over the lifecycle Strengthen quality assurance and reliability of supply Provide the FDA pathways more efficiently regulate postapproval changes in a risk-based fashion Consistent with FDA s Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century A Risk Based Approach (September 2004). 7

8 PhRMA Proposed Definition of Regulatory Commitment a specific description of how a company intends to manufacture and control the drug product that is defined in the dossier, and that is subject to a regulatory action if changed after approval 8

9 A Specific Description How much detail is enough? Product and process specific high risk areas and failure modes - link to patient (safety and efficacy) Where to draw the line between the supportive information and commitments? Does it mean the supportive information is not important? Does the supportive information still need to be submitted to support a change? 9

10 Manufacture What are the expectations for Description of drug substance/ product manufacture process? What process parameters and ranges should be included? Is the master batch record a regulatory commitment? 10

11 Control How do regulatory commitments relate to control strategy? A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) What is impact on change in control strategy? 11

12 Defined in the dossier Which CTD sections typically contain regulatory commitments? M4Q: The CTD-Quality Module 2 Quality Overall Summary (S.1-S.7 and P.1-P.8) Module 3 Body of Data (S.1-S.7 and P.1-P.8) Appendices Regional information Literature References 12

13 intended if changed When/How are regulatory commitments updated? What supporting information is needed for the change(s)? What documentation is needed for the changes made within the internal PQS? 13

14 Scientific Considerations for Change Management Assess how the change could affect the process/product or effectiveness of Control Strategy product-specific failure modes Assess the potential severity of the effects of the change Link to Patient Design and execute an evaluation plan to assess the effects of the change on the product and process, considering the risks Formal risk assessment can be highly valuable in assessing potential effects of changes and designing an evaluation plan 14

15 PQS Considerations for RC Paradigm Shift Culture of Quality Manufacturers take full responsibility for quality of their products All manufacturing changes must be evaluated under the applicant s Pharmaceutical Quality System (PQS) Focus on meeting patients expectations Regulators expectations considered minimal approach Strive for continual improvement Management and organizational commitment to prioritizing quality Each person in organization understands and embraces their role in quality 15

16 Regulatory Considerations for RC RC and risk categories are likely to be proposed by the applicant and subject to regulatory assessment. Science and risk-based approach desired for establishing RC Product and process understanding High risk parameters identified and controlled? Low risk parameters justified or demonstrated? Control strategy justified and supported? Where does it go? Format? Updates? 16

17 Potential Strategies to Reduce the Filing Category of Changes Comparability protocol or Change Management Plan Testing and/or sampling beyond standard testing Use modern technologies which significantly increase the detectability of failure modes (e.g. LC/MS for new drug substance supplier, PAT for adaptive process control, IVIVC for dissolution testing, ) Demonstrate the process is in a state of statistical control, capable, robust Others??? 17

18 Why is Now a Good Time to Have This Discussion! 18

19 Office of Pharmaceutical Quality Office of Program and Regulatory Operations Acting Director: Giuseppe Randazzo Immediate Office Acting Director: Jane Woodcock Deputy Director: Lawrence Yu ONE QUALITY VOICE Put Patients First Office of Policy for Pharmaceutical Quality Acting Director: Ashley Boam Office of Biotechnology Products Director: Steven Kozlowski Science and Risk Based Approaches to Quality Assessment Office of New Drug Products Acting Director: Sarah Pope Miksinski Office of Surveillance Acting Director: Theresa Mullin Office of Lifecycle Drug Products Acting Director: Susan Rosencrance Lifecycle Knowledge Management Office of Process and Facilities Acting Director: Christine Moore Office of Testing and Research Acting Director: Lucinda Buhse

20 Closing Remarks Regulatory Commitments is an important & timely concept for both regulators & industry Guidance on pharmaceutical product lifecycle management is being developed ICH Q12 OPQ sets us up nicely to have the needed science, risk and lifecycle discussions Stay tuned. 20

21 FDA Working Group: Acknowledgments CDER: A. Boam, S. Chatterjee, T. Gooen, R. Iser, N. Kim, S. Kozlowski, E. Lacana, B. Lane, J. Maguire, C. Moore, D. Palmer, D. Peng, P. Qiu; M. Ramanadham, A. Thomas, A. Yeaton CBER: J. Bishop, J. Eltermann, M. Farshid; M. Gruber, C. Joneckis, M. Kennedy, N. Kirschbaum, I. Markovic; L. Norwood, S. Rubin, K. Wonnacott CVM: M. Harmon, L. Huffman Office of Chief Council: D. Beers 21