Post-Approval Change Management: Challenges and Opportunities An FDA Perspective

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1 CMC Workshop From Drug Development to Global Supply to Patients April 15-17, 2013, Washington, DC Post-Approval Change Management: Challenges and Opportunities An FDA Perspective Christine M. V. Moore, Ph.D. Acting Director, Office of New Drug Quality Assessment FDA/CDER

2 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Communities (formerly known as SIACs) or affiliates, or any organization with which the presenter is employed or affiliated. For work prepared by US government employees representing their agencies, there is no copyright and these work products can be reproduced freely. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 2 2

3 Outline Background on regulations and guidance for post-approval changes Risk-based approaches for post approval changes Change protocols Potential future directions for postapproval changes 3

4 Change Management Today Pharmaceutical manufacturers are becoming increasingly frustrated with the change control requirements in a global environment Hurdles to manufacturing changes in an global environment include: Differing requirements for changes Costs of filing changes Different timing for approval of changes from multiple health authorities Innovator firms are seeking greater freedom to operate and ease of change control 4

5 Pathways to Pharmaceutical Manufacturing Changes (FDA) Can modify change reporting category No reporting required Design Space Annual Report CBE/CBE-30 PAS Distribute product without Prior Approval Prior Approval required before product distribution 5

6 FDA Change Regulations 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 Prior Approval Supplements (PAS) 21 CFR (b) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Changes Being Effected (CBE/CBE-30) 21 CFR (c) A supplement must be submitted for any change. 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 6

7 Change Reporting: FDA vs. EMA Variation Category Major Substantial Moderate Minor Minimal FDA Prior Approval Supplement (PAS) Change Being Effected 30 Days (CBE-30) Change Being Effected (CBE) Annual Report (AR) EMA Type II Type IB Type IAIN Type IAAR 7

8 FDA Guidances Related to Change Management Changes to an Approved NDA or ANDA (2004) Gives example listing of many changes and related reporting categories Companion Guidance Documents: Changes to an Approved NDA or ANDA: Questions and Answers (2001) Changes to an Approved NDA or ANDA; Specifications Use of Enforcement Discretion for Compendial Changes (2004) CMC Postapproval Manufacturing Changes Reportable in Annual Reports (DRAFT, 6/24/2010) SUPAC Guidances Provide both change categories and method of evaluation of the effects of the change Specific to dosage form type Draft Comparability Protocol Guidance Comparability Protocols Chemistry, Manufacturing and Controls Information (DRAFT 2/25/03) 8

9 Guidances Related to Change Management - SUPAC SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1995) SUPAC-IR Questions and Answers about SUPAC-IR Guidance (1997) SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1997) SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms Manufacturing Equipment Addendum (Draft, 1999) SUPAC-SS: Nonsterile Semisolid Dosage Forms: Scale Up and Post- Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1997) SUPAC-SS: Nonsterile Semisolid Dosage Forms Manufacturing Equipment Addendum (Draft, 1998) PAC-ATLS: Postapproval Changes Analytical Testing Laboratory Sites (1998) 9

10 Current FDA Guidance for Post-Approval Changes Most FDA change guidances are now 1-2 decades old Risk based approach used Assumes that all products within a drug product category have same risk Often overly conservative, occasionally overly liberal (e.g., narrow therapeutic index drugs) No leeway for well understood risks to product quality or process 10

11 Current FDA Regulatory Approaches - Limitations Science and risk based approaches under QbD have evolved pharmaceutical manufacturing Currently, no additional flexibility beyond approved design space for post-approval changes Existing guidance recommends many manufacturing changes be filed as a supplements, independent of their criticality in a specific process 11

12 Examples of Risk from Product Design Solid Oral Dosage Forms Product Design Aspect Drug loading CQAs Potentially at Risk Content uniformity Drug substance solid state Dissolution, Stability BCS Class Therapeutic index Release profile (IR, MR, ER) Dissolution/Bioavailability Delivered dose Bioavailability 12

13 Simplified Example of Risk Assessment Film-coated IR tablet made by blending/direct compression CASE 1: Low dose drug (0.5% drug loading) Highly stable API Chronic use CASE 2: High drug loading (~40%) Moisture sensitive API As needed use Drug Product CQA Blending Compression Coating Description N/A Low Low Identification N/A N/A N/A Assay N/A N/A N/A Content Uniformity High Moderate N/A Degradation N/A N/A Low Dissolution N/A Moderate Low Microbiology N/A N/A Low 13 Drug Product CQA Blending Compression Coating Description N/A Low Low Identification N/A N/A N/A Assay N/A N/A N/A Content Uniformity Low Low N/A Degradation N/A N/A High Dissolution N/A Moderate Low Microbiology N/A N/A Low 13

14 Lower Risk Products Certain product are inherently lower risk: Dependent on API, formulation and release characteristics Some solid oral dosage forms Most liquid oral dosage forms Many non-sterile topical dosage forms CDER is examining potential approaches to ease change reporting for these lower risk products, potentially as Annual Report 14

15 Moving Forward How can manufacturers who understand the risks of their product achieve more flexible post approval changes? 15

16 Protocol Regulations NDAs & ANDAs Change Protocols for NDA/ANDA- 21 CFR (e) An applicant may submit one or more protocols describing: specific tests studies acceptance criteria to demonstrate the lack of adverse effect on the identity, strength, quality, purity, and potency of the drug product Can be included in an NDA or as a PAS Justifies a reduced reporting category for the change Reduces the potential risk of an adverse effect Does not waive reporting of change 16

17 Protocol Regulations BLAs Change Protocols for BLAs 21 CFR (e) An applicant may submit one of more protocol describing: specific tests validation studies acceptance limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity or potency of the product Protocols and changes to protocols to be submitted as a PAS Also accepted in original BLAs Justifies a reduced reporting category for the change Reduces the potential risk of an adverse effect Does not waive reporting of change 17

18 Why use a Change Protocol? Allows for reduced reporting categories of postapproval changes Enables faster distribution of product after a manufacturing change Eases coordination with multiple health authorities Achieve early agreement on change plan from regulators Allows multiple changes or repetitive implementations of a specific change 18

19 How to File a Change Protocol Recommend inclusion in regional section of application 3.2.R in CTD format Mention in cover letter for a supplemental application Recommend mentioning in the Quality Overall Summary and main text of the application for an original application Aids the reviewer in timely identification of the protocols and for evaluating the application and protocol simultaneously 19

20 Changes in Change Protocols Changes to an approved change protocol must be made as a Prior Approval Supplement Consequently, the change, evaluation method and acceptance criteria to be undertaken in the proposed protocol should be well understood prior to submission If the change fails to meet the agreed upon criteria in the protocol, a prior approval supplement would be needed to change the evaluation method or acceptance criteria. Material manufactured by the changed process should not be distributed before approval 20

21 CGMP Expectations for Changes Any modification of the process, facilities, equipment, operating conditions, etc, must be performed under firm s quality system in compliance with cgmps The same quality management principles apply regardless if a change requires a regulatory filing or not Data supporting modification should be retained onsite Data may be reviewed in future inspections 21

22 When are protocols appropriate? When an applicant wishes to make future changes beyond the alternatives/variations approved in the application When the applicant understands the potential risks of the change and how to evaluate them How will effects of change be evaluated? What determines the success of a change? For changes that will not require efficacy, safety or pharmacokinetic evaluation 22

23 When is a protocol NOT appropriate? For changes that require safety, efficacy, nonclinical, or pharmacokinetic evaluation Changes for which the adverse effect cannot be evaluated by studies, tests, etc Changes that warrant submission of a new IND 23

24 Change Protocols and Design Space For drug product, change protocols for movements within a design space are not expected to be included in an NDA Working within a design space is not considered a change, in accordance with ICH Q8(R2) Procedure for movements within a design space are managed on site under firm s quality system Such procedures help to manage residual risk of movements to areas of the design space unverified at commercial scale Subject to review on inspection Transparency of change management process and knowledge retention beneficial to reviewer and inspector Change protocols could be useful for expanding or modifying a design space 24

25 Protocols and Design Space (cont.) Change protocols in the submission could be requested for design spaces for biotechnology drug substances in accordance with ICH Q11 Depending on the level of residual risk, it may be appropriate for an applicant to provide proposals on how movements within a Design Space will be managed postapproval Indicate how process knowledge, control strategy, and characterization methods can be deployed to assess product quality following movement within the approved design space Approaches for complex molecules are still being formulated 25

26 Potential of Change Protocols Change protocols have the potential to enhance regulatory flexibility and ease post approval changes Opportunity to facilitate continual improvement and process optimization Synergy with understanding obtained in Quality by Design (QbD) approaches 26

27 Risk Based Approach Understand relationships and risks between: Patient Product Manufacturing Process Risk assessments can be supported by laboratory or pilot scale data Potential to use change protocols to support a wide breadth of changes: Optimize process Support continual improvement Provide flexibility in scale/throughput 27

28 Considerations for Protocols Potential risk of the change on the critical quality attributes of the product Evaluate effects downstream of change Possibly grouped together based on: Unit operation Potential effect to product CQAs Ability of control strategy to detect the effect of the change Is enhanced sampling or non-routine tests needed to verify product quality? Suitability of the change throughout all regions of potential operations (e.g., design space) 28

29 Summary CDER is working toward updating post-approval change approaches Protocols provide a current flexible pathway to reduce reporting categories for changes to an approved application Risk based approaches can be used to support broader changes ONDQA is accepting change protocols in original and supplemental NDAs Discussion prior to submission is highly recommended 29

30 Thank you! Questions, comments, concerns: 30

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