# Presentation: 780638

## Supplements and Other Changes to an Approved Application

- By:  Richard J. Stec Jr., Ph.D.
- February 7, 2007

## Need for a New Approach to Approve and Implement Post Approval Changes

- Regulatory workload for industry and FDA
- 20-30 post-approval supplements over the lifecycle of a generic product
- 3,846 supplements filed to Office of Generic Drugs in 2006
- Ability to implement change
- Typical CMC PAS review time:		9-18 months
- Timeline from development to approval:	1-4 years
- Assure availability of high quality - low cost drugs to consumers
- Encourage innovation
- Prevent drug shortages

## What Drives the Generic Industry to Submit Post Approval Changes?

- Changes brought about by raw material suppliers
- Discontinuation of the drug substance
- Product moved to a new manufacturing site
- Manufacturing process change
- Manufacturing changes
- Process improvement
- New equipment
- Facility consolidation, expansion or relocation
- Alternate raw material, drug substance and packaging material sources
- Compendia changes and upgrades to analytical methodology
- Outsourcing

## Current Regulatory Framework for Notification of CMC Changes

- Prior Approval Supplements
- Regulatory pathway that provides FDA the ability to perform a scientific assessment that the proposed change will not have an adverse effect on drug safety and efficacy
- CBE-30 and CBE-0 Supplements
- FDA reviews each of these submissions after the sponsor has implemented the change
- Sponsor may be requested to perform additional studies or provide additional data to support the change
- Applicability of the filing category may be clarified prior to submission
- Annual Reports
- Is this the most efficient means to utilize                FDA resources to review CMC changes?

## What could a Risk-Based Post-Approval CMC Change Process Look Like?

- Maintain the current evaluation criteria
- Does the change have the potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product?
*Major changes*
- Require **Prior Approval** by FDA before implementation
- e.g., new facility, new process, new API supplier
*Moderate changes*
- Utilize company’s internal CMC Quality Systems to qualify the change
- Report change to FDA at time of implementation
*Minor changes*
- Report annually (current process)

## CMC Quality Systems

- Model CMC Quality System structure after 21CFR820 Quality System Regulation
- Subparts B, D-K most applicable
- Most elements of CMC Quality System structure are already in place to implement post approval change regulation
- Quality system procedures
- Organizational structure
- Document controls
- IQ/OQ/PQ
- Equipment, process and method validation procedures
- Change control procedure
- CAPA

## NDA / ANDA Changes Guidance

- Re-issue to provide greater specificity of *major changes* that would require FDA approval prior to implementation
- e.g., changes to rubber stopper formulations are not well addressed in current guidance
- Develop a decision tree to provide sponsors a framework to determine if the change can be qualified using internal CMC Quality Systems
- Submission of change in the following annual report submission

## Can the System Work?

- Requires awareness of company’s senior management to CMC changes
- Inspection of the CMC Quality System would become part of FDA’s routine GMP inspection process
- Would require Office of Regulatory Affairs to partner in new approach
- Pressure test proposal against existing data
- Evaluate history of changes being effected supplements that were determined non-approvable or could not be implemented

## Opportunities to Reduce the Supplements through a CMC Quality System Approach

- Under current rules-based prescriptive approach,  CBE-30 supplements could be eliminated for:
- Manufacturing changes to companion applications after approval of the lead supplement
- A change in a drug substance or drug product manufacturing process that reduces levels of bi-products and impurities
- A move to an alternate testing laboratory within a company or externally
- A move to an alternate solid dosage form packaging site within a company or externally
- A new analytical method that provides greater assurance of product quality
- Addition of specifications to comply with global compendia
- Adjustment in the operating parameters of a terminal sterilization process within the approved Fo range

## Additional Opportunities to Reduce the Regulatory Burden

- Under current rules-based prescriptive approach, prior approval supplements may no longer be necessary to approve:
- Addition of a new drug substance supplier previously approved in an existing application with the same dosage form
- Minor changes in the size or shape of a container for a sterile drug substance or drug product
- Adjustment of in-process specifications based on manufacturing history
- Deletion of a non-compendia test after appropriate product history

## General Comments: CMC Quality SystemRisk-Based Approach

- Regulatory burden to effect the change projected to remain the same as current prescriptive approach
- Drug safety and efficacy would not be jeopardized
- Future approach would utilize effective manufacturing Quality Systems that are currently in place
- Agency could focus resources on change that has the greatest potential to impact product quality
- Anticipated to minimally increase scope of CGMP inspections
- Would provide for faster implementation of change

## General Comments: CMC Quality SystemRisk-Based Approach

- Incorporates Quality by Design principles
- Generic manufacturers generally hold broad production experience across multiple products manufactured in the same or similar manner
- Adaptive to wide differences in manufacturing processes and equipment
- Responsive to the changes in technology and industry practices
- Unlikely generic industry would implement CMC-related risk management strategies
- Continuous process development post product              launch not the practice

- Thank You