# Presentation: 945821

## Post Approval Changes for Bulk Drug Manufacturing —Status Report

- Post Approval Changes in Drug Substance Manufacturing, and Selection of Starting Materials
- John Smith, Ph.D.
- ONDC / FDA
- AAPS Annual Meeting - Toronto, Canada
- November 12, 2002

## Overview

- “Post Approval Changes in Drug Substance Manufacturing” (slides follow)
- BACPAC I
- BACPAC II
- “Selection of Starting Materials” was discussed as part of this round table, but no slide introduction was presented

## Status of BACPAC

- BACPAC I guidance is final
- BACPAC II guidance is still in draft

## BACPAC II:Moving on from BACPAC I

- BACPAC guidances divide DS manufacturing into two parts (early/late)
- BACPAC I covers changes made from beginning of synthesis up to the Final Intermediate
- Various exceptions (e.g., naturally derived materials, adventitious agents)
- BACPAC II covers changes to FI specification and changes made after the Final Intermediate (the “Last Step”)

## Changes after the FI(Changes to the “Last Step”)

- Case 1
- Case 2
- Case 3

- Pure DS

- Final chemical reaction and workup

- FI

- Crude DS

- Final chemical reaction and workup

- FI

- Pure DS

- Recrystallization

- Mixture of diastereomeric salts

- Racemic DS

- Enantiomerically pure DS

- Single diastereomeric salt

## Avoiding the Term “Intermediate”

- In BACPAC I, “intermediate” referred to materials differing in chemical structure from the DS
- In BACPAC II, must refer to materials [mostly] identical in chemical structure
- Free acid/base vs. salt; crude vs. pure; racemic vs. enantiomerically pure
- What to call them? Not intermediates in the BACPAC I sense (“Forms of the DS”)

## What Is Meant by “Step”And Other Analogous Terms?

- Step, operation, procedure, process, stage
- In BACPAC I, step usually involves a chemical reaction
- Currently no agreement; all are used with multiple meanings
- Future agreement seems unlikely (not enough different words to cover all the meanings)
- BACPAC II covers changes after the FI (not just the “last step”)

## Significance of the FinalSolution “Step”

- Really mean final solution “operation”or final solution “process”? (FSP)
- BACPAC I promotes idea that changes before the FSP can affect impurity profile but are unlikely to affect the physical properties (unless the change in impurities itself affects crystallization process)
- Subdivide BACPAC II changes into those before or after FSP?

## When Is Testing of DS Physical Properties Enough?

- Or, when should DP be made and tested to show that post-change DS *is* equivalent?
- BACPAC I, testing DS was always enough
- BACPAC II changes in or after FSP more likely to alter DS physical properties than any BACPAC I change
- Treat BACPAC II changes before FSP like BACPAC I changes?

## When Is Testing of DS Physical Properties Enough? (cont’d)

- Type of DP also important
- BACPAC I, testing of DS physical properties not recommended if not “relevant to dosage form”
- BACPAC II more explicit?
- Type of changes in or after FSP also important
- E.g., how important is initial particle size distribution if DS is milled or micronized?

## Status of BACPAC II

- Still in draft
- Milestones ahead:
- Internal comment by ONDC/OGD chemists
- Working group forwards draft to management
- Management and Regulatory Policy Staff revise guidance as appropriate
- Draft guidance published for public comment
- Working group evaluates comments/revises draft
- Repeat steps 2 & 3
- Final guidance published