# Presentation: 920888

## HOT ISSUES Encountered While Drafting the FDA Drug Substance Guidance

- John Smith, Ph.D.
- FDA / CDER / OPS / ONDC
- DIA Annual Meeting
- Chicago, IL
- June 17, 2002

## Presentation Outline

- ICH CTD-Q
- Process Controls
- Reprocessing & Reworking
- Starting Materials
- Summary

## ICH CTD-Q

- Impending step 4 status of CTD-Q was major influence in decision to revise the 1987 Drug Substance Guideline
- CDER recognized the potential for firms to interpret CTD-Q format in different ways
- Primary purpose of revised DS and DP Guidances is to aid firms planning to submit applications using the CTD format

## ICH CTD-Q (cont’d)

- Format of revised guidances will conform to headings in CTD-Q
- Section headings
- Order in which topics are discussed
- Revision also provides opportunity to update guidances
- Reprocessing and reworking
- Starting materials

## ICH CTD Overview

- Module 1 (Administrative - Regional)
- Module 2 (Executive Summaries)
- Module 3 (Quality (i.e., CMC Information))
- Module 4 (Nonclinical)
- Module 5 (Clinical)

## ICH CTD-Q Overview (cont’d)Module 3 (Quality)

**<S> Drug Substance**
**<P> Drug Product**
**<R>*** Regional Information*
*Batch Records, Methods Validation Package, Comparability Protocols*
**<A>*** Appendices*
*Viral inactivation, cross-contamination issues & novel excipients*
**<C>*** References*

## ICH CTD-Q Overview (cont’d)Drug Substance

- S.1 General Information
- S.2 Manufacture
- S.3 Characterization
- S.4 Control of Drug Substance
- S.5 Reference Standards
- S.6 Container Closure System
- S.7 Stability

## ICH CTD-Q Overview (cont’d) Drug Product

- P.1 Description and Composition
- P.2 Pharmaceutical Development
- P.3 Manufacture
- P.4 Control of Excipients
- P.5 Control of Drug Product
- P.6 Reference Standards
- P.7 Container Closure System
- P.8 Stability

## ICH CTD-QDrug Substance vs. Drug Product

- For the most part, little concerning DP is discussed in DS Guidance
- Potential areas of overlap
- Physical properties of the DS that have an effect on the performance characteristics of the drug product
- Data from drug product studies can influence specification of DS

## Hot ICH CTD-Q Issues

- Not always clear where CTD-Q intended certain types of information to be submitted
- Consensus?
- Within CDER (DS Guidance vs. DP Guidance)
- Between CDER/CBER
- With other regions
- Some issues may need to be resolved by the ICH IWG on CTD-Q

## Process Controls

- Hot issues primarily relate to CTD-Q
- Division between:
- Information *reviewed* in application, vs.
- Information *evaluated* during CGMP inspections (but not *reviewed* in application)
- Critical process controls vs. non-critical
- What are process controls anyway?
- Harmonization (DP Guidance / Field / CBER / other ICH regions)

## Process Controls (cont’d)

- Critical vs. non-critical process controls
- Critical
- S.2.4 Controls of Critical Steps and Intermediates
- Not critical
- S.2.2 Description of Manufacturing Process and Process Controls
- Definition of “critical”
- Q7A definition?

## Process Controls (cont’d)

- Critical vs. non-critical process controls
- Partitioning of information on process controls into two sections...
- ...Has given rise to _mistaken_ impression that information in S.2.2
- Will not be reviewed
- Can be changed without Agency notification
- Obviously incorrect, since route of synthesis only described in S.2.2
- BACPAC I / Changes Guidance / [BACPAC II]

## Process Controls (cont’d)

- What are process controls anyway?
- Harmonization of concepts
- DP Guidance / Field / CBER / other ICH regions

## Process Controls (cont’d)

**Drug Substance**
_**Quality Controls**_

## Reprocessing and Reworking

- ICH Q7A Definitions
- Reprocessing
- Introducing an intermediate or DS...back into the process and repeating...appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process
- Reworking
- Subjecting an intermediate or DS that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain [material of] acceptable quality (e.g., recrystallizing with a different solvent)

## Reprocessing and Reworking (cont’d)

- Review Issues Not Resolved by ICH Q7A
- Q7A addresses reprocessing and reworking as they relate to CGMPs
- Review issues arise when a reprocessing or reworking process is—*or should be*—described in an application
- Original application
- Post approval

## Reprocessing and Reworking (cont’d)

- Describing a Reprocessing or Reworking Operation in an Application
- To include a reprocessing or reworking operation as part of the established process
- 1987 DS guideline: if reprocessing is to be “routinely” employed
- ICH Q7A: if reprocessing is used for a “majority” of batches
- To obtain approval to release one or more reprocessed or reworked batches

## Reprocessing and Reworking (cont’d)

- Making a Reprocessing or Reworking Operation Part of the Established Process
- Should be submitted in a supplement unless described in original application (1987 DS Guideline, Changes Guidance)
- What to call it after approval?
- “Established” reprocessing or reworking operation?
- Batches can be released on basis of normal testing

## Reprocessing and Reworking (cont’d)

- Obtaining Approval to Release Batch(es)
- E.g., when DS is to be recovered from dosage forms (1987 DS Guideline)
- Other situations need clarification:
- Reworked DS of high concern?
- Reworked intermediates of less concern?
- Delegate to CGMPs?
- Reprocessed DS and intermediates?
- Of little concern if DS synthetic and/or well-characterized?
- Not acceptable for biologic or poorly characterized DSs?

## Starting MaterialsCDER Definition

- “Definition” in 1987 DS Guideline
- Contributes important structural element to DS
- Commercially available
- Compound whose name, chemical structure, chemical and physical properties, and *impurity profile* are “well defined” in chemical literature
- Obtained by commonly known procedures (primarily for semisynthetics)

## Starting MaterialsMinor Criteria

- Contributes Important Structural Element
- Differentiates starting materials from reagents and protecting groups
- “Minor” because it’s a given (sine qua non)
- Obtained by Known Procedure
- Applies to semisynthetics, not synthetic DSs
- Paradigm shift: Starting material for semisynthetic DS consists of cells, animal tissues or organs, or plants or plant parts

## Synthetic SMsKey Criteria

- Commercial Availability
- Contract manufacturing of a chemical does not make it commercially available
- “Well Defined” in Chemical Literature
- 1987 DS Guideline says if a chemical is not commercially available, it should be well defined in literature to be considered a starting material

## Synthetic SMsA New Perspective

- Practical Definition of Starting Material:
- Marks the start of the manufacturing process *described in an application*
- Manufacturing steps *before* are not described
- Manufacturing steps *before* need not be performed in accordance with CGMP
- Changes in manufacturing steps *before* need not be reported to Agency
- Each branch of a synthesis will begin with one or more starting materials

## Synthetic SMsA New Perspective (cont’d)

- Focus Less Intently on Inherent Starting Material Characteristics, More on Synthesis
- Why should some manufacturing steps be described in an application (those *after* the starting material) while others (those *before* the starting material) need not?
- How many steps in a synthesis should be described in an application?

## Reasons for Reporting Manufacturing Process

- Reasons Cited in 1987 DS Guideline
- Determines specific solid-state form of DS
- If determined in final solution step (BACPAC), then not a reason for organic synthesis steps?
- Determines nature of impurities in DS
- Related substances, residual solvents, and inorganic impurities from catalysts & reagents
- Provides evidence to support the proposed chemical structure (identity) of the DS

## Synthetic SMsPossible Approach

- Consider criteria based on:
- Impurity issues
- Identification issues

## Synthetic SMsPossible Approach (cont’d)

- Impurity issues
- Synthesis steps that don’t contribute to impurity profile of DS need not be reported?
- New criteria should address impurities (organic, inorganic, solvents) that might arise from changes in how the SM is made

## Synthetic SMsPossible Approach (cont’d)

- Identification issues
- A starting material should be easily identifiable
- Compounds of similar structure should not be easily misidentified as the starting material

## Synthetic SMsActual Approach Takenin Draft DS Guidance

- ?

## Summary

- Some “Hot Issues” encountered during the revision of 1987 DS Guideline were discussed
- ICH CTD-Q
- Process Controls
- Reprocessing and Reworking
- Starting Materials

## Summary (cont’d)

- What’s Next for the Draft DS Guidance?
- Will Be Published For Public Comment
- Currently, still with working group (DSTC)
- Internal comment period (TLs and DDs)
- Revised by working group (DSTC)
- OK’d by CMC Coordinating Committee
*Revised & OK’d by Regulatory Policy Staff*
*OK’d by CDER Director*
*Public comment: maybe 2nd half 2002?*

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