# Presentation: 491184

## eCTD Quality/CMC Issues

- Norman R. Schmuff, Ph.D.
- Deputy Division Director
- Div New Drug Chemistry III, ONDC
- FDA, CDER

## Outline

- History of FDA CMC e-submission efforts
- Quality/CMC Location Information
- Repeated sections
- Topics appearing in multiple sections
- Lifecycle management & supplements
- Issues to be resolved
- Future directions
- Location issues in Module 3

## Early FDA SGML-Based Initiatives

- Publication: SGML for Regulatory Submissions
- Early 1990s?, DIA Journal?, RAPS Journal?
- FDA Presentations
- June 1992
- CANDA Conference
- Aster Publishing
- New Brunswick, NJ
- July 1992
- CANDA Conference
- IIR
- Princeton, NJ

## Early SGML-Based Projects

- DTD for CMC submission
- Shown October 1993
- GCA (Graphic Communication Assn) Meeting
- Philadelphia, PA
- Viewing of instance on Unix, Macintosh, and PC
- Simultaneous activities at HPB, PharmaSoft
- MERS (Multiagency Electronic Reg Submission)
- January 31, 1994
- Meeting at FDA w/ HPB (Bob Kapitany), PharmaSoft (Per Manell)

## Repeated Section & Location Issues in Module 3

- ICH Documents:www.ich.org
- CTD–Q (M4–Q)
- CTD–Q Questions and Answers
- eCTD Specification
- eCTD Questions and Answers
- FDA Documents:www.fda.gov/cder/guidancewww.fda.gov/cder/regulatory/ersr/default.htmwww.fda.gov/cder/regulatory/ersr/ectd.htm
- Guidance for Industry: Drug Substance
- Guidance for Industry: Drug Product

## Repeated Quality Sections

- See especially eCTD specification page 6-11
- Always use eCTD attributes, even for non-repeating sections, with a single attribute value* <ELEMENT attribute=xxxx>
- P.4 Control of Excipients
- See eCTD Q&A

- NOTE: For ***print*** CTDs, don’t use attribute names where there is only a single attribute value e.g. S.2  Manufacturer (amoxicillin, ABC Inc)

## Repeated Drug Substance Sections

- Multiple drug *substances* (e.g. Augmentin)
- Repeat entire drug substance section
- Use name attribute <m-3-2-s-drug-substance substance=“amoxicillin” manufacturer=“ABC, Inc”>
- Multiple drug substance *manufacturers*
- Preferred view for reviewers is with sub-sections grouped together
- Folder and organization is not prescribed

## One Drug Subs, Two Manufacturers

- 3.2.S	DRUG SUBSTANCE
- ...
- ...
-  3.2.S.4	Control of Drug Substance
-   3.2.S.4.1		Specification (manuf-1)
-   3.2.S.4.1		Specification (manuf-2)
-   3.2.S.4.2		Analytical Procedures (manuf-1)
-   3.2.S.4.2		Analytical Procedures (manuf-2)
-   3.2.S.4.3		Validation of Analytical Procedures (manuf-1)
-   3.2.S.4.3		Validation of Analytical Procedures (manuf-2)
-   3.2.S.4.4		Batch Analyses (manuf-1)
-   3.2.S.4.4		Batch Analyses (manuf-2)
-   3.2.S.4.5		Justification of Specification (manuf-1)
-   3.2.S.4.5		Justification of Specification (manuf-2)

## Repeated Drug Product Sections

- Co-packaged drug products(e.g. drug w/ diluent)
- Repeat entire drug product section
- Use name attribute
- Different strengths or packages
- Separate where logical
- Documents generally should be common

## Topics Appearing inMultiple Sections(see appended slides in file on website)

## Lifecycle Management

## Lifecycle Management Operation Attributes*

- New: no relationship w/ previous files
- Append: existing file is associated with new file
- Replace: existing file is replaced
- Delete: no file is submitted, used mainly for errors

- *ICH eCTD Specification v 3.2,  Appendix 6 http://www.fda.gov/cder/regulatory/ersr/ectd.htm

## Lifecycle Management for Chemistry Supplements

- In initial submission
- Consider “granularity” Annex of the CTD Organization document* (i.e., number of files)
- Consider sections likely to be supplemented
- All “operation” attributes set to “new”
- In subsequent submissions (amends & supps)
- Use the same structure
- Include only files that have changed
- Use appropriate “operation” attribute

- *”Organisation of the Common Technical Document...”_[http://www.fda.gov/cder/guidance/7042fnl.doc](http://www.fda.gov/cder/guidance/7042fnl.doc)__ [not PDF version]_

## CTD Granularity

| Module 2 | 2.1 | The TOC is only called for in the paper version of the CTD; there is no entry needed for the eCTD |  |
| --- | --- | --- | --- |
|  | 2.2 |  |  |
|  | 2.3 Note 1 | Introduction |  |
|  |  | 2.3.S Note 2 | 2.3.S.1 |
|  |  |  | 2.3.S.2 |
|  |  |  | 2.3.S.3 |
|  |  |  | 2.3.S.4 |
|  |  |  | 2.3.S.5 |
|  |  |  | 2.3.S.6 |
|  |  |  | 2.3.S.7 |
|  |  | 2.3.P Note 3 | 2.3.P.1 |
|  |  |  | 2.3.P.2 |
|  |  |  | 2.3.P.3 |
|  |  |  | 2.3.P.4 |
|  |  |  | 2.3.P.5 |
|  |  |  | 2.3.P.6 |
|  |  |  | 2.3.P.7 |
|  |  |  | 2.3.P.8 |
|  |  | 2.3.A | 2.3.A.1 |
|  |  |  | 2.3.A.2 |
|  |  |  | 2.3.A.3 |
|  |  | 2.3.R |  |
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## Example: CMC Supplement Adding a New Test to DP Spec

- Initial submission has:
- One file for “Specification” (3.2.P.5.1)
- Several files for P.5.2 and P.5.3 (1 for each method)
- All have “new” operation attribute
- Supplement #1, sequence #005 has:
- One file for “Specification” (3.2.P.5.1) “replace”
- One file for P.5.2, “new”
- One file for P.5.3, “new”

## Issues to be Resolved

- Drug Master Files integration
- Module 2 Quality Overall Summary
- Content
- For supplements
- P.2 Pharmaceutical Development (ICH Q8)
- Incorporation of risk-management (ICH Q9)

## Possible Future Directions

- HL7 XML-based stability data file?www.fda.gov/cder/ondc/Presentations/2001/Stability/Default.htm
- Analytical Information Markup Language? (ASTM, NIST)animl.sourceforge.net

## Topics Appearing inMultiple Sections

- Note that information regarding P.2.x section(s) may be subject to change, pending the outcome of Q8 (currently at Step 2)

## Drug Product Stability

- P 2.1.1 Pharm Development (PD) – Drug Substance
- Drug-drug, drug-excipient interactions
- P 2.6 PD – Compatibility
- One-time compatibility with diluents / devices
- P 8.3 Stability Studies
- Stability protocol constitution / dilution

## Components and Composition

- P 1 Description and Composition of the Drug Product
- Unit dose
- P 2.1.2 PD – Excipients
- Choice, amounts, impact on dp performance
- Justification of ranges
- P 2.2.1 PD – Formulation Development
- Clinical trial formulations
- P 2.2.2 PD – Overages

## Components and Composition(cont’d)

- P 3.2 Batch Formula
- P 4.1 to 4.6 Control of Excipients
- R Regional Information
- Batch records

## Dissolution

- S.3.1  Elucidation of Structure and Other Characteristics
- DS dissolution
- P 2.1.1 PD – Drug Substance
- DP manufactured from different particle sizes
- P 2.2.1 PD – Formulation Development
- Profiles linking clin trial product to that proposed for market
- P 2.2.3 PD – Physicochemical and Biological Properties
- Q6A disintegration rationale

## Polymorphism

- S.1.3	General Properties
- Polymorphic form(s) present in the proposed active
- S.2.2	Description of Manufacturing Process			and Process Controls
- Which polymorphic form is synthesized
- S.3.1	Elucidation of Structure and other			Characteristics
- Studies performed to identify the potential polymorphs
- List all identified polymorphs

## Polymorphism (cont’d)

- S.4.1	Specification
- Test, acceptance criteria & ref to anal procedure
- S.4.2	Analytical Procedures
- S.4.3	Validation of Analytical Procedures
- S.4.4	Batch Analyses
- S.4.5	Justification of Specification
- Appropriateness of acceptance criteria
- P.2.1.1	(PD) Drug Substance

## Polymorphism (cont’d)

- P.2.2.3	(PD) Physicochemical and			Biological Properties
- P.5.1	Specification
- Test, acceptance criteria & ref to anal procedure
- P.5.2	Analytical Procedures
- P.5.3	Validation of Analytical Procedures
- P.5.3	Batch Analyses
- P.5.6	Justification of Specification
- Appropriateness of acceptance criteria

## DS Physicochemical Characteristics (cont’d)

## DS Physicochemical Characteristics (cont’d)

## DS Physicochemical Characteristics (cont’d)