# Presentation: 464121

## eCTDsQuality/CMC Issues

- Norman R. Schmuff, Ph.D.
- FDA, CDER
- Acting Deputy Division DirectorDivision of New Drug Chemistry 3

## Outline

- Historical FDA e-submission efforts
- How to read the eCTD DTDs
- Repeated sections
- Location issues in Module 3
- Topics appearing in multiple sections
- Issues to be resolved

## ICH CTD Step-4 GroupSan Diego, Nov 2000

## ICH eCTD Step-4 GroupTyson’s Corner, Sept 2002

## 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)

## A Little XML: Reading a DTD

- XML
- Extensible Markup Language
- Unlike HTML, not a fixed tag set	start tag		end tag<your-new-tag>	< /your-new-tag>
- Two major components
- DTD or Schema — Heading names, Sequence, Optionality, Repeatability, like an outline
- Document Instance — DTD/Scheme with data, like an outline populated with data

## XML Memo Example

- <memo>
- <date> 22 May 2004 </date>
- <to id=“123”> Bill Monroe </to>
- <from id=“345”> Maybelle Carter </from>
- <cc> Bob Wills </cc>
- <topic> Picnic </topic>
- <lead-para> Our annual picnic is scheduled.. </lead-para>
- <body> Some details follow... </body>
- </memo>

## XML Memo

- <!ELEMENT memo (date, to, from, cc*, topic, sub-topic?, lead-para, body+)>
- <!ELEMENT date (#PCDATA)
- <!ELEMENT to (#PCDATA)
- <!ATTLIST to ID #REQUIRED> ...

- MEMO
- Date:
- To:
- From:
- [CC:]
- Topic:
- [Sub-topic:]
- Lead paragraph
- Body
- Body

- +	one or more
- *	zero or more
- ?	zero or one

## eCTD Required Elements

- <!-- ================== ADMIN ==================================== -->
- <!ELEMENT admin (applicant-info, product-description, application-information)>
- <!-- ********************* Applicant Information ******************** -->
- <!ELEMENT applicant-info (company-name, date-of-submission)>
- <!ELEMENT company-name (#PCDATA)>
- <!ELEMENT date-of-submission (date)>
- <!ELEMENT date (#PCDATA)>
- <!ATTLIST date
- format (yyyymmdd) #REQUIRED
- >
- <!-- ********************* Product Description ********************** -->
- <!ELEMENT product-description (application-number, prod-name+)>
- <!ELEMENT application-number (#PCDATA)>
- <!ELEMENT prod-name (#PCDATA)>
- <!ATTLIST prod-name
- type (established | proprietary | chemical | code) #REQUIRED

## eCTD Required Elements From FDA’s Module 1 DTD

- <!-- ================== ADMIN ==================================== -->
- <!ELEMENT admin (applicant-info, product-description, application-information)>
- <!-- ********************* Applicant Information ******************** -->
- <!ELEMENT applicant-info (company-name, date-of-submission)>
- <!ELEMENT company-name (#PCDATA)>
- <!ELEMENT date-of-submission (date)>
- <!ELEMENT date (#PCDATA)>
- <!ATTLIST date
- format (yyyymmdd) #REQUIRED
- >
- <!-- ********************* Product Description ********************** -->
- <!ELEMENT product-description (application-number, prod-name+)>
- <!ELEMENT application-number (#PCDATA)>
- <!ELEMENT prod-name (#PCDATA)>
- <!ATTLIST prod-name
- type (established | proprietary | chemical | code) #REQUIRED

- Note: the absence of “*” or “?” means all of these elements are required, (i.e. none are optional), not surprising since otherwise administrative information might be incomplete

## eCTD Optional Elements(from P.8 Drug Product Stability)

- <!ELEMENT m3-2-p-8-stability
- ((leaf)* ,
- m3-2-p-8-1-stability-summary-and-conclusion? ,
- m3-2-p-8-2-post-approval-stability-protocol-and-	stability-commitment? ,
- m3-2-p-8-3-stability-data?)>

- ?	Optional — element appears once or not at all
- *	Optional and repeatable — element may appear 0 or more times

## Example Content Model (from P.8 Drug Product Stability)

- <	!ELEMENT m3-2-p-8-1-stability-summary-				and-conclusion
- 		((leaf | node-extension)*)>

- ?	Optional — element appears once or not at all
- *	Optional and repeatable — element may appear 0 or more times

## Quality/CMC Information

- Module 1 (Region Specific Information)
- Environmental Assessment
- Module 2 (Summaries)
- 2.3 Quality Overall Summary(Note: only one summary, unlike E & S sections)
- Module 3
- Drug Substance
- Drug Product
- Appendices
- Regional Information

## Submitting to Multiple Applications

- Identical information may apply to multiple applications (i.e. NDAs, ANDAs, BLAs)
- Examples:
- Amendment to original NDAs for different dosage forms
- CMC supplement w/ API change for all approved dosage forms

## Submitting to Multiple Applications

- Current Module 1 DTD does *not* allow a single submission to apply to multiple applications
- Workaround
- Submit the data once, along with the backbone for NDA #1
- Then, submit only the backbone for NDA #2, etc.

- E.g., for applications AP1, AP2, AP3 which have CMC data in common, submit the file in AP1 sequence 0004 where the leaf would have:
- 	xlink:href="m3/32bodydata/32p-drug-prod/xxx.pdf"
- AP2 and AP3 would then be able to cite this source data in their index.xml leaf element with:
- 	xlink:href="../AP1/0004/m3/32body-data/32p-drug-prod/xxx.pdf"

## 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/guidance
- Guidance for Industry: Drug Substance (Draft)
- Guidance for Industry: Drug Product (Draft)
- MaPP 5320.1 www.fda.gov/cder/mapp/5320.1.pdf

- For general FDA eCTD guidance see: www.fda.gov/cder/regulatory/ersr/ectd.htm

## Repeated Quality Sections

- See especially “**Electronic Common Technical Document Specification”**, v 3.2, page ‘6-11’ www.ich.org
- Always use attributes when available, even for non-repeating sections
- Multiple drug substances (e.g. Augmentin)
- Repeat entire, standalone drug substance section
- Use name attribute <m-3-2-s-drug-substance substance=“amoxicillin” manufacturer=“ABC, Inc”>
- P.4 Control of Excipients
- See eCTD Q&A

## Topics Appearing inMultiple SectionsA Few Examples

- Note that information regarding P.2.x section may be subject to change, pending the outcome of Q8

## 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

- P 2.1.1 PD – Drug Substance
- DP manufactured from different particle sizes
- P 2.2.1 PD – Formulation Development
- Profiles linking clinical trial product to that proposed for market
- P 2.2.3 PD – Physicochemical and Biological Properties
- Q6A disintegration rationale

## Issues to be Resolved

- Module 2 Quality Overall Summary
- Content
- Use
- For supplements
- P.2 Pharmaceutical Development (ICH Q8)
- Incorporation of risk-management (ICH Q9)
- Stability data