1. DIA ERS SIAC IND CMC eCTD Submissions Part II – IND to NDA
IND = Investigational New Drug Application
CMC = Chemistry, Manufacturing and Controls
Michelle Herrera Foster, Ph.D.
CTD Quality Consulting

2. Disclaimer
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Change to: In addition to DIA’s continued presence in North America, Europe, and Japan, DIA also serves the following regions:
India (remove italics from Mumbai, India, October 16-18, 2006)
Middle East (7th Annual Middle East Regulatory Conference, Dubai, UNITED ARAB EMIRATES, November 14-16, 2006)
China
Remove Central and Eastern Europe since it’s referenced at the top.
Latin America

3. Topics: IND CMC eCTD Intro to IND Module 3
Considerations for IND eCTDs
Mapping to Source Documents
Examples of IND Granularity
eCTD Templates and Submission-Ready Documents
Conclusions

4. The CTD – Quality Sections Module 3 – ICHM4Q
3.1 Table of Contents
3.2 Body of Data
3.2.S DRUG SUBSTANCE (Name, Manufacturer)
3.2.P DRUG PRODUCT (Name, Dosage Form)
3.2.A Appendices – N/A for IND
3.2.A.1 Facilities and Equipment (Biotech)
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients (see 3.2.S format)
3.2.R Regional Information – N/A for IND
3.3 Literature References

5. Building the NDA from the IND
Module 2 Summaries
Mfg Description, mfg development
Process Validation
Methods Validation
Container Closure
Stability
Facilities/Equipment
Complete details
Keep end goal in mind
IND (Phase 1)
Recommended*
Detailed flow chart, mfg development summary
Only viral safety
Critical parameters
Brief description
Support study duration
Not required
Focus on safety
* Not required except Canada, eCTD

6. Considerations for IND eCTDs
Multiple contributors, contract manufacturing organizations (CMOs), partners
Authors need submission training
Guidelines are often not clear; regional differences
Content expands from phase 1 to 3
Placebo and Comparator require 3.2.P section
Map source documents to eCTD
Choose granularity for optimal life cycle management
Use eCTD Templates
Plan Submission-Ready Documents

7. CMC Source Reports
Sources of information and data to produce eCTD submission documents:
Development reports: characterization reports, formulation development, etc
GMP Documents: specifications, procedures, validation reports, stability reports, etc.
Databases: Batch analysis, stability, etc.
Data sheets (LIMS): Chromatograms, spectra, etc.
Documents from CMOs, suppliers, testing labs
Recommendation:
Map these documents to eCTD sections early on

8. IND Granularity
Granularity depends on the product and life cycle decisions, e.g. two different processes
Granularity beyond the ICHM4 granularity annex can be used, such as sub-sections or attached reports; these are separate documents
More complex products, such as biotech, typically benefit from greater granularity

9. Granularity - Drug Substance
Control of Materials
Analytical Procedures
Green: 1 or multiple documents; see ICH M4 Granularity Annex

10. LCM Decisions – Replace Analytical Procedures
If submit 3.2.S.4.2 as a single file:
When one procedure (e.g. improved HPLC) changes, the entire section must be replaced
If submit 3.2.S.4.2 as multiple files (one for each procedure):
When one procedure changes, just that file gets replaced
Highly recommend submitting procedures and method validation reports (3.2.S.4.3) as individual documents

11. Additional Granularity – example: Biotech Cell Line Development
3.2.S.2.3 Control of Materials:
List of Raw Materials (reference 3.2.A.2 for adventitious agents safety evaluation of animal-derived materials) – granularity for COAs of noncompendials
Cell Line Development
Cell Banking (reference 3.2.A.2 for virus testing of cell banks)

12. CTD/eCTD Templates
Fixed style guide for standardization and granularity
Define content and format for each section, enabling gap analysis
IND  NDA content
Address CTD, ICH, agency guidance
Address regional considerations
Address agency agreements
Customized for each product – annotations
May be expanded into example reports for new authors

13. Submission-Ready Documents
Build the marketing application from Ph 1 to NDA and post-marketing
The modular approach to writing submissions
Each section/attachment is a technical report, or a section within the report
Meet eCTD granularity rules; eCTD-ready
More efficient use of resources, expedites submissions, less cost and stress to the organization

14. Examples of Module 3 Reports
Characterization (3.2.S.3.1)
Formulation Development (3.2.P.2.1)
Manufacturing Development (3.2.S.2.6, 3.2.P.2.3)
Method Validation (3.2.S.4.3, 3.2.P.5.3)
Justification of Specifications (3.2.S.4.5, 3.2.P.5.6)
Process Validation (3.2.P.3.5)
Stability Reports (3.2.S.7, 3.2.P.8)
Stress Studies (3.2.S.3.2, 3.2.S.7)
Container-Closure Evaluation (3.2.P.7)

15. Levels of Submission-Ready Reports
Key results, conclusions
For QOS
Summary
Summary of methods
Module 3
Body of Report
Discussion
Figures, graphs
Raw data
GMP Info
Appendices
May not be submitted, on file
Protocols

16. Conclusions CMC submissions have unique considerations:
Multiple authors, CMOs, partners
Granularity and Life Cycle Management (LCM)
Regional differences
Summaries of source documents
Authors need submission training
Transition to eCTD for LCM benefits
Start early to plan and author; consider submission-ready report formats from IND to NDA
Do a piece at a time for peace in time

17. Contact Information
Michelle Herrera Foster, Ph.D. CTD Quality Consulting