8th Annual Electronic Submissions Conference

1. Efficient Preparation of eCTD Documents for Chemistry, Manufacturing, and Controls 8th Annual Electronic Submissions Conference Michelle Herrera Foster, Ph.D. Principal, Sr. Regulatory Affairs Consultant CTD Quality Consulting

2. Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

3. Introduction to CMC Submissions: Chemistry, Manufacturing, and Controls • Clinical Applications: • IND – Investigational New Drug Application • CTA – Clinical Trial Application (EU) • IMPD – Investigational Medicinal Product Dossier (EU) • Marketing Applications: • NDA – New Drug Application • BLA – Biologics License Application • ANDA – Abbreviated New Drug Application • MAA – Marketing Authorization Application • Drug Master Files (DMF) • Amendments, Responses to agency questions • Post-Approval Supplements and Variations, Annual Reports

4. Topics • CMC eCTD Challenges • Mapping and Planning • Granularity and Life Cycle Management • Annotated Templates • Submission-Ready Documents • Module 2 Quality Overall Summary • Document Management • Conclusions

5. Challenges - eCTD CMC Docs • Author has more document ownership: • Use of eCTD templates, knowledge of guidance • Granularity and Life Cycle Management • Reviewability of electronic document • Multiple contributors and authors • Regional differences • Efficient systems needed: • Mapping to source documentation • Annotated eCTD templates • Submission-ready document preparation • The Submission Team is key

6. The Submission Team Publishing Sub-Team The Project Team The Submission (eCTD) Team CMC Sub-Team Nonclinical Sub-Team Clinical Sub-Team Labeling Sub-Team Functional Areas

7. The CMC Submission Team • Subject matter experts, technical leads • Multiple authors and reviewers • Functional area management support • Contract Manufacturing Organizations • Partners, regional offices • Regulatory Operations • Authoring assistance; editors • Word processing assistance • The right authors and reviewers

8. eCTD Mapping – Source Docs 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

9. Submission Planning – CTD Map

10. CMC Granularity • Granularity depends on the product and life cycle decisions • More complex products, such as biotech, typically benefit from greater granularity • Granularity beyond the ICHM4 granularity annex can be used, such as sub-sections or attached reports; these are separate documents/leaves

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

12. 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

13. 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)

14. CTD/eCTD Templates • Fixed style guide for standardization and granularity • Customized for each product – annotations • Define content and format for each section, enabling gap analysis • Define acronyms and abbreviations • Hyperlinks in blue text • Address CTD, ICH, agency guidance • Address regional considerations • Address agency agreements • IND  NDA content

15. IND  NDA Content

16. Submission-Ready Documents • Build the marketing application from Ph 1 to NDA and post-marketing • 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

17. Levels of Submission-Ready Reports For QOS, Module 2 Key results, conclusions Summary Summary of methods Module 3 Body of Report Discussion Figures, graphs Raw data GMP Info Appendices May not be submitted, on file Protocols

18. 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)

19. Method Validation Report • Introduction • Summary and Conclusions (for QOS) • Background (method, product, specs) • Summary of Method and materials(for QOS) • Method Development (summarize key parameters, acceptance criteria) • Results and Conclusions • Attachments (raw data, protocol, deviations, etc)

20. Stability Report • Summary and Conclusions • Purpose - proposed shelf life • Stability Protocol • Batches tested, container-closure • Analytical Methods and Acceptance Criteria • Results and Discussion – for ea test • Attachments (raw data, protocol, deviations, etc)

21. Module 2 - The QOS #1 Be Succinct #2 Provide Rationales #3 Bottom Line Up Front #4 Address Key Agency Concerns #5 Link to Module 3, reasonable reuse Tips: • Write the summary first, to summarize the vision of Module 3, integrated with other summaries • Use the QOS as a development tool to capture strategy and approved key messages

22. Document Management eCTD Documents: Source Documents: DRAFT 3.2.S.4.2 Analytical Procedures FINAL/ARCHIVE 3.2.S.4.2 Analytical Procedures Standard Test Methods Submit to Regulatory Agencies Controlled Document Life Cycle Submission Document Life Cycle

23. DIA EDM Reference ModelCMC Domain: STABILITY OF DRUG PRODUCT 3.2.P.8.1 Stability Summary and Conclusions 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment 3.2.P.8.3 Stability Data Primary Stability Supportive Stability Forced Degradation Photostability In-Use Stability Stability of Intermediates

24. Conclusions • CMC submissions have unique considerations: • Multiple authors, CMOs, partners • Granularity and LCM • Regional differences • Summaries of source documents • Authors need submission training • An effective submission process and submission team for planning, authoring, and review is key • Start early to plan and author; map early on • Consider submission-ready report formats from IND to NDA • Consider writing the summary first • Do a piece at a time for peace in time

25. Contact Information Michelle Herrera Foster, Ph.D. CTD Quality Consulting Michelle@ctdquality.com 978-356-0872