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

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. 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

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

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

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

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

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

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

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

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

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)

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

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

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)

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

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

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