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Converting Your CMC Submissions to the CTD Quality Format

Converting Your CMC Submissions to the CTD Quality Format. Michelle Herrera Foster, Ph.D. CTDQuality.com 12/03 DIA Meeting. ICH M4Q Quality. The CTD. Mod 1 Regional. QOS = Quality Overall Summary (40-80 pages + attachments). Mod 2. Summaries. 2.3 QOS. Non-clinical. Clinical.

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Converting Your CMC Submissions to the CTD Quality Format

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  1. Converting Your CMC Submissions to the CTD Quality Format Michelle Herrera Foster, Ph.D. CTDQuality.com 12/03 DIA Meeting

  2. ICH M4Q Quality The CTD Mod 1 Regional QOS = Quality Overall Summary (40-80 pages + attachments) Mod 2 Summaries 2.3 QOS Non-clinical Clinical Module 3 Quality Module 4 Nonclinical Module 5 Clinical Michelle Herrera Foster, Ph.D.

  3. Frequently Asked Questions • What requirements are new? • What’s different between regions? • Any special considerations for each section? • Is the CTD used for clinical applications? • How do we prepare a CTD efficiently? Michelle Herrera Foster, Ph.D.

  4. Topics • Points to Consider for the Transition • Correlating the CTD to NDA, BLA, MAA • New Sections Required by the CTD • Regional Requirements • Module 2, Quality Overall Summary • Module 3 Quality (by functional area) • The “ICTD” – Investigational CTD • The SMART Process Michelle Herrera Foster, Ph.D.

  5. Points to Consider • Know the guidelines: ICH and regional • Provide training to prepare for the change • Know your company’s submission needs • Consider future variations and supplements • eCTD: Work with Documentation & IT groups • CTD Team: Different functions and regions • Start early, at the IND stage! Michelle Herrera Foster, Ph.D.

  6. Correlating the CTD to NDA, BLA, MAA(full outline available by request) Michelle Herrera Foster, Ph.D.

  7. New Sections Requiredby the CTD • 3.2.S.2.4 Controls of Critical Steps and Intermediates • 3.2.S.2.6 Manufacturing Process Development • 3.2.P.4 Control of Excipients: methods validation and human/animal origin • 3.2.A.2 Adventitious Agents Safety Evaluation • 3.2.A.3 Novel Excipients Michelle Herrera Foster, Ph.D.

  8. “New” Sections in the U.S.:Formalization of Expected Information • 3.2.S.3, 3.2.P.5.5 Impurities • 3.2.S.5, 3.2.P.5.6 Justification of Specifications • 3.2.P.2 Pharmaceutical Development Michelle Herrera Foster, Ph.D.

  9. Regional Requirements • Module 1: Forms, Labeling, DMF Letters, Environmental Assessment • 3.2.R RegionalInformation • Executed Batch Record (U.S., in English) • Method Validation Package (U.S., EDQM) • Comparability Protocols (U.S.) • Process Validation Scheme (EU) • Medical Device (EU) • Reviewer-Specified Information • Market-Specific Information (e.g. specs) Michelle Herrera Foster, Ph.D.

  10. Module 2The Quality Overall Summary (QOS) • Summary is 40 pages text • Present key product parameters and data • Format same as Module 3 • Content consistent with Module 3 • Content integrated with other summaries • Explain any deviations from the guidelines • “Expert report” critical assessments. • Canadians require table formats. Michelle Herrera Foster, Ph.D.

  11. Module 3 Drug Substance (DS) Michelle Herrera Foster, Ph.D.

  12. Module 3 Drug Product (DP) Michelle Herrera Foster, Ph.D.

  13. Module 3 Appendices Michelle Herrera Foster, Ph.D.

  14. DS ManufactureSpecial Considerations • Detailed flow charts: materials, parameters, testing • Critical steps: Define and justify testing • Biotech: Batch numbering, pooling, cell line development, elution profiles, column/membrane lifetimes • Intermediates: QC and stability data • Mfg Development: Batch history, mfg changes • Comparability: Side-by-side flowcharts and data Michelle Herrera Foster, Ph.D.

  15. DS CharacterizationSpecial Considerations • Origin of impurities: synthetic, degradation pathways • Isomerism, stereochemistry, polymorphism • Intermediates • Biotech/proteins: Post-translational, heterogeneity, bioactivity, immunogenicity • Process impurities: residual solvents and extractables/leachables Michelle Herrera Foster, Ph.D.

  16. DP ManufactureSpecial Considerations • PharmDev: Development of formulation/process, container-closure, compatibility, comparability • Sterile processes: hold times, transfers, storage • Sterile Process Validation (FDA guideline) • Container-closure (FDA guideline) • Sub-modules for diluents and placebo Michelle Herrera Foster, Ph.D.

  17. AnalyticalSpecial Considerations • Compendial excipients: USP, EP, JP • Non-compendial: Provide specs • DS and DP Specs: Release, shelf-life • Describe alternate methods • Provide bridging data for revised procedures • Provide representative chromatograms • Batch analyses: Clinical and commercial lots • Justification of specs: Provide data and rationales Michelle Herrera Foster, Ph.D.

  18. StabilitySpecial Considerations • Data support the label for storage/shipping • Justification of stability-indicating tests • Stress (forced degradation) studies • Pilot studies: justify lots are “representative” • Representative scans, chromatograms • Stability data tables (FDA guideline) Michelle Herrera Foster, Ph.D.

  19. Facilities and EquipmentSpecial Considerations • Precautions taken to prevent contamination • Environmental monitoring • Flow diagrams: product, personnel, waste • Other Products: Campaign, changeover • Cleaning validation summary • Equipment: Product-contact, sterilization Michelle Herrera Foster, Ph.D.

  20. Adventitious AgentsSpecial Considerations • TSE/BSE Certificates of Suitability (EU) • Testing: cell banks, in-process, release • Viral clearance and inactivation studies • History of facility contamination • BSE-free statement Michelle Herrera Foster, Ph.D.

  21. “ICTD”Start in Phase 1 to Build the CTD

  22. The SMART Process for Preparing Submissions Strategy: Plan ahead, first prepare Summary Mapping: Prepare outline with key Messages Authoring: The right authors and Accountability Reviewing: The right reviewers and Resolution Training: Sharing knowledge and Teamwork Michelle Herrera Foster, Ph.D.

  23. Conclusions • The CTD guideline addresses core submission requirements and outlines core regional differences. • Consult regional guidelines and reviewers! • The CTD format for the IND is accepted by FDA and most European agencies, and required by Canada. Michelle Herrera Foster, Ph.D.

  24. Conclusions (contd.) • Planning ahead is key to success and rapid approvals. • Start your CTD in Phase 1. • The CTD facilitates global notification of manufacturing changes. • Your CMC submission is a living document that you have to live with for the lifetime of your product! Michelle Herrera Foster, Ph.D.

  25. References ICH: International Conference on Harmonization www.ich.org FDA: Food and Drug Administration (U.S.) www.fda.gov EMEA: European Medicinal Evaluation Agency (EU, Europe), www.emea.eu.int www.ctdquality.com Michelle@ctdquality.com 978-922-6017

  26. Have a peaceful transition

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