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Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies


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BioTechLogic's Tracy TreDenick delivered a compelling presentation discussing process validation & regulatory strategies for Fast-Track and Breakthrough Therapies at BPI West - March 20, 2018

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Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies

  1. 1. Process Validation & Regulatory Strategies for Fast-track and Breakthrough Therapies Tracy TreDenick March 20, 2018
  2. 2. Overview • Background – FDA’s Expedited Pathway Designations – Breakthrough Therapy (BT) Designation by Therapy – Expedited vs Traditional Development Program Timelines – Common Challenges for Breakthrough Therapy Products • Regulatory – Common Process Development Challenges for BT Products – Common Analytical Challenges for BT Products – Common Manufacturing Challenges for BT Products – Key’s to a Successful Regulatory Strategy – Understanding Scientifically Complete CMC Sections • Process Validation – Keys for Successful Validation • Summary Slide 2 Company Confidential
  3. 3. BACKGROUND Primary focus of presentation will be on Breakthrough Therapies (Gene Therapy) Slide 3 Company Confidential
  4. 4. FDA’s Expedited Pathway Designations Slide 4 Company Confidential
  5. 5. BT Designation by Therapy Slide 5 Company Confidential (1) Hemophilia, Cystic Fibrosis, etc. (2) 10 for Hepatitis C (3) PTSD, Depression, GVHD, Peanut Allergy, etc.
  6. 6. Expedited vs Traditional Development Program Timelines Breakthrough Therapy Program Traditional BLA /NDA Program 2 Phase 1 Clinical Study 18 months Several months 2 Decision on BT Application N/A EOP 1 Meeting Confirms Breakthrough Therapy Status 6 months N/A Phase 2/3 Clinical Study 24 months Phase 2: Several Mo. to 2 years 2 Phase 3: 1 to 4 years 2 EOP 3/PreNDA/PreBLA Submission Meeting NDA/BLA Preparation 6 months NDA/BLA Review 6 months 10 months Development Timeline ~ 5.2 years 1 ~7.4 years 1 Slide 6 Company Confidential 1 timeline-by-two-years 2 Breakthrough Therapy designation accelerates a CMC program by almost 2 years.
  7. 7. Common Challenges for Breakthrough Therapy Products • Small Yields • Limited Time Impacts Development – Process Design (Stage 1 of PV) – Analytical Method Development and Validation – Ability to gain detailed process understanding and experience • Quality Programs Must Be Accelerated – Material Qualification Programs • Traditional Paradigm for Financial Investments Happen Sooner • “Phase Appropriate” GMPs – There are approximately 2 fewer years for product development, so commercial GMPs need to be implemented sooner • Change Management is a Challenge – Must be able to demonstrate comparability to initial process Slide 7 Company Confidential
  8. 8. REGULATORY STRATEGIES CASE STUDY – Gene and Cell Therapies Slide 8 Company Confidential
  9. 9. Common Process Development Challenges for BT Products – Critical Quality Attributes: These need to be established earlier on to begin Process Design activities, which is challenging when analytical methods might not be adequately developed / qualified. – Change Management: Breakthrough Therapy designation typically based on ‘Phase 1 Process’ - therefore scale-ups and formulation changes must be minimized for Phase 2/3. – Process and Analytical Comparability: Comparison of process used in Phase 1 Clinical Trial (e.g. Breakthrough Therapy process/material) and proposed commercial process (e.g. scale-up), and plans to establish analytical comparability with potentially under-developed methods. – Process Validation Approaches: Lack of material or batches to perform typical ‘process design studies’ e.g. viral clearance, filter validation, residual or impurity profiling studies including bioburden, etc. The number of available validation lots before filing of NDA/BLA may be less than the typical 3-5 lots. Slide 9 Company Confidential
  10. 10. Common Analytical Challenges for BT Products – Stability: Limited material and limited lots available to propose shelf-life. – Reference Standard Program: Typically companies start with interim standard and then establish commercial reference standard. But, methods need to be validated sooner so commercial reference standard can be established sooner. – In-Process and Release Specifications: Volumes for USP methods are a challenge. For example, 100 mL needed for pre-filtration bioburden, when process only yields 200 mL. – Finished Product Control: Some of the finished product tests take a long time. BT product might expire before that time (e.g. Sterility). – Justification of Specifications: Traditionally more batches and statistical analysis (e.g. 95-99% tolerance interval) are desired. BT products have very limited number of batches therefore limited knowledge of process and analytical variability. – Method Development: Limited time to develop challenging methods such as infectious titer and potency. Slide 10 Company Confidential
  11. 11. Common Manufacturing Challenges for BT Products • Contract Manufacturing: Because a non-traditional and compressed development approach is taken for many activities, CMOs feel the risk of manufacturing and non-compliance is on them, not the Sponsor. • Commercial Manufacturing Site: Companies typically select their commercial manufacturing site just prior to Phase 3 , or while in Phase 3, and perform a transfer. This has to be determined earlier given the accelerated timelines and analytical comparability challenges. • Material Qualification Program: A well designed material qualification program becomes more comprehensive as a development program progresses (See USP 1046). But in case of BT Products, it must be implemented much sooner. Slide 11 Company Confidential
  12. 12. Key’s to a Successful Regulatory Strategy • Open and transparent communication with the FDA is essential throughout the entire approval and post-market process. • The pharmaceutical company mindset of not wanting to further explore certain information for fear of needing to revalidate based on those discoveries has no place in this new reality. • New information will be learned pre- and post-launch, and plenty of amendments will need to be filed. • Given the compressed development timeframes, less stability data will be available at submission. Additional data will be submitted via amendments during the review cycle, and in some cases, post-market. • Launch commercial process with limited experience and optimize post- approval–the classic three runs is not the guiding force within this construct. • The level of flexibility regulators will extend is determined for each specific product on a case by case basis. – Factors taken into consideration include: riskiness of product characteristics, seriousness of the condition and medical need, complexity of manufacturing processes, state of the innovator’s quality system and merits of the innovator’s risk-based quality assessment including Critical Quality Attributes (CQA). Slide 12 Company Confidential
  13. 13. Key’s to a Successful Regulatory Strategy, Continued • Evaluate ways to leverage historical development and manufacturing knowledge to show process consistency and to ensure patient safety and product supply are not compromised • Have early conversations about CMC activities that may be incomplete at launch:  Process Validation, stability studies on commercial product, manufacturing scale/tech transfer data and complete control system data • Propose use of representative pilot scale lots for stability shelf-life • Identify alternative risk-mitigation approaches (e.g. post-marketing commitments for process validation) • Propose (nontraditional or novel) statistical models early for setting specifications • Ensure a “scientifically complete” CMC Section • Early discussions on analytical method validation and establishment of the commercial reference standard Slide 13 Company Confidential
  14. 14. Understanding “Scientifically Complete CMC Sections” • Provide sufficient detailed information on the manufacturing process – Cell bank manufacturing methods including a list of reagents used, descriptions of release tests, and COAs – Plasmid, vectors and drug product process descriptions including release tests – Well classified process parameters (e.g. ranges for operating parameters, limits for in-process controls and acceptance criteria for in-process acceptance criteria) • Prioritize assays for development and validation, e.g. potency and infectious titers • Completion of (non-traditional) manufacturing process validation • Well written comparability protocol using validated assays • Clear description of in-process test methods, because typically they are not filed in the Test Method Description Section. This is important because sometimes these will take precedent over release tests, until adequate data are available. • Consider a post-approval product lifecycle management plan that is included in the filing to support deferred CMC activities. Slide 14 Company Confidential
  15. 15. PROCESS VALIDATION STRATEGIES CASE STUDY – Gene and Cell Therapies Slide 15 Company Confidential
  16. 16. Keys for Successful Process Validation • Critical quality attributes and process characterization work must occur much earlier than a typical pharmaceutical development process. • In many cases, consider broader product quality ranges for non-Critical Quality Attributes until further manufacturing experience is acquired post-approval. • Keys to Success: – Gaining knowledge from the product and process development- EARLY – Understanding sources of variation in the production process - EARLY – Determining the presence of and degree of variation - EARLY – Understanding the impact of variation (e.g. DOE studies) on the process and end product - EARLY – Controlling variation in a manner aligned with Critical Quality Attributes (CQA) and the risk a given attribute introduces to the process – EARLY Slide 16 Company Confidential
  17. 17. Keys for Successful Validation, continued • Enhance analytical methods and understanding to offset more limited process understanding and to support future comparability work. It is extremely important to involve commercial Quality Control representatives in the assay development design. • Traditional Process Validation of 3 to 5 lots typically not possible. What to consider: •Novel statistical models and approaches will need to be applied in many cases. Representative samples and assays for these models will likely need to be acquired from sources, like prior knowledge and use of comparability protocols. •An FDA-negotiated number of full scale PPQ batches using the commercial process. •A commitment to manufacture additional PPQ batches as a post marketing commitment. Slide 17 Company Confidential
  18. 18. Summary • Characterize the process early • Validate methods early based on prioritization • Initiate “Process Design” as soon as expedited designation granted • Consider a non-standard approach to Process Validation, starting communications with FDA about the intended approach early • Initiate development of a regulatory acceptable Reference Standard programs early • Method development and validation need to be expedited • Develop strategies to mitigate material constraints (e.g. small scale for stability) • Comparability often does not follow standard practice • Communicate statistical strategies to establish specifications • Effective Regulatory Writing Slide 18 Company Confidential
  19. 19. Acknowledgements • Dr. Ashley Ruth • David Fetterolf • Julie Spyrison • Patrick Giljum Slide 19 Company Confidential
  20. 20. Thank you Slide 20 Company Confidential