Accelerated Commercialization of a Drug Substance Process Under FDA Breakthrough Designation

Transcription

1 Accelerated Commercialization of a Drug Substance Process Under FDA Breakthrough Designation Scott Tobler, Tamas Blandl, Gargi Maheshwari Global Vaccines and Biologics Commercialization Merck and Co., Inc. WCBP Conference - January 29, 2015

2 KEYTRUDA Background Approval of KEYTRUDA (pembrolizumab) High affinity, humanized monoclonal IgG4 antibody that binds to PD-1, and prevents binding to PD-L1 and PD-L2 Data from a Phase 1 study supported accelerated FDA approval For treatment of patients with unresectable or metastatic melanoma, and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 2

3 KEYTRUDA Background Key Regulatory Milestones for the CMC Team Announced FDA breakthrough designation April 2013 Multiple FDA interactions Throughout 2013 Completed rolling submission to FDA February 2014 Additional filings submitted to ex-us regions Throughout 2014 FDA grants approval September

4 Base timeline for commercialization (4 years) Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Transfer Ph III Clinical Mfg/ Stability Y2 Q3 Y2 Q4 Y3 Q1 Y3 Q2 Y3 Q3 Y3 Q4 Control Strategy PPQ Campaign Y4 Q1 Y4 Q2 Y4 Q3 Y4 Q4 File

5 Accelerated timeline for commercialization (1.5 years) Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Control Strategy Transfer Clinical Mfg / Stability PPQ Campaign Additional considerations Analytical comparability back to original site/process required Supply forecasts volatile throughout this timeframe Additional clinical indications Dose uncertainty File

6 Enablers for acceleration for the commercialization team Resources Outsourcing (internal and external networks) Prioritization and careful linkage of activities Parallel workstreams Accepted technical risk across workstreams (until final package assembled) Planning for possible re-work 6

7 Resources: CMC Team Structure Quality Lead DS Working Group Product Development Team DP Working Group Project Team Leader IDST Supply Chain Working Group Maintained our core structure of our Integrated Development & Supply team Large increase in working group membership, subteam lead roles, etc Outsourcing still requires internal resources Global Clinical Supplies Analytical Working Group CMC/Regulatory Working Group Global Marketing Team

8 Rapid + Parallel Initiation of PC and Manufacturing Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Control Strategy Transfer Clinical Mfg / Stability PPQ Mfg File Risk Assessments Pre-PC Pre-PPQ Post-PPQ Risk assessments First of several iterations of risk assessment (Pre-PC) completed prior to manufacturing experience to inform PC study design Later iterations provided opportunity to trigger additional mitigations, but no further PC work for filing

9 Rapid + Parallel Initiation of PC and Manufacturing Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Control Strategy Transfer Clinical Mfg / Stability PPQ Mfg File Risk Assessments Pre-PC Pre-PPQ Post-PPQ Scale down model Data available for formal comparison Scale down model qualification No formal qualification prior to PC (used target runs in PC studies) Risk was mitigated by leveraging platform experience with facility Issues addressed late into PC program

10 Design and execution of PC Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Control Strategy Transfer Clinical Mfg / Stability PPQ Mfg File USP PC Execution DSP PC Execution Complete PC package executed to develop Control Strategy Response surface, factorial, and one-factor designs to study more than thirty parameters across eight unit operations Managing compressed timelines Multiple sequential DOEs executed only for the production reactor step Multivariate analyses included, but did not attempt a design space

11 Development of the Control Strategy General Process Knowledge (Risk Assessments) (DOEs) Viral Clearance Additional Characterization Studies Manufacturing Experience Process Control Strategy Parameter classification CPP, KOP, or non-key Proven acceptable ranges In-process controls, limits Definition of intermediates and hold time limits Resin/membrane lifetime limits

12 Addressing new findings after start of PPQ Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Control Strategy Transfer Clinical Mfg / Stability PPQ Mfg File New inputs into control strategy (during or after PPQ / prior to file) Late arriving PC data and analysis Post PPQ analysis documented to assess impact Assess results for any new parameters or new ranges Gap analysis annotated in file to connect PPQ to final control strategy

13 Addressing new findings after filing Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Transfer Clinical Mfg / Stability Continued PC Control Strategy PPQ Mfg File Continued process characterization (post filing) Additional PC experiments triggered to gain further understanding: some lower risk parameters (with potential consistency impact) additional potential interactions and linkages between steps wider PARs, room for future flexibility How to handle in Quality and Regulatory space? Restrictive outcomes: proactively implement in manufacturing, then update regulatory as appropriate Permissive outcomes: maintain in technical documents for deviation support

14 Manufacturing process opportunities Y1 Q1 Y1 Q2 Y1 Q3 Y1 Q4 Y2 Q1 Y2 Q2 Continued PC Control Strategy Transfer Clinical Mfg / Stability Improvements? PPQ Campaign File Barriers to changes, post-clinical manufacturing Limited time for implementation Process comparability, PC laboratory work already in progress Drivers for process changes Supply (yield, run rate) Minor operational robustness enhancements

15 Operational enhancements to increase facility productivity Several operational opportunities identified during clinical manufacturing campaign to increase batch yield Cell culture volume management Filter and piping flushing Alleviating a key tank bottleneck DS filling procedures Ongoing operational excellence and facility utilization efforts also led to shorter DSP run times

16 Realized yield improvements (and reduced variability) Clinical Campaign PPQ Campaign Clinical Campaign PPQ Campaign Yield: Recovery and Initial Capture Yield: Polishing Yield: Formulation, DS filling Mass of Filled DS

17 Concluding Remarks To support program under FDA Breakthrough Designation, the DS working group accelerated using: Resources Complex team structure and increased requirement for coordination Outsourcing (internal and external networks) Prioritization and careful linkage of activities Development of a complete control strategy, appropriately justified with data Some operational opportunities pursued, but process options for improvement deferred Acceptance of technical risk from speed and parallel work Platform process and platform analytical methods Required flexibility and willingness for some re-work across various interrelated areas