PPQ-to-Approval Timelines Acceleration Approaches at BMS

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1 PPQ-to-Approval Timelines Acceleration Approaches at BMS Marcus Boyer Bristol-Myers Squibb Associate Director Process Life-cycle Management Syracuse, NY USA Kristen Manchester Bristol-Myers Squibb Sr. Engineer Drug Substance Process Champion Syracuse, NY USA

2 Discussion Points Distinction between continuous and ongoing or continued process verification How does continuous process verification differ from traditional process validation? Advantages and challenges of continuous process verification BMS case-studies: Departure from traditional process validation 2

3 Continuous versus Ongoing Process Verification Continuous Process Verification An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8) Ongoing or Continued Process Verification Assuring that during routine production the process remains in a state of control. (EU Draft Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission) (FDA Guidance for Industry; Process Validation: General Principles and Practices) Quality Target Product Profile Process Reproducibility Critical Quality Attributes istical-process-control/ Manufacturing Control Strategy ion.com/verification/ /pharma/verification_nmr/ 3

4 Traditional Process Validation (Eudralex Annex 15) Use of a minimum of three consecutive batches manufactured under routine conditions to confirm reproducibility during process performance qualification (PPQ) is generally considered acceptable. A process validation protocol should leverage development data or documented process knowledge to define: Critical quality attributes Critical process parameters Associated acceptance criteria 4

5 Continuous Process Verification (Eudralex Annex 15) Alternative approaches may be justified where the control strategy demonstrated that the process is capable of consistently delivering quality product with a high degree of assurance during development. The control strategy should define: Incoming materials Critical quality attributes Critical process parameters Regular evaluation of the control strategy Process Analytical Technology and multivariate statistical process control may be used as tools for verification. 5

6 Challenges of Continuous Process Verification Manufacturers and regulators share the goal of increasing the speed of getting drug to patients Process Knowledge + Robust Monitoring Risk-Based Continuous Verification Speed to Patients True continuous process verification may be difficult to implement, especially for accelerated programs due to: Limited time for process development and characterization Limited manufacturing experience to set meaningful statistical process control limits Maturity of data collection and monitoring systems Concurrent review and accelerated approval timelines may limit launch supplies

7 Departure from Traditional Process Validation BMS has recently commercialized multiple molecules with breakthrough or fast track designation; working with Health Authorities on low-risk acceleration within the traditional framework Extension of risk-based acceleration begins to approach the continuous process verification paradigm A hybrid approach requires a substantial amount of product and process knowledge from manufacturing experience Use of platform technology to support development Widespread implementation of statistical process control program(s) for ongoing process verification Especially useful for post-commercial process and facility changes 7

8 Equipment Grouping CASE STUDY 1 8

9 BMS Case Study 1: Equipment Grouping 3x Risk-based Approach 3x Equivalency: N/A N/A N/A Traditional n+2 Approach: 8 PPQ Runs Design and installation data Operability data (temp profiles, addition volumes, kla) Data from previous products Grouping Approach: 5 PPQ Runs BMS has submitted applications with process performance qualification (PPQ) data from a subset of bioreactors, plus equipment equivalency data. US approval of first such submission for a new facility resulted in post-marketing commitments to provide additional data. Data could have been monitored or reported under an ongoing process verification plan.

10 Extension of Equipment Grouping Strategy No requirement for all bioreactors, no replication within one train 8-lot campaign becomes 3, preserving the 3-lot paradigm Justification for this approach may be stronger when the facility has been previously qualified for other product(s) 3x Risk-based Approach Equivalency: N/A N/A N/A Traditional n+2 Approach: 8 PPQ Runs Design and installation data Operability data (temp profiles, addition volumes, kla) Data from previous products Grouping Approach: 3 PPQ Runs

11 Prospective Capacity Expansion Planning CASE STUDY 2 11

12 BMS Case Study 2: Prospective Capacity Expansion Planning Manufacturing capacity expansion often necessary as demand grows Variations for expansion require significant time Initial file might be accelerated if the path to expansion is smoothed BMS proactively discussed within-site expansion with FDA during initial review FDA agreed to inspect manufacturing area not included in initial file Supplement was ready and agency expected submission as soon as initial approval was granted ory-workers-jacksonville-nc/

13 Extension of Proactive Capacity Expansion Planning Within-site expansion using continuous process verification Limit the scope of initial full-scale demonstration to speed completion Comparable equipment, people, and analytical tests across site Leverage ongoing process verification knowledge from statistical process monitoring program Approval based on a continuous process verification protocol would be low-risk Post-approval scale up or tech transfer using continuous process verification Example: launching at clinical scale speeds initial file Continuous process verification protocol for post-approval scale-up or transfer measured against clinical and launch lots ctory-workers-jacksonville-nc/

14 Risk-Based Stability Requirement CASE STUDY 3 14

15 BMS Case Study 3: Risk-based Stability Requirement Drug substance (DS) and drug product (DP) stability data often on the critical path for CMC file A year may pass between start of DS production and 6 month stability data Especially for capacity expansion filings, stability profile may be well established and favorable Low risk that comparable DS material from new site will have a different stability profile Even lower risk that unchanged DP process will interact with new DS site to produce a different stability profile BMS submitted a new DS site without DP stability data Data collection in parallel with review

16 Extension of Risk-based Stability Requirement A comparable product has a low risk of a different stability profile Submit variation based on time zero data (release and characterization results) Example: No DS stability data at time of filing for DS site change No DP data

17 Conclusions To accelerate approval of exciting new drugs, BMS has employed risk-based compression of traditional process validation data requirements. These modest departures remain within the current paradigm, but offer tangible timeline benefits. Further defendable options for acceleration exist which begin to approach the continuous process verification paradigm.