A holistic regulatory approach to accelerated CMC development

Transcription

1 A holistic regulatory approach to accelerated CMC development Seán Barry Ph.D Pharmaceutical Assessor Health Products Regulatory Authority CMC Strategy Forum 2017 Disclaimer: The opinions expressed are my own and do not necessarily represent those of the HPRA or EMA

2 Pathways with accelerated clinical development - Adaptive pathway - Conditional approval - PRIME - Accelerated approval - Fast track designation - Breakthrough therapy Potential bottleneck due to constraints of CMC development

3 CMC considerations for accelerated development Despite the reduced timeframes, no compromise to patient safety is allowed. Therefore, product and process characterisation is required much earlier Full process validation studies incomplete? Only Phase 2 batches at time of filing? Launching from clinical site? Stability studies ongoing? Control strategy still evolving? How should regulators and industry approach accelerated quality development?

4 Accelerated clinical development programmes must strike a balance between regulatory flexibility and ensuring the critical aspects of CMC are not compromised What are the solutions?? Post-approval validation Prior knowledge Use of models PACMPs Holistic approach

5 General CMC strategies for accelerated schemes * Some activities are started sooner than traditional development There is a greater focus on consistent supply post-launch rather than process optimization The QTPP and CQAs should be defined early May need to fix cell line at Phase I in order to avoid the need for comparability studies Scale up from clinical to commercial material postapproval, pre-launch with appropriate bridging data Manufacture DP PPQ batches using clinical DS batches prior to completion of DS PPQ batches * Mostly relevant for recombinant proteins/mabs etc.

6 Continuous process verification In-line/on-line /at-line controls & PAT Depends on level of process understanding Prior knowledge Process Validation Concurrent Validation PV conducted in parallel with routine production Possible when there is a very strong benefit/risk Ongoing process verification Relies on a protocol Indicates how process knowledge, control strategy and characterisation methods will be used

7 Ongoing process verification - protocols Already routinely used for e.g. full scale validation of resin lifetime and reprocessing (e.g. re-filtration) Full realisation of leveraging data from post-validation studies will require wider use of protocols Protocol should indicate how process knowledge, control strategy and characterisation methods will be use to assess product quality throughout the lifecycle Protocol should include tests and acceptance criteria that will be used to further demonstrate that the process remains in a validated state Result of ongoing process verification activities should be available during inspection

8 When can post-approval validation schemes be used? Level of flexibility is case-by-case and depends on: 1. Seriousness of the indication and the level of unmet medical need 2. Product characteristics 3. Manufacturing processes complexity 4. Applicant s risk assessment 5. Possibly the manufacturer s PQS (ICH Q12)

9 When can post-approval validation schemes be used? Communication with regulator is critical Be clear and transparent regarding missing data and provide a plan to acquire data post-approval (with proposed timelines) Clear demonstration of process understanding Can combine available process validation data with validation protocol(s ) to fill the gaps Demonstration of process knowledge Process Validation Requirements

10 Small scale models Greater use of models can reduce the subsequent process validation burden Build into early development with a view to establishing the PARs early in the clinical programme Using small scale data to justify all PARs allows the PV batches to be run at set-point/nors Even if process changes during development, many PARs will still be relevant, particularly true for scale-up when PARs are scale independent Additional data from prior knowledge could complement some gaps in small scale data

11 What is Prior Knowledge? Any relevant information gained from the development of one product which can be leveraged for the manufacture and control of another product (My thoughts not an official definition!) mab1 mab2 The main challenge is how to show information from one product is relevant for another What role for literature data? Recombinant mab?

12 There are considerable possibilities for utilizing prior knowledge in the development and control strategy Preliminary QTPP Define CQAs Define preliminary CPPs, IPCs, PARs Small scale studies Process validation Prior Knowledge Prior Knowledge Prior Knowledge Prior Knowledge What to document in the file Explain how prior knowledge was used in: Establishing the input set points Setting the outer boundaries of the process ranges Defining the CPPs Assigning CQAs... (what about setting criticality of attributes where there is a different indication, dosage etc?). Note: EMA has limited experience with the use of Prior Knowledge or platforms in the dossier, so any novel approach would benefit from early Scientific Advice

13 Leveraging prior knowledge to define the criticality of process parameters mab1 mab2 mab3 mab4 New mab Flow rate CPP CPP CPP CPP CPP Load ratio CPP CPP CPP CPP CPP Load conductivity KPP KPP KPP KPP KPP Peak collection start/stop CPP KPP KPP KPP KPP Eluate ph KPP KPP KPP KPP KPP Load ph CPP KPP CPP KPP? Column bed height CPP CPP KPP CPP? Prior knowledge Product specific CPP = Critical process parameter KPP = Key process parameter

14 Can ranges from previous products be used to justify current ranges? mab1 mab2 mab3 mab4 Input Buffer ph Buffer conductivity Output Standard IPC programme Load ratio Output Range finding studies (PV/small scale) SEC, ciex, yield, HCP, DNA... For each combination of PARs (input) there is a known output (IPCs and other quality data from PV/small scale) Could a model be built for each unit operation to show that for a similar product and manufacturing process, the proposed operating ranges always result in a product of acceptable quality?

15 PARs for each step can be supported by a combination of small scale, full scale and prior knowledge Enhanced IPC programme Filling with a more restrictive control strategy File with an increased number of IPCs, process parameters and release tests Outline in a PACMP the strategy for removal of some of these additional tests post-approval

16 Combination of ongoing process verification and prior knowledge Example 1 Product-specific small scale data available but 3 full scale PV batches not available PARs justified based on small scale data and prior knowledge from full scale Additional data from full scale PV batches provided post-approval Example 2 PV batches run at set point/nor but productspecific small scale data not available to challenge ranges Small scale and full scale data from prior knowledge Additional small scale/full scale data provided post approval to validate PARs These approaches have yet to be seen in a dossier

17 Post approval change management protocols (PACMP) In the context of the lifecycle approach, certain validation and/or upscaling/change activities may be agreed to be conducted post-marketing with the use of appropriate regulatory tools available (e.g., post approval change management protocols). Becoming more common, however full potential has not yet been realised Opportunity for the applicant to perform a gap analysis and present a plan to the regulator how the knowledge gap will be addressed post approval Untapped resource for expected bottlenecks in accelerated pathways

18 Specifications and accelerated development Continues to be challenging how to set clinically meaningful specs when only a few batches available? Wide specifications could be approved with commitment to revise after certain number of batches produced Balance between specs which ensure a safe & efficacious product and avoiding unnecessary batch rejection File with an increased testing panel, some of which can be removed post-approval as more batch data become available Data may not yet be available to support removal of testing of e.g. HCP, DNA, Protein A etc. from specs

19 Theoretical example for setting specifications with few batches Potency results for 3 lots 98%, 100%, 102% Proposed acceptance criteria: % 1 Specifications will be revisited after more batch data is available X Unlikely to be accepted 2 Specifications will be revised after 10 batches? May not be accepted 3 PACMP submitted Specifications revised via variation after 10 batches Revised acceptance criteria will be based on the following statistical approach... Plan for how specs will be clinically qualified Any OOT data will be investigated as part of the PQS More likely to be accepted

20 Some final thoughts on accelerated pathways from an assessor s viewpoint An accelerated time line does not mean a premature dossier. Accelerated pathway products can be closer to late stage IMP however an accelerated dossier IMPD! Currently a rolling review model for quality/cmc is possible as part of the PRIME scheme but not other accelerated procedures engage early through scientific advice Full validation of methods required All sections of Module 3 to be completed!

21 Conclusions Having less data at the time of approval should not compromise patient safety Several avenues exist to address the bottleneck due to CMC development A holistic approach utilizing the combined tools of post-approval validation, prior knowledge, small scale models and PACMPs could take CMC off the critical path However there may be a trade between initial reduced manufacturing flexibility and earlier approval Both industry and regulators should continue to explore new approaches to overcoming the CMC challenges of accelerated development

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