Experience of Post approval change management protocol in EU. Mats Welin Senior expert Medical Products Agency Uppsala, Sweden

Transcription

1 Experience of Post approval change management protocol in EU Mats Welin Senior expert Medical Products Agency Uppsala, Sweden

2 Regulatory oversight What is in the filed dossier Descriptions of processes and monitoring thereof, validation, testing of starting material, intermediates, drug substance, drug product etc.- Basis for approval of application GMP related issues quality systems, knowledge managment, adherence to GMP requirements, trending, change control etc. Basis for approval of site 2

3 Regulatory oversight (cont.) To reach a preferred state in accordance with Q8-11, these two parts need to work together- e.g. certain residual risks identified in an assessment could be cleared through appropriate GMP related systems assuring that the process is in control. This calls for an enhanced collaboration between inspectors and assessors and possibly more product related inspections. Identified and hopefully outcome of Q12. 3

4 Post Approval Change Management Protocols (PACMPs) Introduced in the EU legislation 2010 (2010/C 17/01 ) Option for a faster and more predictable implementation of changes post-approval. Uses a step-wise procedure starting with an evaluation of the strategy for the change followed by a separate evaluation of the data produced based on the agreed strategy.

5 PACMP Strategy Planned studies Acceptance criteria Methods + Traditional approach Evaluation of a proposed variation as a whole (Strategy + Results) Strategy Planned Results studies + Acceptance criteria Methods Early Step 1: Submission of a Protocol MAA / Type II Variation Results Quick Step 2: Implementation of the change Type IB Variation for biologics/ia or IB for small molecules

6 Post Approval Change Management Protocol (PACMP) Apply to all medicinal products for human and veterinary use including biotechnological or biological products. Irrespective of whether a traditional or enhanced Quality by Design (QbD) approach has been used for product development.

7 Post Approval Change Management Protocol (PACMP) May be included in an original marketing authorisation application or (line) extension application, or be submitted as a stand alone variation. Not feasible for biological medicinal products where non-clinical/clinical data are needed as part of the comparability exercise. A PACMP should not include changes that would in itself result in a line extension.

8 Post Approval Change Management Protocol (PACMP) Protocols should be specific to a product although the same management strategies may be applicable to other products and processes. Companies are recommended to submit PACMPs only for those changes that they are highly likely to implement and whose feasibility has already been investigated and is supported by relevant data. Inclusion of several PACMPs for a given process may cause problems as the prechange starting point may differ depending on the number introduced.

9 Post Approval Change Management Protocol (PAMPC) - Content of the protocol EU guideline on Quality: Questions and Answers Post approval change management protocols (EMA/CHMP/CVMP/QWP/586330/2010)

10 Post Approval Change Management Protocol (PAMPC) - Content of the protocol Justification for the need for a specific change(s) within a reasonable timeframe. Commitment to update the approved protocol, due to significant changes to test methods/acceptance criteria or new knowledge or regulatory requirements. A detailed description of the change. Data from development or pilot scale studies supporting that proposed approach is feasible. Risk assessment of the impact of the change on product quality. Identification for potential risks and details on the strategy of how the risks will mitigated or managed. Appropriateness of the approved control strategy and additional tests needed

11 Post Approval Change Management Protocol (PAMPC) - Content of the protocol, continued Description of the studies to be performed, and the test methods and acceptance criteria that will be used For biologics, the approach to be used to demonstrate the comparability of the pre- and post- change product (IPC test, spec s and extended characterisation studies). A plan for stability studies should be included, if appropriate; For chemical medicinal products, a proposal of how the implementation of the change will be reported, as a Type IA / IAIN variation or Type IB variation For biological medicinal products the reporting shall always be made as a Type IB variation

12 Post Approval Change Management Protocol (PAMPC) - Content of the protocol A prerequisite for the implementation of a change described in an approved protocol is that all studies described in the protocol have been performed, and the results of the studies comply with the predefined criteria set out in the protocol. The variation procedures used for reporting of data cannot include e.g. justifications for deviations to an established protocol or the pre-defined acceptance criteria revision or submission as a standard variation. Worthwhile to discuss with rapporteurs though

13 PACMPs- whats the benefit? Predictability!!! If the protocol is approved and the results as expected, a quick approval can be foreseen with no requests for further data- validation batches can be commercialised Delays due to questions at initial stage not end of the world Faster approval once the variation is ready for implementation 13

14 PACMPs in the centralised procedure (last updated on 01/04/2016) SCOPE TYPE II MAA Line extension New site for manufacture and/or QC testing of the drug substance Bio: 13 Bio: 1 Che: 5 New site for manufacture and/or QC testing of the drug product Bio: 24 Che: 2 Bio: 6 Che: 2 Change to the manufacturing process of the drug Bio: 11 Bio: 6 substance Che: 1 Scale-up of the drug substance manufacturing process Bio: 5 Bio: 2 Bio: 2 Change to the preparation of a cell bank Bio: 2 Change to the manufacturing process of the drug product Bio: 2 Che: 3 Change to the container closure system of the drug substance or drug product Bio: 1 Che: 2 Bio: 1 Che: 1 Che: 1 Other Bio: 3 Bio: 2 Che: 1 TOTAL - For biologics: 81 MAA 20, Type II 59, Extension 2 - For chemicals: 18 MAA 11, Type II 6, Extension 1

15 Why is this? Many variations which are classified as type IIs for biologicals are IB s for small molecules- less incentive to use a procedure starting with a type II variation by default. But if put in the initial application and approved, the reporting category will likely be lower. Therefore also likely to be of interest for small molecules 15

16 PACMPs experience so far Problems seen so far: Primarily linked to the timing of the application of the PACMP Changes not described in sufficient detail Too limited data to support that the change is feasible Too limited data to support the proposed strategy for definition of acceptance criteria Content of the follow-up variation not clearly described

17 PACMPs- future opportunities Combination of PACMPs and worksharing to handle many products undergoing the same change (e.g. change in filling, change of rubber stopper) One application to cover the work to be done can serve for all. Product specific implementation when data is available Matrixing possible based on Risk assessment Possibility of a reporting IA opportunity like for chemicals based on risk assessment for biologicals as well in the future? Possibility of handling within PQS only? 17

18 PACMPs- future opportunities (cont.) Regulators like concrete proposals- If very broad PACMPs covering many products and types of possible changes with options of possible local, non-specified adaptions between sites, this is likely to cause concerns. May be more effective with several more focussed applications. Current regulation quite strict- may need to be revised following Q12.

19 Life cycle managment -Conclusion Holistic approach which needs more extensive interaction assessors/ inspectors Regulation of variations incl PACMPs are living documents- forward your proposals for better fit with need Make use of PACMPs as this will smoothen introduction of variations both for small molecules and biotech- we are happy to discuss your proposals. F2F or written advice Acknowledge the complexity if several PACMPs deals e.g. with the manufacturing process. 19

20 Thank you Questions? 20