How to make use of Post approval change management protocol in life cycle management of pharmaceuticals Mats Welin Senior expert Medical Products Agency Uppsala, Sweden 26th Annual EuroMeeting 25-27 March 2014 ACV, Vienna Austria Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. 2 Life cycle managment • Managing all phases in the life of a product from the initial development through marketing until the product´s discontinuation. • This talk will concentrate on actions post approval- how to improve the process/ product with a sufficient regulatory oversight but still allowing for flexibility. – basics – variations – Post approval change management protocols 3 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 4 Regulatory oversight (cont.) • To reach a preferred state in accordance with Q8-11, these two parts need to work togethere.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 5 Variations • Requested for changes to the MA post approval • Classification of variations depending on level of risk to public or animal health & impact on the quality, safety and efficacy of medicinal product concerned • Variation regulation handled by the Commission. Classification group at EMA-recommendations may or may not be followed. 6 Types of Variations Changes not requiring prior approval Design space Type IA Do and tell Changes requiring prior approval Type IB Type II Extension Variations Assessment adapted to the level of risk 7 Introd uction to 7 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. PACMP Strategy •Planned studies •Acceptance criteria •Methods + Results Strategy •Planned studies •Acceptance criteria •Methods Early Step 1: “Traditional” approach Evaluation of a proposed variation as a ‘whole’ (Strategy + Results) 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 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. 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 result in a line extension. 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. 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) 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 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 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 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 17 PACMPs – experience so far • Primarily used for biotechnological/biological products – 36 applications for biotech products in the centralized procedure • 6 in MAA ( 2 withdrawn during assessment) the rest as type IIs – < 10 applications for chemical products in the centralized procedure No official figures available on national/MRP applications but according to SE experience the number is low with a similar overweight seen for biotech products. 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 19 PACMPs – experience so far • Most applications have referred to process transfers to new manufacturing sites. • Some for changes of the manufacturing process such as – Reorganisation of the process – Change of column matricides/filters – Change of other raw materials – Up-scale of production 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 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 • Possibility of a reporting IA opportunity for biologicals as well in the future? 22 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 23 Thank you Questions? 24