POST APPROVAL CHANGE MANAGEMENT PROTOCOLS IN THE EUROPEAN UNION (EC) No 1234/2008 1 October 2012 CHMP / CVMP Quality Working Party /EMA

Summary 1. Post approval change management protocol (PACMP) 2. Concepts 3. Variation categories in the EU 4. Mechanism for the submission and evaluation of a PACMP 5. The principle of the Change Management Protocol: a 2-step implementation approach 6. Content of a PACMP: generalities 7. Content of a PACMP: The Variations Classifications Guideline 7.1. The Variations Classifications Guideline. Examples 8. Benefits

1. Post approval change management protocol (PACMP) Concept Introduced in EU through Variations Regulation (Commission Regulation (EC) No 1234/2008). Text that supports the Variations Regulation: The Variations Classifications Guideline (2010/C 17/01) Classification of variations into categories. Details, on the scientific data to be submitted for specific variations and how this data should be documented.

2. Concepts A PACMP is a description of specific change(s) that a company would like to implement following marketing authorization and how these would be prepared and verified. A PACMP applies to all types of medicinal products for human and veterinary use including biotechnological or biological products. Traditional or enhanced (Quality by Design) approach has been used for its development. AIM: establish a simple, clearer and more flexible legal framework for the handling mentioned variations of medicinal products, while ensuring a high level of protection of public and animal health.

2. Concepts Incorporates a science and risk-based approach to evaluate impact of change(s) on product quality in a proactive manner. A PACMP should not include changes that would in itself result in a line extension. Each variation should require a separate submission. Grouping variations are allowed in certain cases, in order to facilitate the review of the variations and reduce the administrative burden JUSTIFICATION showing that the changes are related, and that a simultaneous review under a single protocol is meaningful.

3. Variation categories in the EU Minor variation of type IA/IAin: variation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned and does not require prior approval before implementation (“Do and tell” procedure). e.g. variations related to changes in the packaging material not in contact with the finished product, which do not affect the delivery, use, safety or stability of the medicinal product. Major variation of type II : variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned. e.g. variations related to significant modifications of the summary of product characteristics due in particular to new quality, pre-clinical, clinical or pharmacovigilance findings. Source: The Variations Classifications Guideline (2010/C 17/01) & (EC) No 1234/2008

3. Variation categories in the EU Minor variation of type IB: variation which is neither a minor variation of type IA nor a major variation of type II nor an extension and require prior approval before implementation (‘‘tell, wait and do’’ procedure). e.g. Change in batch size (including batch size ranges) of active substance or intermediate More than 10-fold increase compared to the currently approved batch size. Source: The Variations Classifications Guideline (2010/C 17/01) & (EC) No 1234/2008

3. Variation categories in the EU Category Impact on quality, safety or efficacy? Notification and implementation Review time Type IA None / minimal impact Notification: “Do and tell”. within 12 months after implementation 30 days Type IAin Notification: immediate following implementation Type IB Minor potential impact; Classified by default, if change does not fall into another category Notification: before implementation, but no formal approval Implementation: ‘tell, wait and do’ – MAH implements changes unless negative opinion received within 30 days Type II Major potential impact Notification: EMA forwards positive CHMP opinion to EU Commission, and they amend the MA within one year Implementation: following CHMP opinion, without waiting for Commission approval 60 days normally 90 days for indication changes 30 day for urgent safety issues

4. Mechanism for the submission and evaluation of a PACMP May be included in an original marketing authorisation application (MAA) or (line) extension application.  the evaluation of a post approval change management protocol will follow the rules of procedure applicable to the actual MAA. Can be modified via a type II (major change) or type IB (minor change) variation. May be submitted subsequently as a stand alone variation.  the evaluation will follow the rules of procedure applicable for all Quality Type II variations.

5. The principle of the Change Management Protocol: a 2-step implementation approach Without PACMP With PACMP

6. Content of a PACMP: generalities Justification that there is a recognized future need for the specific change within a reasonable timeframe. A detailed description of the proposed change. Risk assessment of the impact of the change on product quality. Discussion on the appropriateness of the approved control strategy to identify and manage these risks. source: EMA/CHMP/CVMP/QWP/586330/2010

6. Content of a PACMP: generalities Description of the studies to be performed, the test methods and acceptance criteria that will be used to fully assess the effect of the proposed change on product quality. A plan for stability studies should be included, if appropriate. In case that the protocol describes several changes, a justification showing that the changes are related, and that a simultaneous review under a single protocol is meaningful. For small molecules, a proposed reporting category for step 2 (type IA or IB variation). For biologics, the approach to be used to demonstrate the comparability of the pre-, and post-change product. (spec’s and extended characterisation studies). The reporting shall always be made as a Type IB variation. Source: EMA/CHMP/CVMP/QWP/586330/2010

7. Content of a PACMP: The Variations Classifications Guideline Classification of variations into categories  Administrative changes Quality changes Safety, Efficacy and Pharmacovigilance changes Specific changes to Plasma Master Files and Vaccine Antigen Master Files Details, on the scientific data to be submitted for specific variations and how this data should be documented.

7.1. The Variations Classifications Guideline. Examples A) Administrative change B) Quality change

8. Benefits Expedited review and/or inspection at step 2 of PACMP procedure. Predictability and transparency in terms of requirements and studies needed to implement a change. Faster implementation, if the pre-determined criteria of the PACMP are met; use of the PACMP could allow an applicant to implement CMC changes and place a product in distribution sooner than without the use of the PACMP procedure.

9. References Variations Regulation (Commission Regulation (EC) No 1234/2008) The Variations Classifications Guideline (2010/C 17/01) EMA/CHMP/CVMP/QWP/586330/2010 Experience of Post approval change management protocol in EU. Mats Welin Senior expert Medical Products Agency Uppsala, Sweden. Post-approval Change Management Protocols Current Status and Next Steps on the Way towards a Global Tool. Dr. Markus Goese Lead EU CMC Regulatory Policy F. Hoffmann-La Roche Ltd, Basel – Switzerland. EMA/13667/2015

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