MAH Responsibilities including the Management of CMOs. QP Forum Workshop. Robert Byrne and Eoin Duff Quality Assurance Alexion Pharmaceuticals

MAH Responsibilities including the Management of CMOs QP Forum 2017 - Workshop Robert Byrne and Eoin Duff Quality Assurance Alexion Pharmaceuticals 25 th April 2017

Alexion Pharmaceuticals in Ireland A global biopharmaceutical company focused on developing and delivering life-transforming therapies for patients with devastating and rare diseases. Alexion s Global Supply Chain Headquarters, Dublin - Laboratories Packaging facility Biologics manufacturing facility (under construction) Alexion Athlone Manufacturing Facility Vial fill-finish facility Biologics manufacturing facility (under construction) 2

Workshop content Brief overview focussing on MAH Responsibilities Qualified Person and the MAH Global Manufacturing Compliance Challenge Examples 3

Workshop content Interactive discussions Management of CMOs Marketing authorisation dossiers Annex 16 - Non-EU marketing authorisations Handling of unexpected deviations Medicines shortages Other topics? 4

MAH Responsibilities Core Principle The ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the MAH 5

MAH Responsibilities with Respect to GMP EU Directives Maintain MA in line with scientific advances Ensure continued and appropriate supply to meet patient need (Topic 4) EU GMPs PQR review Outsourcing Quality defects, risk-reducing actions, disruption to supply Irradiation cycle design approval and location of records Sites of QP certification Reference and retention samples Reference: Concept paper on Good Manufacturing Practice and Marketing Authorisation Holders (EMA/582064/2016) 6

Qualified Person and the MAH European Regulator or Not? Registration Dossier Medicines Shortages Unexpected Deviations Management of CMOs 7

Global Manufacturing of Medicinal Products ACME Pharmaceuticals DP FP DS 8

Contract Manufacturing - Regulator Focus? Survey - Has management/oversight/disposition of CMO manufactured batches been requested during audit of MAH site(s) within the last 3 years? 10/24 14/24 9

Compliance Challenges 10

Workshop Focus Topics 11

Topic 1. Management of CMOs Focus area What approach works best? Quality Agreement in association with customer audits 100% oversight executed batch record review, change control and deviation review and approval Risk based approach Major/Critical deviations and product/regulatory impacting change controls etc. 12

Survey Results Does your company's QA group perform any level of executed batch record review, batch specific Deviation or batch specific Change Control review for batches (API/Drug Substance/Drug Product/Finished Product) manufactured by CMO prior to release? 23/24 01/24 13

Survey Results What oversight is provided by your company for CMO manufactured batches? Quality Agreement and Customer Audit Only Other 14

Survey Results Is certification of any of the following CMO manufactured batches provided by your company's Qualified Person (QP)? 70% 60% 50% 40% 30% 20% 10% 0% Drug Substance/API Drug Product Finished Product (Packaged Product) No Certification Provided 15

Survey Results Does your company use a risk based approach to determine the level of oversight provided for CMO manufactured batches? Yes 13.0% 26.1% 60.9% No All releases are performed by CMO with no batch release activity/review performed by the MAH 16

Survey Results In your opinion should the MAH perform batch review/release/certification of batches manufactured by CMO if the responsibility has been given to the CMO and is documented in the relevant Quality Agreements? 11/24 13/24 17

Topic 2. Marketing Authorisation Dossiers Focus Dealing with MA dossiers Do you have full visibility of the current version? Is it complete? Is it harmonised across jurisdictions? Aspect 1 Dealing with manufacturing sites Aspect 2 Dealing with regulatory authorities 18

Topic 3. Annex 16 - Non-EU marketing authorisations Focus area - How does Annex 16 apply to non-eu marketing authorisations outside of EU? The functions of the qualified person shall be. to ensure that every batch of a medicinal product to which the authorisation relates has been manufactured and checked in compliance with. (iii) the provisions of the marketing authorisation, certificate of registration, certificate of traditional-use registration or other standard which relates to the said product References: EU GMPs Annex 16 Certification by a Qualified Person and Batch Release S.I. No. 539 of 2007 Medicinal Products (Control of Manufacture) Regulations 2007 19

Topic 4. Handling of Unexpected Deviations - QP discretion Aspect 1 QP is employed by the marketing authorisation holder Aspect 2 QP is employed by a manufacturing/packing/batch release site that is not the marketing authorisation holder Challenge Complete visibility of the marketing authorisation is not available to the QP 20

Survey Results Is final batch certification by Qualified Person (QP) performed by your company or by a subcontracted party? Subcontracted to another company By my company 0% 10% 20% 30% 40% 50% 60% 70% 80% 21

Topic 5 Medicines Shortages Focus MAH/Manufacturing site interaction 22