Materials Management Traceability, CEPs and managing non-conforming sites

Transcription

1 Materials Management Traceability, CEPs and managing non-conforming sites IMB Information Day, 14 th October 2010 Dr Cormac Dalton Inspector 13-Oct-10 Slide 1

2 Managing Supply Supply Demand Supply chain Broker / Trader / Repacker Non compliance Rework Reprocess Return Suspension Revocation QP Declaration 13-Oct-10 Slide 2

3 Content Proposed revision to EU GMP Chapters 1 & 5 The Pedigree Concept New published procedures from EDQM & EMA Managing non-conforming API sites Managing Non-Compliance Reports from Agencies Case Studies 13-Oct-10 Slide 3

4 Proposed EU GMP Chapter revisions Chapter 1 (re: Product Quality Review, section 1.4) A review of starting materials including packaging materials used in the product, especially those from new sources Proposal to include a review of supply chain Chapter 5 (re: Starting Materials, section ) The Pedigree Concept 13-Oct-10 Slide 4

5 What is Pedigree? A pedigree is a family tree for an active pharmaceutical ingredient (API) tracing its history or supply chain from critical raw material(s) used in the manufacture of the API to the manufacturer of the dosage form. The pedigree should be reviewed periodically to ensure that it is up to date (Chapter 1 proposal) GMP Guide revision (Chapter 5 proposal): Pedigree = Traceability 13-Oct-10 Slide 5

6 Elements of Traceability Knowledge & Knowledge Management (ICH Q10) Fully mapped supply chain Technical agreement(s) Audit program (reports and program for ongoing audits) CEP oversight (next slides) Documentation Labelling Checks performed on incoming receipt Vendor non-conformance management QP declaration based upon an established criteria 13-Oct-10 Slide 6

7 Is this additional regulatory burden? No This is not an additional requirement The documentation of the qualification and verification of the supply chain are well established GMP requirements Many concepts were discussed at previous Information Day Materials Management, IMB Information Day Oct-10 Slide 7

8 New EDQM / EMA Guidance Suspension or Cancellation of a Certificate of Suitability (March 2009) Procedure for dealing with serious GMP non-compliance for voiding/suspension of CEPs thus requiring co-ordinated administrative action (March 2010) d_procedural_guideline/2009/10/wc pdf Procedure for handling rapid alerts arising from quality defects (March 2010) d_procedural_guideline/2009/10/wc pdf 13-Oct-10 Slide 8

9 Definition of a CEP CEP = Certificate of the European Pharmacopoeia (also known as a Certificate of Suitability) Issued by the EDQM based upon an assessment of data from the API manufacturer (equivalent to Drug Master File (DMF) or Active Substance Master File (ASMF)) A CEP can only be issued for a Ph. Eur. monographed substance (e.g. Omeprazole sodium Ph. Eur. but not Omeprazole potassium) API manufacturer subject to EDQM inspection IMB participate in both assessment & inspection programs 13-Oct-10 Slide 9

10 Key aspects of a CEP A CEP is valid for 5 years from the date of first issue and valid indefinitely following the 5-year renewal Some CEPs may have a retest date period, based upon assessment of stability data Some CEPs have additional analytical tests and test methods as an Annex to the CEP Point to note when considering A) supplier qualification and approval B) reduced testing (Chapter 5 revision) CEPs can be suspended or withdrawn and this action directly impacts upon the Finished Product manufacturer 13-Oct-10 Slide 10

11 Managing Non-Compliances Two scenarios for discussion: CEP Suspensions/Withdrawals from EDQM Non-Compliance Reports from Competent Authorities 13-Oct-10 Slide 11

12 Reasons for CEP Suspension Inspection showing critical and/or major deficiencies leading to the conclusion that the company does not operate in compliance with GMP, and/or showing that manufacture does not comply with the dossier submitted for the CEP application Refusal by a company to be inspected in the framework of the EDQM Certification scheme A CEP is not in compliance with the requirements of the procedure and the holder has not submitted suitable information to maintain it A suspension can last for up to two years and until lifted 13-Oct-10 Slide 12

13 Reasons for CEP Withdrawal Withdrawal by the holder of the CEP due to, for example: cessation of production, closure of the site, or because the CEP is no longer of interest Withdrawal by the EDQM in cases where urgent action needs to be taken and no corrective actions are possible, for example in the following situations: after a suspension, the company is not able to fulfil the requirements of the CEP procedure with regards to the updating of the application and compliance with GMP the CEP is not in compliance with the requirements of the procedure and the holder is not able to provide suitable information to maintain it the company holding the CEP no longer exists Withdrawal is indefinite 13-Oct-10 Slide 13

14 Case Study 1 EDQM Notification 2009 re Company A API Manufacturer in Asia Several Major Deficiencies identified during a GMP inspection in 2009 Potential for cross-contamination between APIs, poor microbial control of process water, suspected falsification of documents. Regulatory Action EDQM suspended the CEPs for three APIs (API 1, 2 & 3) EDQM closed the application for a CEP for another API (API 4) NOTE - The company also manufactured other APIs (5 & 6) that were not the subject of any CEP EDQM provided this information to allow Agencies take the necessary action regarding any MA or application referring to these CEPs 13-Oct-10 Slide 14

15 Case Study 1 Regulatory Impact IMB Regulatory Impact Assessment 4 MA Holders, holding 7 MAs were impacted by CEP Suspension One MA (W Tablets) - API 2 registered in Ireland (Suspended CEP) Two MAs (X Tablets) - API 3 registered in Ireland (Suspended CEP) Two MAs (Y Tablets) - API 5 registered in Ireland (No CEP for API 5) Two MAs (Z Tablets) - API 5 registered in Ireland (No CEP for API 5) Note: API 5 was a different salt form of API 3 13-Oct-10 Slide 15

16 Case Study 1 Regulatory Impact Registration Format All products were registered through Mutual Recognition Marketing Status Six of the seven products were on the market place, including Ireland Product W Tablets was not yet marketed and the MAH confirmed to IMB that it would not launch until the GMP issues had been resolved Distribution Status Most of the batches that were marketed had no remaining stock at primary wholesaler level in Ireland Alternative API suppliers Company A was the primary source of API in all products All MAs had other registered API suppliers but none had been recently used 13-Oct-10 Slide 16

17 Case Study 1 API 5 (no CEP) MAH position on CEP suspension was: The EDQM CEP action does not impact their products because their products contain API 5, and this API is not the subject of any CEP The MAH did acknowledge that the API 5 was manufactured in the same site as the APIs whose CEPs were suspended, and so a risk assessment was performed for their finished product batches already on the EEA market Risk Assessment found that the quality of the current and previously marketed batches of product was not affected and that no additional measures had to be taken IMB advised that no new batches should be released to the market containing any API from Company A without evidence that the site is GMP compliant 13-Oct-10 Slide 17

18 Regulatory Agency Opinions IMB considered that the quality of all APIs being manufactured at the site was now in doubt All products containing any API from the site were implicated by the EDQM CEP action Other EU agencies took action such as: (a) placing on hold the assessment of all affected MA applications where the agency acted as Reference Member State (b) deleted the site as an API manufacturer in the registration files with immediate effect 13-Oct-10 Slide 18

19 Key points of risk assessment exercise Inventory management finished product and API, lot & expiry etc. and correlation with period of CEP suspension QP Justification for retention of product on the market place: The nature of the deficiencies and the assessment of the risk presented by the deficiencies The test results for the API and finished product Further API testing performed and additional items investigated at API site 13-Oct-10 Slide 19

20 Risk Assessment (continued) Unused API stock quarantined pending the results of testing Cessation of finished product manufacture using said API until investigation completed and the CEP suspension lifted Regulatory activities Removal of API site from MAs and approved supplier list (variation) Activation of alternative, registered API manufacturers 13-Oct-10 Slide 20

21 Case 1 some learnings IMB did not request any recall or other market action for the batches on the Irish market with API from affected site Decision based upon various risk assessments received (from all three MAHs), on assessment performed at the Board and a review of pharmacovigilance data IMB did not recommend to any other Agency a recall action in their territory. A Rapid Alert was not issued. IMB requested MAH to advise on subsequent results of analytical testing and to consult with the Board in advance of a decision to resume QP release of batches Common output patient & animal safety! 13-Oct-10 Slide 21

22 Case Study 2 Statement of GMP Non-compliance was received from an EU Agency in 2009 following GMP inspection Inspection output serious GMP Deficiencies identified at a finished product manufacturer within the EEA The non-compliances included a lack of sterility assurance and potential contamination issues Five Medicinal Products were implicated (all sterile products) One Investigational Medicinal Product was possibly implicated in one Clinical Trial Actions taken or proposed by the inspecting Authority Revocation of the full Manufacturer s Authorisation Recall of batches already released Prohibition of supply 13-Oct-10 Slide 22

23 Case Study 2 Regulatory Impact IMB Regulatory Impact Assessment One Irish MA was implicated by this GMP Non-Compliance report A Powder and Solvent for Solution for Injection This was a diagnostic, hospital-only product in Ireland Distribution Status Four batches had been marketed in Ireland to date Registration Format A new Incoming MR application was in-house for another product manufactured by the same manufacturer assessment notified No Irish Clinical Trials were identified as being implicated 13-Oct-10 Slide 23

24 Risk Assessment & Regulatory output The MAH required more information on the deficiencies and had difficulties obtaining it from the manufacturing site Risk assessment was delayed from MAH and was ultimately inadequate Class I Rapid Alert received from EU Agency Recall to wholesale and hospital level occurred 13-Oct-10 Slide 24

25 General points to note Investigation of CEP Suspensions and Non-Compliance Reports are time-consuming and complex Cross functional approach within IMB Human / Veterinary Quality & Medical Assessment Inspection Pharmacovigilance Quality Defect & Recall Multiple finished product manufacturers Multiple MA holders Multiple risk assessments Common output patient & animal safety! 13-Oct-10 Slide 25

26 Impact of a CEP suspension Once a CEP has been suspended or cancelled, the holder has to inform its customers of the situation to allow them to take responsibility with regard to the concerned substance and any related marketing authorisation or marketing authorisation application (EDQM, March 09) Suspension of a CEP from an API site can also impact other APIs manufactured at the same site (with or without a CEP) Review of the CEP status of an API facility is good practice for finished product manufacturers and regulatory agencies Application of Quality Risk Management to assess the impact of API non-compliance on marketed products 13-Oct-10 Slide 26

27 QP Oversight A well constructed Technical Agreement ensuring continuous communication from the API site to the finished product site Notification of planned changes to site that could impact your API of interest or the site s GMP Compliance rating Notification of output of regulatory inspections Notification of status changes to any CEPs Well constructed Annual Product Reviews Continuous audit program (risk based) of API sites 13-Oct-10 Slide 27

28 QP Oversight (continued) Periodic CEP evaluation by finished product manufacturers is good practice Include as part of Product Quality Review evaluation (Chapter 1.4) Include as part of Self Inspection Program (Chapter 9) Include as part of Supplier Audit Program Frequency of periodic evaluation based upon a risk assessment output Demonstration of EDQM website 13-Oct-10 Slide 28

29 Demonstration of EDQM website Log on to EDQM website Certification Section Current link to CEP Database search function A proceduralised system should be in place describing the CEP evaluation process and investigation and management of nonconformances 13-Oct-10 Slide 29

30 EDQM Homepage 13-Oct-10 Slide 30

31 EDQM Certification Scheme 13-Oct-10 Slide 31

32 EDQM - Database 13-Oct-10 Slide 32

33 EDQM Database Cinnarizine Ph. Eur. 13-Oct-10 Slide 33

34 Final words Chapters 1 & 5 elaboration on traceability Review of CEPs and associated annexes Overview of the CEP maintenance process is good practice and further strengthens the supply chain qualification program Management and investigation of CEP suspensions / withdrawals and Non-Conformance Reports are challenging Both require input from MA Holder(s), Manufacturer(s) and Competent Authorities and well constructed Risk Assessments Investigations do not always result in product recall Common output from all parties patient & animal safety! 13-Oct-10 Slide 34

35 Questions / Discussion? Thanks to the Compliance Department of the Irish Medicines Board Thank you for listening Cormac.Dalton@imb.ie Compliance@imb.ie Oct-10 Slide 35