Traceability, CEPs and managing non-conforming sites · Traceability, CEPs and managing...

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

Transcript of Traceability, CEPs and managing non-conforming sites · Traceability, CEPs and managing...

13-Oct-10 Slide 1

Materials Management

Traceability, CEPs and managing non-conforming sites

IMB Information Day, 14th October 2010

Dr Cormac DaltonInspector

13-Oct-10 Slide 2

Managing Supply

• Supply• Demand• Supply chain• Broker / Trader / Repacker• Non compliance• Rework• Reprocess• Return• Suspension• Revocation

• QP Declaration

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

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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 5.25 – 5.28)

• The Pedigree Concept

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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

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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

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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 2008

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New EDQM / EMA Guidance

• Suspension or Cancellation of a Certificate of Suitability(March 2009)http://www.edqm.eu/medias/fichiers/NEW_PAPHCEP_08_17_R1_Su.pdf

• Procedure for dealing with serious GMP non-compliance for voiding/suspension of CEPs thus requiring co-ordinated administrative action (March 2010) http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004721.pdf

• Procedure for handling rapid alerts arising from quality defects (March 2010)http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004712.pdf

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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

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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 consideringA) supplier qualification and approvalB) reduced testing (Chapter 5 revision)

• CEPs can be suspended or withdrawn and this action directly impacts upon the Finished Product manufacturer

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Managing Non-Compliances

• Two scenarios for discussion:

• CEP Suspensions/Withdrawals from EDQM

• Non-Compliance Reports from Competent Authorities

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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!

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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

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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

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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

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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!

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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 impactof API non-compliance on marketed products

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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

QP Oversight (continued)

• Periodic CEP evaluation by finished product manufacturersis 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

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Demonstration of EDQM website

• Log on to EDQM website• www.edqm.eu

• Certification Section• http://www.edqm.eu/en/News-General-Information-164.html

• Current link to CEP Database search function• http://extranet.pheur.org/publications/recherches_CEP.shtml

• A proceduralised system should be in place describing the CEP evaluation process and investigation and management of non-conformances

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EDQM Homepage

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EDQM – Certification Scheme

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EDQM - Database

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EDQM Database – Cinnarizine Ph. Eur.

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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!

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Questions / Discussion?

• Thanks to the Compliance Departmentof the Irish Medicines Board

• Thank you for listening

[email protected][email protected]• +353-1-6764971

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