QP Current Practices, Challenges and Mysteries. Caitriona Lenagh 16 March 2012

Transcription

1 QP Current Practices, Challenges and Mysteries Caitriona Lenagh 16 March 2012

2 Agenda QP Roles and Responsibilities QP Current Practices Supply Chain Verification Study Specific Information Lot Specific Information QP Release Mysteries What happens when things go wrong?

3 QP Roles and Responsibilities Qualified Person must: Ensure product has been manufactured in accordance with»gmp»product Specification File»Clinical Trial Application Certify in a register or equivalent document that product satisfies provisions of Article 13, 2001/20/EC.

4 QP Roles and Responsibilities IMPs manufactured in a third country to standards at least equivalent to EU GMP How does the QP ensure these requirements are met in practice?

5 QP RELEASE PROCESS 1. Supply Chain Verification 2. Study Specific Information 3. Lot Specific Information

6 QP RELEASE PROCESS 1. Supply Chain Verification

7 Supply Chain Verification Why is the supply chain so important? Regulators place significant emphasis on verification BSE/TSE Heparin Incident Need to be aware of the origin- may not be what it seems! Provides confidence in sites involved in the supply chain Assurance that any risks are managed QP must Have knowledge of the COMPLETE supply chain involved in manufacturing

8 Supply Chain Verification Manufacturing includes Process of formulating Drug Product Packaging (Primary and Secondary) Labelling Analytical Testing sites (Release and Stability) Storage including cell bank storage for biological

9 Sites to be verified Chemical Drug Substance Confirmation of compliance with at least Local or National GMP for Manufacturing Analytical Testing Storage No requirement for QP assessment to EU GMP compliance

10 Sites to be verified Biological Drug Substance QP assessment for compliance with EU or equivalent EU GMP Working Cell Bank (preparation, maintenance and storage) Manufacturing Analytical Testing (release and stability) Storage

11 Sites to be verified Why Essentially the same as the DP Difficult to be an Established Process Greater variation Higher risk Member States requirements vary

12 Sites to be verified Drug product QP assessment for compliance with EU or equivalent EU GMP Manufacturing Analytical Testing (release and stability) Storage

13 Sites to be verified What does the process involve? Risk Assessments to formally document the process of verification Identify each site involved Determine if on-site audit is required Justification provided if on-site audit is not required

14 Continued Who can confirm EU GMP / equivalent EU GMP compliance European Medicines Agency EEA member state Competent Authority e.g MHRA Competent Authority within a country with a Mutual Recognition Agreement in place QP Under the supervision of a QP

15 Criteria Scope of the audit appropriate Outcome satisfactory Certificate confirming EU/equivalent EU GMP compliance Documentation remains valid Copy of audit report, audit summary or supporting documentation QP resume or evidence of QP eligibility

16 QP Declaration May be confused with the lot specific QP Statement of Release Signed by QP, confirming manufacturing sites to be used outside of the EEA operate to equivalent EU GMP standards Protocol and Product specific Submitted as part of the CTA to the relevant Competent Authority QP is taking personal responsibility for certifying the sites

17 QP Declaration All sites verified- only sites of manufacture, packaging and labelling detailed Czech Republic- QP Declaration to also included sites of release and stability testing Sweden- Details of site verification to be provided in an additional memo May be issued at client risk pending favourable outcome of inspection/audit Determined as part of Risk Assessment

18 Common Pitfalls All sites used in the supply chain (e.g. analytical testing labs) not identified to QP Can occur at various stages in the study Sub contracted sites forgotten Assessment not performed Possible delays

19 Common Pitfalls Scope of GMP certification does not cover scope of work performed (e.g. manufacturing line or dosage form) Inspection report covers Buildings 1,2 and 3; product manufactured in Building 4 Inspection report covers solid dose- sterile injectable in the study

20 Common Pitfalls Site address or location incorrect (e.g. postal address vs building address) Inspection report details postal address Building Address different Sites of actual manufacture at a separate location Queries could be raised

21 QP RELEASE PROCESS 2. Study Specific Information

22 Study Specific Documentation Remember QP Legal Duties Each batch of product has been manufactured..according to GMP, Product Specification File (PSF) and Clinical Trial Application (CTA) QP must have knowledge of CTA which should be consistent with PSF

23 Continued Study Specific Documentation Clinical Trial Application Form (Annex 1) Protocol IMPD / simpd / SmPC / Commercial Specifications IMPD Summary of Changes Document (if applicable) Master English Label Text and Country Specific Text (as submitted) Almac CTA Questionnaire

24 Continued Document of greatest relevance to the QP.IMPD Contains the quality data that has been submitted to the Competent Authorities Data provided on Drug Substance Drug Products IMP, Comparator, NIMPs, e.g. Rescue medication Placebo

25 Continued What is the Product Specification File? Responsibility of the Sponsor A changing reference document May consist of a number of files in different locations QP MUST have access to any information if required Assessed by Inspectors

26 Continued Contains or makes reference to: Specifications / Analytical Methods Starting materials, packaging, intermediate, bulk and finished Manufacturing Methods In-process testing & methods Approved Label Text Randomisation Codes Technical Agreements Stability Data Storage & Shipment information

27 Common Pitfalls Changes to the IMPD need to be communicated immediately Why? Newly imported lots (including new imports from bulk lots previously released) need to comply with the currently approved version of the CTA i.e. IMPD in the intended country for release May result in delay of release

28 QP RELEASE PROCESS 3. Lot Specific Information

29 Lot Specific Information Remember QP Legal Duties. Each batch of product has been manufactured and assembled according to GMP, PSF and Clinical Trial Application QP must therefore have knowledge of the specific lot of Drug Substance Drug Product Placebo

30 Documentation required For Drug Substance, Drug Product, Placebo Certificate of Analysis To verify compliance with the specification in the IMPD / simpd Lot specific GMP Statement for the manufacture, testing & packaging / labelling To verify manufacture in accordance with GMP

31 Continued Critical or major deviations / Out of Specification investigations for manufacture / storage / testing Drug Product Placebo Why? To identify any possible impact on Product quality Patient Safety

32 Continued Biological Drug Substance Critical or major deviations / OOS for API manufacture /storage / testing Why? GMP starts from maintenance of the Working Cell Bank QP must assess to identify possible impact on Product quality Patient safety

33 Continued Stability Memo and supporting stability data In support of extension plan Must be comprehensive Substantial Amendment may need to be filed later Why? QP must confirm shelf life for Drug Product complies with available stability data.

34 Continued Memo to confirm the Manufacturing and testing sites as applicable Why? To confirm supply chain remains in accordance with IMPD/sIMPD QP Declaration (if applicable)

35 Continued Documentation required for EU Licensed Drug Products Commercial pack direct from manufacturer QP Certification Wholesale dealer Statement of Authenticity / Pedigree document Manufacturer supplied Brite Stock Memo from QP to confirm product compliance with MA with any exceptions identified (e.g. labelling)

36 Continued Non- EU Licensed Drug Products Difficulties when establishing supply chain Confirm EU GMP / EU GMP equivalency of supply chain Preference is to use EU licensed Drug Products where possible The specific documents required are assessed on a case by case basis QP involved during submission Advise on exact means of verification Recent Almac experience- MHRA acceptance

37 Common Pitfalls Finished Goods Lot Is the entire supply chain for product to be released consistent with IMPD / QP Declaration? Are the languages on the labels consistent with the destination countries? Cold chain product Any temperature excursions justified?

38 Continued Licensed Drug Products Does the CTA take into account any modification in relation to the MA or equivalent? Are NIMPs in the study truly NIMPs? Is the Drug Product the same as that detailed in the CTA? Is the expiry date the same or less than the expiry date of the licensed lot? Be wary of counterfeit material?

39 Common pitfalls - Shelf life detailed in IMPD not reflected in drug product labelling - Regulatory Authorities or QP not informed of changes - Critical path- may result in delay in QP Release!

40 QP release Remember QP Legal Duties QP is to certify batches prior to use in a Clinical Trial Study Specific and Lot specific information in place QP release Lots specific Checklist Details checks to verify compliance CTA Questionnaire Provides details of regulatory status in country for release Blinded QP Statement of Release

41 Updates Annex 13 compliant Manufacturer s Authorisation Number Expiry date IVR controlled Strongly controlled within inventory when label does not detail expiry date Challenges to sponsor when product leaves QP inventory system Is there adequate control at patient level? Enhanced regulatory scrutiny in QP s involvement in IVRS design

42 Updates QP Facilitation Programme at site Aimed to remove QP release from the critical path Quality Compliance Manager placed onsite Information gathering Establishing relationships Educating Beneficial to both Sponsor and Almac

43 Mysteries What happens when things go wrong? Controls in place have not been effective? Manufacturing sites inspections indicate critical findings Lot specific non conformities identified post release Recall Panic- not an option

44 Continued Common goal for both Sponsor and QP Patient Safety Maintain Drug Supply Minimal study impact Communication of paramount importance Sponsor and QP QP and Regulators

45 Continued Additional information required Sponsor supplied Risk Assessment Almac Risk Assessment Impact Assessment Discussions with Regulator as required Outcome determined; Product to Remain at site Be recalled Be released

46 Summary QP Roles and Responsibilities QP Current Practices Supply Chain Verification Study Specific Information Lot Specific Information QP Release Mysteries What happens when things go wrong?