Overview of HPRA Sampling and Analysis (S&A) Programme

Transcription

1 Overview of HPRA Sampling and Analysis (S&A) Programme Relevance for Manufacturers Kevin O Donnell, Maria Filancia and Patrick Saunders GMP Conference 12 th November 2014

2 Structure of the S&A Programme

3 Objective & Scope This is a risk-based surveillance programme focussed on patient and animal health protection Objective: To independently monitor the quality of medicinal products in the Irish marketplace and those manufactured in Ireland for export To give effect to national and EU legislation for the independent surveillance of H&V medicines (including investigational medicinal products for human use) and their active constituents Scope: All MA types National, MRP/DCP, Centrally Authorised Products Active Substances & Excipients Unauthorised & Borderline products (e.g. Enforcement samples) 12th November

4 Key Features of the Programme Approx. 400 samples per year are tested or examined Products are prioritised for surveillance work using a formal risk ranking tool developed at the HPRA Wide ranging types of analysis and checks are performed Physico-chemical testing (e.g. identity, assay, related subs, dissolution) Microbiological testing (e.g. TAMC as per Ph. Eur.) Biological tests (e.g. Bio-assays, PCR, etc) Product usability tests & checks (e.g. eye drop products) Packaging & Labelling checks Presence of correct safety information in Package Leaflets Presence of correct and legible Braille Indications of falsification 12th November

5 Key Features of the Programme An annual S&A plan is developed with input across HPRA (Quality Defect staff, PhV staff, Inspectors, Assessors, etc.) Most samples are tested using company test methods the methods should already have been validated the adequacy of the test methods can be formally assessed in-use Product compliance is assessed against: Registered specifications & other MA requirements Compendial monograph requirements Braille declarations, etc. Follow-up actions are taken when OOSs and method issues are identified 12th November

6 Testing Laboratories HPRA uses labs in Ireland and in other EEA countries for testing work Public Analyst s Laboratory, Galway (HPRA s OMCL) physicochemical testing State Laboratory, Co. Kildare physico-chemical testing (Enforcement samples) Various other OMCLs in other countries, e.g. UK - Physico-chemical testing (e.g. NIR) Czech Republic & Finland Microbiological testing Sweden & Denmark Biological Testing & some Physicochemical testing (e.g. NMR) The labs work to ISO and a set of GMP-related guidelines The labs are either externally accredited or assessed (by the OMCL Network s own Mutual Joint Audit (MJA) programme) 12th November

7 European Dimensions Strongly aligned with EU surveillance programmes esp. for MRP/DCP and Centrally Authorised Products Significant use is made of the OMCL Network For test capability not available to HPRA in Ireland (e.g. biological assays, NMR) For lab capacity considerations Mutual Recognition of test results is important - extensive Proficiency Testing Scheme (PTS) in operation annually Cost effective and helps avoid duplication of effort Co-ordinated workplans, sample exchange and sharing of results occur Best practices and problem issues shared 12th November

8 European Dimensions cont d HPRA is active in the OMCL Network at a European & Global level Member of the Network s General Advisory Committee Member of the Network s Advisory Committee for Centrally Authorised Products Current member of several Working Groups (Counterfeit Medicines WG, API WG, Unlicensed Products WG) Rapporteur for several projects e.g. Project identifying Key Learnings from the Heparin Contamination Case triggered three large scale heparin surveillance projects e.g. Ongoing development of better approaches to risk-based surveillance work new risk assessment tool under development th November

9 The Annual S&A Plan

10 Test types Safety warnings Braille checks Parallel imported/distributed products checks General Packaging & Leaflet checks, e.g. presence of PLs in packs Packaging & Labelling Checks Lab Analysis Physico-chemical Microbiology Biological Tests e.g. Can product be used as per leaflet instructions? Product Usability Checks Dealing with Sample-only Requests From other HPRA staff 12th November

11 EXTENT OF THE 2014 PROGRAMME: 410 Samples, spanning ~ 800 TESTS TYPE OF ANALYSIS PLANNED NO. OF SAMPLES PHYSICO-CHEMICAL 241 MICROBIOLOGICAL 25 BIOLOGICAL 16 PACKAGING AND LABELLING 123 PRODUCT USABILITY 5 12th November

12 Actual Physico-Chemical testing 2014 Approx. 250 samples in 2014 Generic medicines (atorvastatin, esomeprazole, acetylsalicylic acid...): To support HPRA interchangeability assessments 6 molecules, 88 products analysed for assay and dissolution Authenticity checks: e.g. PDE5 inhibitors, alprazolam, capecitabine, NIR spectroscopy & packaging examinations APIs and API Starting Materials (mainly FT-IR spectroscopy) Nicotine content by HPLC in vials for e-cigarettes Milk Thistle products (Silymarin content by HPLC) Subdivision of Tablets on human and veterinary products EP monograph requirements 12th November

13 Actual Biological Testing samples to date Panitumumab (monoclonal antibody) product various assay and other biological tests Heparin APIs: Species id (PCR), %Mn (ICP-MS) Heparin FP: %Mn (ICP-MS), Impurities (NMR & SAX-LC) Enoxaparin API: Species id (PCR), %Mn (ICP-MS) Enoxaparin FP: Impurities (NMR & SAX-LC) Tinzaparin API: %Mn (ICP-MS) Tinzaparin FP: %Mn (ICP-MS), Impurities (NMR & SAX-LC) 12th November

14 Actual Microbiological testing samples to date Total Yeast and Mould Count (TYMC) as per Ph. Eur. Total Aerobic Microbial Count (TAMC) as per Ph. Eur. Specified Micro-organisms (e.g. E. Coli) as per Ph. Eur. Several OOSs identified and follow-up actions are in progress 12th November

15 Packaging & Labelling Examinations 121 samples in 2014 to date Safety Information in Product Info (checks done at HPRA office) New restrictions: e.g. not to be used by patients with Parkinsons and severe renal impairment Cough & Cold meds: e.g. restriction for children under six years of age Presence of the Black triangle Braille compliance (NCBI) Against the Braille Declaration registered for the product Parallel Imports (PPAs, DPRs and PD CAPs) Note: some of these samples were examined also for safety info and Braille compliance 12th November

16 Product Usability Checks 4 samples to date in 2014 e.g. Container closure system checked as a consequence of a complaint received on a veterinary product. No issue identified However, the same sample was found to be noncompliant as regard difficulties in opening the peel back PL label. 12th November

17 2015 S&A planning has started! Generic / Interchangeable medicines (assay/dissolution) Generic Levothyroxine testing assay and dissolution Heparin Testing: NMR by Swedish OMCL Vet Cephalosporins: Safety variation implementation checks: e.g. contraindication re use in poultry (including treatment of eggs) Domperidone products: Safety variation implementation checks: e.g. New posology info and restricted indications Fentanyl Patches: Safety variation implementation checks re patch visibility to minimise the risk of exposure to non-patients 12th November

18 Sampling and Analysis Work Processes key interactions with Manufacturers and MAHs

19 The Lifecycle of a Sample S&A Request Log-in and Validation Risk Assessment and Planning Sample Collection Sample Dispatch to Lab Receipt of COA and Follow-up actions 12th November

20 When might we contact you Risk Assessment and Planning HPRA requires certain items from manufacturers to facilitate the surveillance work (Supporting Items Request Form): 1. Copies of Analytical Methods and Specifications 2. Chromatography Columns (not always) 3. Reference Standards and Placebos 4. Relevant Certificates of Analysis 5. Current Chromatograms from QC testing HPRA will either request these items from the Manufacturer or MAH 12th November

21 Supporting Items Request Form 12th November

22 When might we contact you Sample collection For Marketing Status information on the product For information on which Wholesalers may have the product To arrange a date for sampling at your premises (if relevant uncommon- e.g. mainly for sampling APIs and Excipients) 12th November

23 When might we contact you Receipt of COA and Follow-up Actions To inform you or the MAH of the results To follow-up on any OOSs or Test Method deficiencies identified To follow-up on any other issues identified (e.g. problems with Ref. Standards) 12th November

24 Actioning the surveillance results NO ISSUES IDENTIFIED Inform MAH/Manufacturer of the GOOD news Close the Case OOS IDENTIFIED Contact MAH or Manufacturer to start investigating the issue Comment on the OOS, review manufacturing records for deviations, change controls, similar OOSs, OOTs etc. Review QC records. Test a reference sample may be done in parallel with retesting at the HPRA lab Possibly test a marketplace sample Review stability data for OOSs and significant OOTs 12th November

25 CASE STUDY: Analytical Method Issues

26 Case Study: Method Issues XX Hard Capsules Related Substances method 1 Stability problem identified with a test solution. (No specific maximum time for the injection of the solution was given.) 2 The required elution order of three related substances could not be obtained. (The MAH acknowledged that the correct order and separation were not always obtained by their QC lab either.) 3 The company method used multiple naming conventions for the same peaks. Method was very unclear and difficult to follow. 4 The analysis identified a peak that was stated to be rarely present. It was discovered that the peak was misidentified due to a method error in naming the peaks in the reference standard chromatogram provided by the MAH. 5 Other calculation errors / issues in the method. 12th November

27 Case Study: Actions Taken Multiple rounds of correspondence with the MAH no clear resolution of the issues 1. The MAH was requested to submit an assessment of the surveillance findings by the QP responsible for batch certification to the Irish market. 2. The QP was to provide a justification for the continued certification and release of the product to Ireland. 3. The QP was to provide a statement on the compliance status of batches already on the Irish market, given the various problems identified with the test method. 4. The methods were to be corrected and re-validated. 5. The revised methods and validation data were to be assessed as part of a Type IB variation. 12th November

28 Key S&A Findings in 2013

29 Key Findings in 2013 Lab OOSs 275 samples tested, the majority complied with their specifications Several OOS results were obtained, e.g.: 11 products OOS for assay (of active substance) 8 products failed the Ph. Eur. subdivision of tablets test 3 products OOS with the Ph. Eur. uniformity of mass of delivered dosages test 1 product OOS for alcohol content excipient in paediatric product 1 product OOS for related substances 1 unauthorised product OOS for dissolution 2 intermediates used to produce a biological active substance were OOS by PCR Appropriate follow-up actions were taken in each case 12th November

30 Dealing with OOS Results Discrepancies between OMCL results and company release results do occur Analytical method issues need to be resolved before taking any action Sometimes additional sampling and testing is performed If the sample was not tested with the company method, the company method is obtained and applied The manufacturer will be requested to open an investigation When OOSs are confirmed as valid, the case triggers a Quality Defect investigation which applies risk-based principles to determining whether market action is needed Most cases do not result in market action, but some recalls do occur e.g. Recall of a vet product with OOS Ph. Eur. microbiological results for mesophilic bacteria, yeast and mould content 12th November

31 Key Findings in 2013 Method Issues 21 deficiencies identified in analytical methods and specification documents used by manufacturers, e.g. Non-robust Related Substances methods could not adequately separate the impurities (poor resolution, wrong elution order) Insufficient procedures for identifying impurities, esp with RRTs Presence of incorrect calculations in test methods (e.g. a correction factor applied twice in an assay test) General lack of detail in methods (e.g. the need to prepare duplicate samples when running the test, how to handle certain test solutions to ensure a valid test result is obtained, temperature details, etc.) 12th November

32 Method Issues cont d Problems in Sample & Mobile Phase preparation details: Shaking Times, Filtration Steps, Heating Times and ph Adjustments are often missing or not detailed in the methods used in QC labs Problems with Reference Materials Incorrectly labeled storage conditions Incorrect instructions for use (assay vs. identification) Reagents used as Ref. Standards Appropriate follow-up actions were taken in each case 12th November

33 Key Findings in 2013 Packaging & Labelling Issues 162 samples checked, the majority complied 19 non-compliances identified 3 products had incorrect safety and other information in package leaflets 3 unauthorised products carried medicinal claims on their packaging. 13 products had Braille non-compliances the Braille on 5 products did not match what was registered the Braille on 7 products were of poor quality or were comprised of the wrong dots 1 product had no Braille 12th November

34 Key Messages

35 Key Messages for Manufacturers Ensure QC test methods contain sufficient and clear instructions for standard and sample preparation, System Suitability, etc. If there are ancillary documents that support the use of a particular test method, ensure those are referenced in the main method document and that they are controlled documents Ensure that calculations in test methods are correct Ensure that related substances methods are capable of unambiguously identifying peaks Critique methods based on RRT identification only Ensure robustness experiments are built into method validation exercises not a formal requirement of ICH Q2R1 When we request your test methods, ensure you provide the methods actually used in your QC lab 12th November

36 Key Messages for Manufacturers Ensure the arrangements with your MAHs give assurance that your site is provided with the correct version of the Module 3 information and with correct versions of labels and leaflets, etc. How is this assurance obtained? Is your QC lab using the currently registered test methods and specs? Are you using the correct version of package leaflets? Ensure that you know and understand the implementation requirements for MA variations (Type IA, IAin, IB, II) Ensure you obtain a copy of the Braille Declaration your MAH sent HPRA do you know what is in it? Ensure your arrangements for complying with it are robust 12th November

37 Questions / Discussion 12th November