MA Compliance Reviews Implications for Manufacturers

Transcription

1 MA Compliance Reviews Implications for Manufacturers Breda Gleeson, Market Compliance Inspector GMP Conference 12 th November 2014

2 Scope Role of the Manufacturer in MA Compliance MA Compliance Reviews Significance of Reviews Types of Reviews Review Triggers HPRA Expectations 12th November

3 Role of the Manufacturer in MA Compliance Manufacturer has a responsibility for ensuring Product is manufactured and certified in compliance with MA documentation Compliance of MA documentation provided by the MAH to support manufacture and batch certification Manufacturer must have a knowledge of and assurance in relation to the systems and processes that support and control MA compliance 12th November

4 MA Compliance - Considerations How is registered product information managed and controlled by the MAH? How are regulatory commitments and regulatory changes managed, tracked and implemented? CMC and artwork At what point in the process are commitments and changes communicated to the manufacturing site? 12th November

5 Other Considerations... How are commitments and changes communicated to the manufacturing site? What documentation is provided to the QP to support batch certification / release activities, and how is this generated and controlled? Is the documentation updated in a timely manner? How is it actually managed on a day-to-day level and by whom? Who tracks and oversees the implementation of variations and regulatory commitments? 12th November

6 MA Compliance Review Assesses the compliance of medicinal product(s) and their manufacturing process(es) with the registered dossier(s) Full review versus partial CMC and / or artwork Artwork - only MAs with recent safety variations, etc. Entire product portfolio, or limited no. of products managed via a particular processing route 12th November

7 MA Compliance Review Full review - usually performed on a reactive basis Evidence of significant MA non-compliances Serious concerns with the management of MA documentation and the robustness of the QMS Overall lack of assurance in relation to the compliance of the entire product portfolio Partial review - reactive or proactive Reactive: Evidence of MA non-compliances, but limited to a certain market, product range, processing route or type of non-compliance e.g. CMC Proactive: Effective means of monitoring compliance status 12th November

8 MA Compliance Review - Triggers for Manufacturers Increasing trend in MA noncompliances - PQRs, Audits, etc Amalgamation / transfer of a number of MAs Company merger / take over Poor history of MA compliance MA Compliance Review Manufacturing site transfer 12th November

9 CA Request for MA Compliance Review HPRA may request review Approx 1-2 per year Main HPRA triggers Recurring or multiple reports of quality defects involving MA non-compliances Adverse findings during inspections at MAH Offices, regarding variation management mainly 12th November

10 MA Non-Compliances No. of MA Non-compliances % of Total Quality Defects 4% 9% 7% 10% 11% CMC- related Artwork -related % Manufactured in Ireland 27% 54% 58% 42% 28% Recall in Ireland CIUN in Ireland th November

11 MA Non- Compliances Implementation of non-approved change(s) Nonimplementation of CA approved change(s) Non-submission of expected variation(s), as per CA request 12th November

12 Implementation of non-approved change(s) Change(s) implemented without variation submission Change(s) implemented prior to variation approval CMC-related changes mainly 12th November

13 Management of CMC Changes - Ideal Manufacturer Raises change control Assesses the need for regulatory pre-approval (possibly in conjunction with MAH RA Group) Informs MAH Office of intended change (If Competent Authority approval required) MAH Submits variation to Competent Authority Tracks variation approval status Notifies the manufacturing site of the outcome of CA assessment and the implementation timeline Tracks variation and oversees its implementation Manufacturer Implements variation on time Communicates to the MAH when the variation has been implemented 12th November

14 Non-implementation of CA approved change(s) Failure to implement change(s) Delay in implementing the change(s) within agreed timeframe Artwork-related amendments mainly 12th November

15 Management of Artwork Changes - Ideal MAH Prepares an artwork change and assesses the need for regulatory pre-approval (Type 1B or II) Variation submission for pre-approval ideally managed via change control Informs manufacturing site of intended change Submits variation to Competent Authority Tracks variation approval status MAH Notifies the manufacturing site of the outcome of CA assessment and the implementation timeline Tracks variation and oversees its implementation Manufacturer Implements variation on time Ensures all superseded packaging is removed and destroyed Communicates to the MAH when the variation has been implemented 12th November

16 Variation Implementation Timelines 1 Month All batches certified for release on or after the implementation deadline must contain update(s) Stock dispatched from primary and secondary wholesalers on or after the implementation deadline must include update(s) 3 Month All batches certified for release on or after the implementation deadline must contain update(s) No restriction on stock at wholesale level, unless otherwise stated in approval notification 6 Month All batches certified for release on or after the implementation deadline must contain update(s) No restriction on stock at wholesale level and the old stock may continue to be distributed 12th November

17 Non-submission of expected variation(s), as per CA request Failure to submit variation(s) and maintain MA in-line with CA requirements, e.g. PRAC safety recommendations Artwork-related amendments, mainly safetyrelated 12th November

18 Management of Artwork Changes - Ideal MAH Prepares an artwork change and assesses the need for regulatory pre-approval Variation submission for pre-approval ideally managed via change control Informs manufacturing site of intended change Submits variation to Competent Authority Tracks variation approval status MAH Notifies the manufacturing site of the outcome of CA assessment and the implementation timeline Tracks variation and oversees its implementation Manufacturer Implements variation on time Ensures all superseded packaging is removed and destroyed Communicates to the MAH when the variation has been implemented 12th November

19 MA Compliance Review - HPRA Expectations Approved protocol - robust and detailed Adequate resources assigned Training of personnel prior to commencing review Review fully documented - detailed records Notify HPRA of reportable non-compliances during review Submission of report to HPRA on completion of review 12th November

20 MA Compliance Review Protocol Scope clearly defined Full review or partial Products and markets Artwork and / or CMC Items to be checked SmPC, printed packaging components - package leaflet, outer carton, primary label, blister foil, etc Manufacturing Documentation, e.g. Master Batch Records, In-process and FP specs, approved suppliers, procedures supporting sterility assurance (e.g. filter integrity checks), etc. 12th November

21 MA Compliance Review Protocol Responsibilities outlined Clear instructions on how the compliance checks should be performed Repositories / data source(s) used to obtain the registered details Key reference parameters Modules 1 & 3 of the MA Date of variation approval, target implementation date, actual implementation date and date of batch certification CA requests for submissions of variations and Regulatory Commitments 12th November

22 MA Compliance Review Protocol Key identifying parameters, e.g. Package Leaflet: code no., issue date or approval date Registered FP specification, issue date or approval date Clear instructions on how to identify a noncompliance Actions to be taken on confirmation of a noncompliance, including timelines 12th November

23 Non-compliance Identified - Actions to Take Identify impacted batches Batches QP certified and awaiting release Market(s) to which impacted batches distributed Assess the risk posed Risk assessment Assign a quality defect classification Determine if any remedial actions are required Determine if the noncompliance is reportable Cessation of QP certification Quarantine action HPRA Guidance Note If reportable, HPRA and / or other CAs to be informed 12th November

24 MA Non-compliance Review Report Submission of report to HPRA on completion High level summary of the review performed and its outcome Details of all non-compliances identified Root causes CAPAs 12th November

25 Conclusion Significant number of MA non-compliances implicating Irish manufacturers identified in recent years Manufacturers need to play a greater role in the investigation of such non-compliances, particularly the batch release site Recommend that manufacturers introduce proactive monitoring of MA compliance to assess a) the compliance status of its products and b) the status of MA documentation provided by the MAH to support manufacture and batch certification Regular trending of MA non-compliances Partial MA compliance reviews Integrate into self-inspection programme 12th November