IVD Inspections Technical Update Dr Dragana Milic Medical devices inspections

Transcription

1 IVD Inspections Technical Update 2018 Dr Dragana Milic Medical devices inspections 1

2 Objectives Harmonisation - internal and external (PQ Medicines/Vaccines/Vector Control and MDSAP) Transparency (clarify rules and requirements) Are we hitting the mark, what can we do better together? 2

3 MDSAP Requirements of mature national regulatory authorities including: USA FDA, Australian TGA, Health Canada, Japanese PMDA, Brazilian ANVISA These are MDSAP Authorities (Medical Devices Single Audit Program) Observers WHO - Diagnostic Prequalification Program European Union (a decision about full participation?) 3

4 MDSAP Recognized Auditing Organisations conduct audits of a medical device manufacturers that satisfy the QMS requirements of 5 Regulatory Authorities. WHO requirements about to be added. Single Audit Program Initiated in 2012 by the International Medical Device Regulators Forum - IMDRF - ex GHTF Pilot ended 2016, transition until end

5 CONCEPT Assess and recognize Auditing Organisations Regulatory Authorities Share audit report and certificate Audit and certify Make regulatory decisions Market Authorisation Medical Device Manufacturers 5

6 Reference and Guidance documents PQDx_014 Information for Manufacturers on the Inspection of Manufacturing Site(s) ISO 13485:2003 and 2016 Medical Devices-Quality management systems Requirements for regulatory purposes ISO 14971:2007 (2012) Medical devices-application of risk management to medical devices IMDRF and GHTF Documents 6

7 Assessment Types 7

8 Full Assessment Priority product Yes No Dossier screening Dossier incomplete Dossier complete Dossier review Site inspection Laboratory evaluation PREQUALIFICATION DECISION Maintenance of PQ Status 8

9 Abridged procedure Priority product No Review on-site dossier aspects Yes Site inspection Laboratory evaluation PREQUALIFICATION DECISION Maintenance of PQ Status 9

10 Inspection Process (Seek techn. assistance) Terminate No Stage 1 Ready for Inspection Plan Yes List of questions Dossier Screening Dossier Review No No Stage 2 Inspection Compliant (<7 level 4 NC) 2 rounds CAP Yes Recommendation for PQ Yes Yes Compliant? No 2 rounds CAP No Terminate 10

11 Required information Full and Abridged Inspection Element Quality Management System Required documents Quality manual including staff organogram List of current quality management procedures (SOP) Standard operating procedures for: Complaint handling and vigilance Control of nonconforming goods/processes Change control/change notifications (product and processes) Risk management Supplier evaluation and control, verification of purchased product Design and development Audit report of the most recent full regulatory inspection/audit and all subsequent surveillance inspections/audits Any valid quality management system certificate(s) (e.g. ISO 13485) Name and contact details of the responsible person at the site of manufacture regarding the inspection 11

12 Required information Full and Abridged Inspection Element Required documents Product Labelling (instructions for use (IFU), component and box labels Photographs of kit, box including contents, kit components Accessories (including photographs) Copy of current product regulatory approval certificate(s) Summary of changes initiated or applied to the product subsequent to the above regulatory approvals 12

13 Required information Full and Abridged Inspection Element Required documents Manufacturing Full address, including latitude and longitude of the manufacturing facility(s) Site floor plan Manufacturing flowchart including in-process control points List of critical raw materials ( including details of the supplier of each material) List of outsourced processes with direct product impact (e.g. outsourced manufacturing of components (conjugated antibodies, strips, reagents ), outsourced laboratory testing, packaging, printing, etc.) including details of the supplier for each process 13

14 On site inspections and MDSAP WHO is taking into account the outcomes of MDSAP inspections. WHO is reviewing MDSAP reports and where they include the evidence of manufacturer s compliance with relevant requirements a WHO inspection may be: Waved Shortened Undertaken as planned Exceptions - for couse inspection; or requested during screening or dossier assessment process. 25/09/

15 International Alignment WHO s activities WHO is worknig with MDSAP, AOs and manufacturers Content of the MDSAP report to enable utilisation in lieu of WHO inspection: Includes relevant requirements of ISO Includes eidence of compliance with WHO specific requirements Evidence of implemenetation of TSS, TGS, standrads Product specification requirements 25/09/

16 International alignment Content of the report continued: Risk management (appropriate for intended use) Design inputs/outputs including TSS Performance requirements, Design validation: Usability in resource limited settings Clinical data, performance data Stability Labeling, IFU QC requirements Feedback provisions Other 25/09/

17 Prerequisite for an onsite inspection Copenhagen, Denmark September

18 Quality Management System Fully implemented quality management system (design & development, manufacturing including quality control, storage, distribution) Meets ISO 13485:2003 requirements with the transition to 2016 version still often delayed ( external reasons seem preveiling) Product design, Validation of processes Products undergoing prequalification must be in routine manufacturing Sufficient capacity to ensure reliable delivery Quality control processes follow risk principles, performance tested according to claims in instruction for use Storage conditions, temperature and humidity, validated for intermediates, components and kit, real time data required 18

19 Risk management Risk management to meet ISO 14971:2007 (2012) Throughout product lifecycle Risk management for product realisation (design, manufacturing, storage, transportation), user and patient Risk management file Risk management plan Risk analysis Risk evaluation and control Residual risk acceptable? 19

20 Product Stability Product stable to meet challenging conditions (hot, wet, dry, dusty) Stability ensured by design Stabilty ensured through teh control of critical processes Transportation studies (simulate "worst" conditions) Long term stability at limiting conditions In-use stability studies (open kit, strip, vial) Data to support all claims available on-site Consistency of product labelling (component, kit and shipping box) 20

21 Routine Manufacturing Transfer from R&D to production completed Evaluated and approved suppliers (think of services!) Validated processes (acceptance ranges determined, in-process controls established) Standardized batch sizes Established non-conformance management and "out-of-specification" processes Batch manufacturing records established (include all manufacturing information, full traceability of material and equipment) Trained personnel (requirements determined, training plan, records) 21

22 Abridged Inspection Copenhagen, Denmark September

23 Abridged Inspection Aim: To avoid duplication Reduce time Reduce cost When: If a stringently assessed regulatory version is submitted for prequalification If a non-stringently assessed (rest of the world) regulatory version of the product is submitted for prequalification assessment but a stringently assessed regulatory version also exists (no difference between the two versions) 23

24 Stringently Assessed Approved by a GHTF/IMDRF founding member regulatory authority and assessed at a level comparable to that required by WHO Competent Authorities from the Member States of the European Union Directive 98/79/EC on in vitro diagnostic medical devices Associated Notified Bodies MDSAP authorities US FDA Health Canada Japanese Ministry of Health, Labour and Welfare Australian TGA Brazilian ANVISA 24

25 Full and Abridged Inspections PQ Stage Full assessment Abridged assessment Dossier review Yes No Site inspection Full Inspection Abridged inspection (information package requested) Laboratory evaluation Yes Yes 25

26 Objectives of Abridged Inspections Less time spent on site Fewer inspectors (usually one inspector and one technical expert) 26

27 Inspection planning Inspection team determined Communication with manufacturer (suitable inspection dates, required documentation) Manufacturer to agree on the inspection team (Brief CVs provided) Inspection plan provided one to two week prior to the inspection 27

28 The onsite Inspection Opening meeting, debriefings, full transparency Open exchange of information between WHO and Manufacturer throughout the entire process Inspection of the full site to review the manufacturing process Manufacturing of the WHO/or a similar product is required Access to all requested documents and records Sampling process with risk based emphasis Review and confirmation of raw data related to the dossier submission including all validations, stability studies and performance data 28

29 The onsite Inspection Follows MDSAP model Utilises MDSAP report format and Ninconformities Grading and Exchange (NGE) form. 29

30 Risk Management Purchasing MDSAP Audit Sequence of ISO and Regulatory Processes Management Measurement, Analysis and Improvement Design and Development Production and Service Controls Device Marketing Authorisation and Facility Registration MD Adverse Events and Advisory Notice Reporting Device Marketing Authorisation and Facility Registration 30

31 MDSAP Model, its application by WHO and how/why it makes sense? Design and Development Priority criteria for selection of design files for review: Complaints of known problem with a particular device, Product risk Recent design changes particularly design changes made to correct quality/design problems Reviewing complaints and NCs enables this selection 31

32 MDSAP Model, its application by WHO and how/why it makes sense? Production and Service Controls Priority criteria for selection of production processes for review: Corrective and preventive action indicators of process problems Production processes for higher risk products Processes with direct impact on devices quality. 32

33 MDSAP Model, its application by WHO and how/why it makes sense? Production and Service Controls continued: Purchasing: criteria for selection of suppliers: Indications of problems with supplied products or processes from audit of the Measurement, analysis and Improvement process 33

34 End of Inspection Closing meeting to discuss any findings A list of findings is left onsite for the manufacturer to begin CAPA preparation whenever possible. A report is issued within 30 days of the site inspection unless otherwise informed. (Of note MDSAP reports are required to be issued by AOs within 90 days). WHO challenge - aligning MDSAP reporting format with WHO s reporting timelines. Grading of nonconformities is automated and independently reviewed before the final report is released. 34

35 Grading of nonconformities Based on the GHTF Model GHTF/SG3/N19:2012 Quality management system Medical devices Nonconformity Grading System for Regulatory Purposes and Information Exchange. Grading nonconformities - Levels 1 to 5. 35

36 Indirect Cl Impact Direct Cl Nonconformity grading GHTF N19 - Nonconformity Grading System for Regulatory Purposes NCs are assigned a grade, Calculated in two steps Grading Matrix Escalation Rules No Documented Process, +1 Release of nonconforming medical device, First Repeat Occurrence 36

37 Corrective action plan Required to be submitted within 30 days of receipt of report Root cause analysis Correction Corrective action Timeline and responsible person/department Evaluation of the effective implementation of the corrective action Two rounds of CAPA are allowed 37

38 Inspection statistics Number of Inspection Number of products reviewed 38

39 Next presentation: Inspection findings What worries us (and you) Expectations 39

40 Where to find information Contact us by Sign up for our mailing list By ing Check our website oratory/evaluations/en/ 40