Validation of sterile Medical Devices manufacturing processes By J. Havel - Havel tuv sud (Qserve Conference 2013)

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Validation of sterile Medical Devices manufacturing processes By J. Havel - Havel tuv sud (Qserve Conference 2013)

  1. 1. Validation of sterile Medical Devices manufacturing processes - A Notified Body’s view Dr. Jan Havel TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 1
  2. 2. MHS – Gate to worldwide markets Full support world wide conformity assessment & testing Europe Conformity assessment procedures according to AIMDD, MDD, IVDD (notified body number 0123) Canada CMDCAS (ISO 13485), CAN/CSA C22.2 NR.601.1 as NRTL Russia Certification via GOST Taiwan Technical Cooperation Program USA FDA 510(k) NRTL, FDA QSReg inspection in compliance with MRA New: • Biocomp Lab • Saudi Arabia CAB • Consulting Japan • Korea CAB TÜV SÜD Product Service GmbH Japan Recognized Certification Body (RCB), Medical Test Lab, certification (PAL, RCB) China SFDA Registration, CCC (China Compulsory Certification) Brazil Product certification via agreements with UCIEE or CERTUSP 13-10-22 Australia Certification as CAB under MRA (Conformity Assessment Body) Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 2
  3. 3. Regulatory Requirements Responsibilities Documentation Regulatory Requirements Validation Connection to Risk Management Consequences for validation TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 3
  4. 4. Why process validation? Medical Device 93/42 EEC Also, medical devices must be packed and sterilzed safely! Where does that requirement come from? EC-Directive 93/42/EEC for Medical Devices TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 4
  5. 5. Why Conformity? Medical device 93/42 EEC Annex II.3 • 93/42 EEC Article 3: • Medical devices, must meet the essential requirements (MDD Annex I). • • 93/42 EEC Article 11: • Compliance to Essential Requiremnts (MDD Annex I) must be demonstrated by a Conformity Assessment Procedure (e.G. Annex II.3). TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 5
  6. 6. Regulatory Requirements of the MDD Directive 93/42/EEC (MDD) Essential Requirements: • Devices delivered in a sterile state must be designed, manufactured and packed in a non-reusable pack and/or according to appropriate procedures to ensure that they are sterile when placed on the market and remain sterile, under the storage and transport conditions laid down, until the protective packaging is damaged or opened. The risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to the patients must be minimized (7.2, 8.3). • Devices delivered in a sterile state must have been manufactured and sterilized by an appropriate, validated method (8.4) • The design must allow easy handling and, where necessary, minimize contamination of the device by the patient or vice versa during use (8.1) TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 6
  7. 7. Manufacturer Responsibilities: Technical Documentation • Objective: Demonstration of Compliance of products with the requirements of the Directive => Especially: Conformity with the essential Requirements TÜV SÜD Product Service GmbH 13-10-22 Content: • Product description • Risk Analysis • Applied standards • Essential requirements • Manufacturing Process • Sterilization Method • Design tests including Test results and clinical Data • Labeling and IFU Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 7
  8. 8. Regulatory Requirements Responsibilities Documentation Regulatory Requirements Validation Connection to Risk Management Consequences for validation TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 8
  9. 9. Validation of manufacturing processes Requirements according to 7.5.2 of EN ISO 13485:2012 • The organization shall validate any processes for production and service provision where the output cannot be verified by subsequent monitoring or measurement. • http://www.ghtf.org/documents/sg3/sg3_fd_n99-10_edition2.pdf TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 9
  10. 10. Accreditors view: Requirements by ZLG: Validation 7.5.2.1 General requirements ... Validation shall demonstrate the ability of these processes to achieve the planned results. The organization must define regulations for these processes including the following, as applicable: a) Define requirements for the assessment and approval of the processes, b) approval of the equipment and qualification of the operators, c) Application of defined methods and procedures d) requirements for documentation and e) revalidation TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 10
  11. 11. Accreditors view: EK-MED decision 3.9 B18 Stages of validation to be implemented by the manufacturer Installation Qualification Operational Qualification (machine capability, Short-term capability, effectiveness of the process control tolerances) Performance Qualification (Long-time capability to produce a product corresponding to its specification) For each stage a corresponding protocol has to be established prior to the Qualification, in which the criteria for the acceptance are defined and where the results for the particular stage will be entered. GHTF/SG3/N99-10 : 2004 TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 11
  12. 12. How often do I need to calibrate/ validate? 7.1 Planning of product realization in EN ISO 13485: • “..... The organization shall establish documented requirements for risk management throughout product realization...“ To minimize risks in relation to • intended use (Education / training / skills of the users!) • Design • Production • Storage and transport TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 12
  13. 13. Regulatory Requirements Responsibilities Documentation Regulatory Requirements Validation Connection to Risk Management Consequences for validation TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 13
  14. 14. Riskmanagement on the example of sterile packaging processes The following features shall be evaluated: a) microbial barrier b) Biocompatibility (Sterilization effects on biocompatibility should be evaluated) c) physical/chemical properties d) compatibility to forming and sealing processes; e) compatibility to the intended sterilization process(es) f) shelf-life limitations for pre-sterilization/post-sterilization storage. ISO 11607-1:2009 5.1.6 ISO 11607-2.:2006 6.1,6.3 TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 14
  15. 15. Validation of processes in risk management: typical errors FMEA in Production Process Step # Failure / component Hazard Root Cause O S D RPN Risk Control O S D RPN Packaging 1 channel creation in the seal Infectio n through insterile Product Insufficient Seal temperature 6 1 8 480 0 packagingvalidation (Integrity testing) 5 1 1 50 0 Packaging 1 channel creation in the seal Infection through in-sterile Product Insufficient Seal temperature 6 1 8 480 0 packagingvalidation (Integrity testing) 1 1 8 80 0 O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number further informationen in e.g. VDA 4.2, DIN 25448, IEC 60812 TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 15
  16. 16. Example of validation depth FMEA in production Process Step # Failure / component Hazard Root Cause O S D RPN Risk Control O S D RPN Packaging Infection through in-sterile Product Insufficient Seal temperature 6 1 8 480 0 packagingvalidation (Integrity testing) 1 1 8 80 0 1 channel creation in the seal O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number Occurrence probability (event/year): 10=10-1 9=10-2 8=10-3 7=10-4 6=10-5 TÜV SÜD Product Service GmbH 13-10-22 5=10-6 4=10-7 3=10-8 2=10-9 1=10-10 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 16
  17. 17. Example of validation depth FMEA in production Process Step # Failure / component Hazard Root Cause O S D RPN Risk Control O S D RPN Packaging Infection through in-sterile Product Insufficient Seal temperature 6 1 8 480 0 packagingvalidation (Integrity testing) 1 1 8 80 0 1 channel creation in the seal O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number Validation of an increase in 10-5 of the risk control or final risk control to 10-10 TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 17
  18. 18. Implementation of risk control measure(s) EN ISO 14971 6.3 Implementation of risk control measure(s) The manufacturer shall implement the risk control measure(s) selected. Verify: • Implementation of each risk control measure • Effectiveness of the risk control measure(s) The verification shall be recorded in the risk management file. risk management file TÜV SÜD Product Service GmbH specification documents 13-10-22 verification documents Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 18
  19. 19. Risk management output Designresults • Information related to the Procurement of components, Production-, installation- and Maintenance processes TÜV SÜD Product Service GmbH 13-10-22 Examples of risk control • Requirements for Quality agreements • consideration of critical outsourced processes • Maintenance requirements of Production Facilities • Storage and Transportation Conditions • Installation instructions • Maintenance instructions • Training of service personnel • consideration of external Service Organizations Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 19
  20. 20. Regulatory Requirements Responsibilities Documentation Regulatory Requirements Validation Connection to Risk Management Consequences for validation TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 20
  21. 21. Validation-plan • The validation plan should reflect the rationale for applied test: – Is the order for the test sequences logical? – For which product characteristics is what standard (state of the art) used? – Are the acceptance criteria logical for the corresponding type of Product/Feature? (E.g. permeability of a sterile packaging)  Material  Sterilization method  fixation in the packaging system – The sampling plans used for selection and testing of packaging systems shall be …. be based upon statistically valid rationale. (e.g. ISO 2859-1, ISO 186 or are following state of the art standards for sterilization e.g in EN ISO 11135-1, EN ISO 11137-2) – Are all the critical parameters are verified based on a risk assessment EN ISO 11607-1:2009 4.3; 4.4.2/3 EN ISO 11607-2 4.2 TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 21
  22. 22. So what parameters are to be considered in general? Output Parameters (Product features) e.g. packaging Seal temperature:120 ± 10°C Seal pressure: 5 ± 1 bar Time: 0,5 ± 0,2 sec TÜV SÜD Product Service GmbH 13-10-22 Aimed Mean value 3σ > UTL LTL • Process input parameters Aim <3σ e.g. sterile packaging Seal strength in N/15mm Slide 22
  23. 23. Relation input parameter – output parameter Input: Machine Output: Product Failure/Defect High Alarm Limit Identified/verified at Process development (or during OQ) LTL Aim Aimed Mean value 3σ > UTL Parameter Set Parameter <3σ LTL Parameter Low Alarm Limit Identified/verified at Process development (or during OQ) UTL Failure/Defect TÜV SÜD Product Service GmbH 13-10-22 Slide 23
  24. 24. Adequate Sampling • The sampling plans used for selection and testing of e.g. sterile packaging systems shall be …. be based upon statistically valid rationale. (e.g. ISO 2859-1, ISO 186) • So what is the basic input into the statistics? What sample pool are we talking about? – EN ISO 14971:2012 Risk acceptance criteria shall be appropriate for the whole life-cycle of the device:  Life-cycle: Starts at initial conception and ends with final decommissioning and disposal of a device = direct link to the amount manufactured products during the defined life cycle.  Risk shall be controlled and to a level as safe as possible according to the state of the art – EN 556-1 – “Sterile” = SAL 10-6 (terminally sterilized) EN ISO 11607-1:2009 4.3; 4.4.2/3 EN ISO 14971:2012 2.7 Annex Z TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 24
  25. 25. Justification of sample size • Based on the risk assessment in risk management – In case of a risk reduction of 10X for In-sterility due to a specific production problem. What process safety is necessary to verify the Risk control measure? TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 25
  26. 26. Sample size • sample sizes in ISO 2859-1 (AQL) do only apply to certain Test methods. Ok, for what now? Only Limited suitable Test System with final product constellation Test System for specific features depending on the production process • cpk is heavily dependent on the chosen range used, but applicable (e.g. >1) – Presumption: Test on normal distribution was successful. • Stick to harmonized standards if sampling amounts are defined: E.g. Sterilization verification at irradiation sterilization or sensor distributions at each sterilization method. TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 26
  27. 27. Test on normality – What to be considered? • What is representative as a sample from a population of data: LTL UTL LTL LTL UTL LTL 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC UTL UTL UTL TÜV SÜD Product Service GmbH UTL LTL LTL – Samples distributed over the whole range of a typical production run – Normality is typically shown per run to make the samples representative – Sample amount shall be sufficient to assure to be representative at a high confidence: Slide 27
  28. 28. Test on normality – What to be considered? • What is representative as a sample from a population of data: – Sample amount shall be sufficient to assure to be representative at a high confidence: Aimed Mean value UTL LTL X X Important question: So how many failures may remain undetected under our approach? X X Samples that would have been detected at >15 samples X 3σ > Aim <3σ We chose 90%/95% and therefore we take 15 Samples. And our software tells us this works! Our p-value is >0,05! TÜV SÜD Product Service GmbH Will your argumentation sustain a trial at court with a p-value determined from a small sample? Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 28
  29. 29. Test on normality – What to be considered? • What is representative as a sample from a population of data: Could I have done more Conflict to EN ISO 14971 and MDD (safe as possible acc. to the state of the art) Do not trust simply on software! Is the chosen solution appropriate in relation to risk of a human life/condition of health? TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 29
  30. 30. Summary • Risk Management is an integral part of the technical file used to show conformity to a medical device to the MDD • Evidence for each final risk estimation in a released risk analysis has to be provided in documentation for the life-cycle of the device for manufacturing process • Sterile product manufacturing process validation shall provide evidence for the risk management that the process is safe and reproducible • The amount of samples shall assure: – To be representative for routine manufacturing including tolerances – State of the art safety of the device:  Considering the amount not detected critical failures  Considering base amount on the decision of a normal distribution  Considerung the right Cpk /AQL level necessary for the life-cycle TÜV SÜD Product Service GmbH 13-10-22 Slide 30
  31. 31. Thank you for your attention! TÜV SÜD Product Service GmbH 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC Slide 31

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