Notified Body perspective: Overcoming common pitfalls observed in industry when following ISO 10993

Transcription

1 Notified Body perspective: Overcoming common pitfalls observed in industry when following ISO Informa Life Sciences Conference Biocompatibility for Medical Devices Amsterdam, November 2017 Christina Reufsteck, TÜV SÜD Product Service, Munich TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 1

2 MHS The gate to global markets Global Support 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 as NRTL Russia Certification via GOST Taiwan Technical Cooperation Program USA FDA 510(k) NRTL, FDA QSReg inspection in compliance with MRA Japan Recognized Certification Body (RCB), Medical Test Lab, certification (PAL, RCB) New: Biocomp Lab Saudi Arabia CAB Consulting Japan Korea CAB TÜV SÜD Product Service GmbH China SFDA Registration, CCC (China Compulsory Certification) Brazil Product certification via agreements with UCIEE or CERTUSP Australia Certification as CAB under MRA (Conformity Assessment Body) Notified Body perspective: Common pitfalls with ISO Slide 2

3 Outline Common obstacles in the following areas: Influences on biocompatibility Chemical Analysis & Toxicological Risk Assessment (Biological) Testing Changes TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 3

4 Influences on the biocompatibility of a device Use of medical device Re-use Reprocessing TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 4

5 Influences on the biocompatibility of a device Sterilization Residues from agent Material alterations due to conditions Mentioned in the current ISO Necessary information: EO sterilization: Conditions and allowed number of cycles Irradiation: Maximum allowed dose EN ISO :2009, 3.3, 4.7, 6.1, 6.2.1; ISO/DIS :2017, 3.8, 4.8, TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 5

6 Influences on the biocompatibility of a device Final device = as used state Use of medical device Re-use Reprocessing TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 6

7 Influences on the biocompatibility of a device Reprocessing Residues from cleaning/desinfection agents Material alterations due to conditions ISO/DIS :2017: The biological safety of a medical device shall be considered by the manufacturer over the whole life-cycle of a device. The same requirement is valid for re-usable medical devices where the biological safety shall be guaranteed after the maximum number of validated reprocessing cycles. Evaluation of product as subjected to reprocessing instruction (e.g. cleaning agents, conditions, no. of reprocessing cycles) EN ISO :2009 no reference; ISO/DIS :2017, 4.7 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 7

8 Influences on the biocompatibility of a device Packaging Transfer of contaminants, glue, ink Transfer of packaging migrants ISO/DIS :2017: packaging materials that contact the device can transfer chemicals to the device Various combinations of devices and packaging materials EN ISO :2009, 3.3, 4.7; ISO/DIS :2017, 3.8, 4.3, 4.8 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 8

9 Information on packaging Necessary information: Packaging configuration and materials Printing ink, adhesives, desiccants, protective equipment (e.g. sleeves, tubing, shipping protection ) Qualification of packaging materials with respect to BC TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 9

10 Influences on the biocompatibility of a device Storage Transfer of packaging contaminants, glue, ink Transfer of packaging migrants Material alterations due to storage/transport conditions ISO/DIS :2017: The biological safety of a medical device shall be considered by the manufacturer over the whole life-cycle of a device. EN ISO :2009, 4.7, 6.1; ISO/DIS :2017, 4.7, 4.8, TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 10

11 Influences on the biocompatibility of a device Packaging and Storage Device Packaging material Packaging migrant TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 11

12 Influences on the biocompatibility of a device Packaging and Storage Device t Device Influence and depth of evaluation depend on device type (liquid vs. solid) and packaging material (polymer, glass ) Whole storage time needs to be covered Only biological testing Qualitative & quantitative data on leachables, then maybe additional biological testing if necessary TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 12

13 Chemical Characterization Important 1 st step in biological evaluation Identification of material chemical constituents and consideration of chemical characterization (see ISO ) shall precede any biological testing as a minimum, the characterization shall address the constituent chemicals of the device and possible residual process aids or additives used in its manufacture. Leachables substances shall be taken into account Focus depends on device type, examples Irrigation solution Surgical instruments Tubings with indirect body contact Implants EN ISO :2009, 4.3, 6.1; ISO/DIS :2017, 4.3, TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 13

14 Chemical Characterization Extraction is a critical process: Document and justify extraction conditions (time, temp, ratio, solvents) Relevant for device-body or device-solution contact Relevant for intended purpose of analysis (simulated use, exaggerated, exhaustive) Get the right substances in the right amount into the extract! Before extraction Condition 1 Condition 2 Condition 3 EN ISO :2012, 10.1, 10.3; EN ISO :2009, 6.6, 8 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 14

15 Chemical Characterization Analytical method The analytical methods used shall be validated, justified and reported Extract analysis with sensitive and selective methods Be able to detect these substances! VOC SVOC NVOC Inorganics EN ISO :2009, 6.1, 6.6, 8 e.g. Headspace GC-MS GC-MS LC-MS ICP-MS LOD/LOQ Limit of detection/quantitation AET Analytical evaluation threshold Consider in Tox Risk Assessment! TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 15

16 Chemical Characterization Results from GC-MS Substance A: x µg/ml = y µg/device Substance B: x µg/ml = µg/device Substance C: Usually values per device per 24 h Estimation of clinical exposure Number of applied devices exposure time Input for risk assessment EN ISO :2009, 6.6 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 16

17 Toxicological Risk Assessment Exposure values Tolerable limit values existing substance-specific limit values substance-specifically calculated limit values (ISO ) generic threshold values (e.g. TTC) Limit/Exposure = MOS MOS 1 generally acceptable Exposure Threshold? Y/N TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 17

18 Toxicological Risk Assessment Exposure values Tolerable limit values existing substance-specific limit values substance-specifically calculated limit values (ISO ) generic threshold values (e.g. TTC) Statement on substances below reporting limit Calculation of allowable limits shall take into account, e.g. Relevant biological endpoints administration route patient population (Attention: EO residuals!) Not suitable for all endpoints (e.g. hemocompatibility, local effects) Performed by knowledgeable and experienced individuals EN ISO :2009, 4.2; ISO/TR 15499:2012, TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 18

19 (Biological) Testing Test item Testing shall be performed on sterile final product, or on representative samples from the final product or from materials processed in the same manner as the final product (including sterilization). Examples to be clarified: Only parts of the device tested Not all variants tested Differences in manufacturing Differences in packaging Differences in sterilization A different device is tested Only materials are tested The choice of test sample shall be justified. EN ISO :2012, 7.1, 7.2; EN ISO :2009: TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 19

20 (Biological) Testing Test item Rationale for leveraging tests from predecessor devices no new materials, no new processing aids, same manufacturing process usually not sufficient Predecessor New device 1 New device 2 Predecessor 1 Predecessor 2 New device Toxicological equivalency has to be demonstrated Differences in configuration/physical form have to be evaluated TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 20

21 Biological Testing Qualification of test laboratory All tests shall be conducted according to recognised current/valid best laboratory/quality practices, for example GLP or ISO/IEC Certificate with respective scope at time of testing. EN ISO :2009/AC:2010, section 4.6 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 21

22 Biological Testing - Justifications Local effects after implantation (ISO ) Implant size & shape Tissue & implantation sites Test period(s)! degradables/resorbables Reference all relevant studies in the BER Interpret results (test item vs. control) EN ISO :2016, 4.2, 5.1, 5.3 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 22

23 Biological Testing - Justifications Systemic Toxicity (ISO ) Species Route of exposure (if not the most clinically relevant one) Exaggerate exposure hazard identification Test period(s) Hemocompatibility (ISO ) Appropriate model or system Simulating the geometry and conditions of contact of the device with blood during clinical applications Species / the number of species EN ISO :2017, 4.1, 4.2, 4.6 EN ISO :2017, 6.1.2, 6.1.6, TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 23

24 Changes The materials or final product shall be re-evaluated if any of the following occurs: a) any change in the source or in the specification of the materials used in the manufacture of the product; b) any change in the formulation, processing, primary packaging or sterilization of the product; c) any change in the manufacturer's instructions or expectations concerning storage, e.g. changes in shelf life and/or transport; d) any change in the intended use of the product; e) any evidence that the product may produce adverse effects when used in humans EN ISO :2009, 4.7 TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 24

25 Changes Case Examples Supplier changed catalyst in polymer production, but will not disclose its identity Are there residues of the catalyst leaching out in amounts of toxicological concern? Manufacturing is transferred to a different location Is the product from the new site chemically and physically equivalent to the old one? A device is now used in a different location within the body Does the new tissue react differently to the device? TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 25

26 Documentation for changes Characterization of possible impact What can happen? Which endpoints might be affected? Approach must be visible How is the risk evaluated? Strategy? Results of risk assessment Conclusion on the biological safety of the device TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 26

27 Avoiding common pitfalls Start Biological Evaluation SAFETY less time less uncertainty TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 27

28 Last Slide Questions? Thank you very much for your attention! TÜV SÜD Product Service GmbH Notified Body perspective: Common pitfalls with ISO Slide 28