Document p24gm47NYEEvwpmJBQ7LQ74k7

Regulatory needs Exchange of a PFAS containing manufacturing device (e.g. tube, filter ...) with a PFAS free alternative Introduction Many medical devices may be affected by the restriction of PFAS in different ways. Even if there are no substantiated data available yet, it can be expected that a high number, if not even most, of the medical devices on the market are affected. Flow-chart no 7a new constituents identified 8b. Possible without further tests 1. Availability of alternative on the market 2. Technical feasibility (lab) 3. Manufacturing feasibility (production, 3 batches) 4. Detailed verification of performance 5. short-term stability test 6. start of long-term stability stest 7. Chemical characterization of the product yes 8. Evaluation of biocompatibility yes at any time 9. Testing in-vitro and/or in-vivo 10. Biocompatibility assessment 11. Complete Risk assessment (incl. favorable long-term stability) 12. Check of all Safety and performance requirements 13. possible involvement of notified body 14. Declaration of conformity 2a not feasable 3a not feasable 4a not fulfilled 5a not fulfilled 6a not fulfilled 8a. not feasable 9a not fulfilled 10a not fulfilled 11a not fulfilled 12a not fulfilled 13a not accepted Discussion Step Discussion Duration (month) Min Max Comments 1 Could be 6.5y or 13.5 y after publication of the Restriction depending on the derogation 2 First check of feasibility 1 4 Depending on the complexity of the replacement and possibly the number of affected products 2a At practically any point it could be found that no alternative is feasible (the requirements are not fulfilled) 3 Check of feasibility in the 2 9 Depending on complexity of the manufacturing environment. replacement, the availability of the Usually, 3 batches must be manufacturing devices (e.g. use of manufactured the devices for other products as well) and possibly the number of affected products 4 Even if the basic performance was (1) (3) Depending on the complexity of the checked in step 2 a detailed replacement and possibly the performance check of products number of affected products - out of manufacturing process is included in the timing for step 5 required by MDR 5 Can be done in parallel with 4; 3 6 3 months after the start of the however at least 3 months of storage (in case of multiple products stability are usually needed for a this timeline is defined by the last first evaluation storage start) 6 Depends on the shelf-life of the (9) (24) If the shelf life exceeds the timeline product. Usually medical devices for all other further steps, they are need a shelf-life of 18 - 48 determining the timeline months to be commercialized (favorable test results usually for 9 - 24 months at elevated temperatures). Long-term stability tests can be started in parallel to step 4 and 5 7 Requirement of ISO 10993-1 and 1 6 Depending on the complexity of the 10993-18 product, the needs for preliminary tests, development of extraction and analytical methods, availability of lab capacity at specialized contract labs 7a If no new constituents are identified in the product only the steps 11 - 14 are further relevant 8 Based on the new constituents a 1 3 Depending on the complexity of the first biocompatibility evaluation replacement and possibly the should be done to verify the need number of affected products of testing and develop a test plan (ISO 10993-series) 8b If no further tests are needed step 9 is obsolete 9 Finalization of test plans, 3 18 Depending on the tests required preparation of test specimens, based on the type of medical device, clarification of test procedures the concerns arising from new with contract labs, testing and constituents (see ISO 10993-series), finalization of test reports by the number of products affected by contract labs (ISO 10993-series; for respiratory pathways devices instead of ISO 10993series the requirements of ISO 18562-series apply the exchange, and the capacities of contract labs 10 Based on chemical 1 2 In case of an external toxicologist, characterization, data regarding tolerable intake of constituents and test results a biocompatibility assessment is prepared by a trained person (e.g., toxicologist) 11 Risk assessment is done based on 1 2 ISO 14971 by a group of product and safety experts 12 Final check of all safety and 1 2 performance requirements of MDR Annex I by a group of regulatory and product specialists 13 In some cases (e.g., medical 2 6 devices class III) the full technical documentation (manufacturing and quality documentation, documents mentioned above in the flowchart) must be verified first by the notified body (MDR) 14 If no involvement of the notified 1 2 body is needed, the Declaration of Conformity can be prepared by the manufacturer after compilation of the technical documentation some discussion is needed in front, during and after development of the assessment Depending on the complexity of the replacement and possibly the number of affected products Depending on the complexity of the replacement and possibly the number of affected products Depending on the complexity of the replacement and possibly the number of affected products and the number of dossiers submitted at the same time to the notified body by different manufacturers. Depending on the complexity of the replacement and possibly the number of affected products Conclusion For the case of replacement of a PFAS-containing manufacturing device with an PFAS-free alternative, no fix timeline can be established. A minimum and a maximum amount of time for such a process from the regulatory perspective is given below. For a better understanding, a rough, schematic project plan is added at the end of the document Those timelines are realistic if: - all steps lead directly to a favorable result - there is only one or a very low number of medical devices affected by the replacement - there are no multiple changes of manufacturing devices that would complicate the process - no new constituents are identified by the chemical characterization - no preliminary involvement of the notified body is needed an absolute minimum of about 12 -14 months is needed. If a longer shelf life as 18 month is required by customers, this minimum period will increase up to 27 months. Those timelines are not realistic if: - many medical devices are affected by the replacement - new constituents are identified by the chemical characterization - chemical characterization is complex - there's a requirement of long-term biological testing (e.g. subchronic toxicity (9 months invivo) or implantation (min. 9 months in vivo) Then the time period needed to fulfill the regulatory needs will increase to about 50 months (more than 4 years). In this calculation some aspects are not considered: - if the replacement(s) fails due to unfavorable results at any time point, new replacements must be found. In a worst-case scenario this can more than double the time needed. - if many manufacturers need at the same time chemical characterization and/or biological testing the bottleneck could be the capacity of the contract labs, leading to delays of some months to 1 year or longer. - if many manufacturers need to involve the notified bodies at the same time for verification of such replacements in the technical documentation, the number of notified bodies may become a bottleneck as well (this fact already led to the extension of the time frame for implementation of MDR). Additional time up to some months or a year would be possible. - in some cases, especially (but not limited to this) if a PFAS-constituent of the medical device is replaced, additionally to the regulatory steps shown in the flowchart above, a clinical trial could be necessary. In these cases, additionally to the given timeline additionally 2 - 5 years would be needed for the replacement, increasing the time needed to 36 - 115 month (3 years - nearly 10 years). Based on these considerations the derogation timeline of 13.5 years for medical devices is considered very short, especially considering that the replacement would be available probably at the end of the derogation period for the manufacturing devices (probably 6.5 years, in some cases possibly 13.5 years). For this reason, for highly regulated products like medical devices a longer derogation timeline is required. We propose an additional derogation time of 5 - 10 years or at least an additional derogation time of 3 - 5 years for medical devices of class I, IIA and IIB and 5 - 10 years for medical devices of class III or devices with replacement of a PFAS-constituent. Even this will not cover fully the absolute worst cases that may occur. Only by such a longer derogation time the supply of vital medical devices to the healthcare system can be ensured. Schematic project plan for replacement of a PFAS-containing manufacturing device Availability of replacement ( < 6,5 y or< 13,5 y after entering in force ) Step Y M 1 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Explanation absolute best case best case possibly needed (best case) worst case possibly needed (worst case) combined duration best case combined duration best case (with clinical trials) combined duration worst case combined duration wordt case (with clinical trials) 8 9 10 11 12 13 14 7b + 11-14 + Clin. Trial Note: In case of the replacement of a PFAS-containing constituent the time-line could be even somewhat longer.