Document yrKQ0xnZ7Z305N41J059yGN3d

PFAS presence in manufacture and use of pharmaceutical excipients Survey Report - 11 September 2023 The International Pharmaceutical Excipients Council of Europe (IPEC Europe) is the association bringing together (pharmaceutical) excipients producers, distributors, and pharmaceutical manufacturers. As excipients are vital components of medicinal products, our unique membership supports discussion and alignment on related subjects helping to improve and ensure their quality, safety and functionality. IPEC Europe develops and promotes harmonised guidelines to create the appropriate quality and functionality standards to improve patient safety.. IPEC Europe circulated a survey on the presence of PFAS in the manufacturing of pharmaceutical excipients. 55% of respondents manufacture excipients or drug products on equipment that contains PFAS materials in their construction. Another 18% are still using investigating, so it is reasonable to say that up to 73% of IPEC members are affected by this proposed ban. Over 1200 excipients are used in drug product manufacture and can be included at up to 95% in the formulation. If the use of PFAS based materials is banned, it will have a significant impact on the ability of pharmaceutical companies to manufacture drug product. PFAS materials are used in these manufacturing installations because they are chemical and water resistant as well as being hard wearing. Investigation into alternatives is at an early stage but early feedback is that replacement materials are much more reactive and softer which could make them erode and become contaminants in the drug product. It is apparent that items made from these materials would need to be replaced more often increasing the waste generated by this industry. Only a minority of members have a project team in place to investigate the scale of the disruption. Banning the use of PFAS materials in the excipient and pharmaceutical industry has a very real chance of removing thousands of drug products from the European market, if not all of them. Even if a derogation is permitted to excipient manufacturers it needs to be extended to the equipment manufacturers supplying this industry. Page 1 of 9 1. Are you a user, distributor or manufacturer of excipients? 25% 5% Manufacturer of pharmaceutical excipients Distributors of pharmaceutical excipients 65% 5% 2. Do you consider the excipient you manufacture/use to be PFAS or derived from PFAS? 13% 10% No Yes Other 77% Other: "There are a limited number of excipients we use which fall within the PFAS definition e.g. propellants used in inhalation devices. However we may require information on a wide range of excipient supplier's manufacturing process/equipment in order to fully assess the impact for the final" "PFAS or PFAS-derived components are not used as raw materials, ingredients or processing aids." "Raw materials, starting material, intermediates for API and synthesis due to unique substance properties." "We have not found any excipients that are PFAS." Page 2 of 9 3. Thinking about your drug/excipient manufacturing process, does the equipment used contain PFAS type materials? 18% Yes No Other 55% 27% Other: "Yet to be fully evaluated for all excipients we produce" "Do not know". "Have not fully evaluated". "Likely but no clear inventory available" "Not in equipment. Water supply has PFAS, but believe it is CIP rinse cycles may use water with PFAS/PFOS at times, but a health risk according to City of Weston water report." "To be checked with suppliers". "Not applicable" "Yet to be fully evaluated for all excipients we produce". filtered out PFAS/PFOS using RO system. is not considered 4. Are you aware of any alternatives that could be used in their place? 35% No N/A Other 47% 18% Other: "still under review but alternatives could be very limited" "Not yet. Still to be investigated with the equipment manufacturers" "Needs to be evaluated case by case. Generally, alternatives for certain peptide chemistry) have been investigated since very long but no good identified." "Some, but not all materials currently have alternatives." transformations (e.g. alternative has been Page 3 of 9 "For some equipment yes, for some currently no replacement material exists that would provide the same technical characteristics. It is uncertain, if replacement material could be developed in the future and if those materials would receive approval by authorities for the same applications as currently PFAS are used in the plants." "At the moment no suitable alternatives known to us for all possible use cases". "Not for now. Requires equipment suppliers to look for alternatives." "Refrigerants: A lot of sensible excipients need suitable and gentle drying techniques. Therefore, for the production of some excipients used for e.g. injections and parenteral nutrition freeze-drying is necessary. In addition to sufficiently long transition periods for existing plants, we need exemptions (as with the F-Gas Regulation) for cryogenic applications in which substitution is practically impossible, even with substitute refrigerants. In the case of the F-Gas Regulation, low temperature uses are excluded because the costs and benefits (in economic and business terms) are not in any relation to each other. "Sealing/construction materials: We do not see any alternative to PTFE / FEP / FFKM as these are currently the best choices. Other sealing materials which are less expensive and more mechanically suitable have a higher risk of chemical deterioration in turn causing product contamination and failure as well as a potential health hazard for workers." "Filter: Filtration over PTFE membranes is carried out to ensure a very low microbial burden. Due to the low solvent resistance of other membranes, we do not currently see any alternative to the filtration step using PTFE membranes." 5. Do you have a project team in place to investigate this? 7% 3% 40% Yes 50% No N/A Other: "We have a project team to investigate all uses of PFAS materials". "Partly. We are aware of the situation but are waiting for the first opinions of the two ECHA expert groups." "Not now" "Not known to me but might be within organisation". Page 4 of 9 6. Will you be creating a project team to look at this issue? 25% Yes No N/A Other 37% 15% 23% Other: "Likely" "Depends on scope of the ban". "Depends on development in the regulations". "Ongoing" "If necessary" "Depends on further developments". "Already have a team in place". "Depending on further development". "Depending on the further outcome of the discussion the project team may be adjusted". "If judged necessary." 7. Do you want to add any further comment? "As a distributor we are not directly involved in the manufacturing process." "I would like to have a clearer view to what will happen if the regulation is put in place as will cause major disruption." "In terms of safety of plants, it will be difficult to replace PFAS, especially when handling liquids and hazardous materials. Even though often only very limited amount of PFAS are present in manufacturing plants, the functionality they provide is crucial to operate the plants in a safe way." "If purchased raw materials for excipients can continue to be produced in Europe is uncertain, too. Suppliers might be unable to find appropriate replacement materials and therefore move their business outside of Europe. Supply chains will be disrupted." "IPEC Europe should ask for derogation of medicinal products inclusive of excipients. The current proposal to derogate only actives will not help the help the medicinal product sector. It needs to be explained to ECHA that drug product approval is inclusive all active and inactive ingredients. Restriction on any will result in disruption and potential drug shortages." "Not in equipment. Process water supply has PFAS, but believe it is filtered out using RO system. CIP rinse cycles may use water with PFAS/PFOS at times, but the level of PFAS/PFOS in water supply is not considered a health risk according to City of Weston water report." "Other industry associations are following this topic." "PFAS are a part of much of the manufacturing equipment (gaskets, seals, tubing, etc.). Many of these do not have alternative materials available." "Pursuant to the present wording of the REACH restriction proposal without a specific exemption for pharmaceutical excipients, IPA excipient grade manufacture for pharmaceutical purposes in the EEA would be rendered impossible." "The German Minister of Economic Affairs warns against over-regulation of chemicals. Page 5 of 9 https://www.welt.de/wirtschaft/article246711172/Habeck-plaediert-fuer-Augenmass-beiRegulierung-von-PFAS-Chemikalien.html " "The impact of this restriction is incredibly broad - it will impact packaging, equipment, and beyond -as it can impact a lot of the materials and products that we use in industry to support our business - I understand from discussions with other groups that the EMA/EC are looking for very specific detailed information on impact". "The whole pharmaceutical, equipment and excipient supply chain must be considered in this review. We have a lot of equipment that contains or uses PFAS materials in linings, seals and gaskets which would impact production of all excipients we manufacture in the case of a ban." "We are only downstream users of contact materials including packaging materials where PFAS could be used as components and/or processing aids. There are many suppliers with many steps in the upstream value chain which means huge obstacles to get an accurate picture on contact materials potentially impacted by the proposed restriction and identifying alternative contact materials that would comply with the new requirements. The level of detail in the accompanying documentation that we usually receive from our material suppliers (Safety data sheet, declaration of compliance) does not allow to effectively and surely identify those materials potentially impacted by the proposed restrictions. From the above, we are convinced that the proposed EU initiative that aims to remove PFAS, should be essentially led upstream by the value chain to allow for a controlled and organised assessment of use, presence, alternatives and removal strategies across all sectors." "Along this lengthy cross-sectorial process that will take several years, the safety and security of pharmaceutical excipients should be of highest collective priority. We thus rely as well on the upstream value chain and authorities to helping make the transition possible." "We see the need for exemptions for refrigerants in cryogenic applications <-40C" "We see the need for the availability of PTFE, FEP and FFKM sealing materials and PTFE lubricants, because they are not substitutable and are already used only where there is no other way." "We see the need for filtration membranes made out of PTFE for filtration uses." "We would like to know how well EXC manufacturers are aware of this upcoming restriction and if they are involved in any lobbying activities related to this topic. Secondly in case they would be impacted if they already started to take action to replace PFAS in their synthesis processes." "In addition, we would want to know if IPEC will be taken any action to assess potential impact on EXC manufacturers and would come with a position paper related to this restriction." Page 6 of 9 Table Non-Active Ingredients (Excipients) Excipients in pharmaceutical products manufactured on equipment that utilises PFAS materials in its construction Propellants for metered dose inhalers (MDI) - not a missing use (mentioned in Table 2), but missing derogation a) annual tonnage and emissions b) The key functionalities provided by PFAS for the relevant use All drug products on the market contain excipients of which IPEC Europe members reported that up to 73% of which are likely to have been made on equipment that contains PFAS materials in its construction. The tonnage of the excipient industry is unknown as excipients come from many different industries chemical, foods and agriculture for example. In excipient manufacture PFAS materials are used widely in the manufacturing installation where they are used as seals, gaskets, pipelining etc. For example: PTFE Seals for sample ports in stainless steel vessels selected as they are water resistant, chemical resistant and hard wearing. PTFE lined tubing for liquid delivery - selected as they are water resistant, chemical resistant and hard wearing. PVDF rotors in mills selected for hard wearing nature and water resistance, alternative materials expand over time. c) number of companies in the sector affected The majority of excipient manufacturing companies are affected, in a recent survey by IPEC Europe 55% of companies confirmed PFAS materials used in plant construction with a further 18% still investigating. d) The availability, technical and economic feasibility, hazards and risks of alternatives e) Where alternatives are not yet available, information on the status of R&D processes for finding suitable alternatives From IPEC Europe member feedback the potential replacement materials for the PFAS items used in construction of manufacturing equipment tend to be more reactive to chemicals and water, they are less hard wearing which could make them a potential contaminant in excipient and therefore drug product manufacture. This then becomes a GMP issue as "construction materials shall not be absorbative or additive to the excipient" The investigation into alternative materials for use in the construction of excipient manufacturing installations has not really started, much of it is outside our direct control and is the material used by equipment manufacturers and suppliers to the chemical and food industries. Page 7 of 9 f) Cases in which substitution is technically and economically feasible but more time is required I. the type and magnitude of costs (at company level and, if available, at sector level) associated with substitution II. the time required for completing the substitution process III. information on possible differences in functionality and the consequences for downstream users and consumers IV. information on the benefits for alternative providers. The development process for a MDI using an alternative propellant can typically take 6-10 years, encompassing formulation development, device development, non-clinical and clinical studies, manufacturing process development and scale up/establishment of the commercial supply chain. Taking the sequential nature of these activities into account, along with the need to complete them for each marketed product globally, more time is required. The cost of replacing these materials in the excipient industry will be significant and cannot be easily estimated at this time. Many companies are targeting 2030 for portfolio transformation but it is difficult to be definitive due to the normal uncertainties associated with medicines development, in particular if additional development studies are required. Take into account this target, along with the associated development uncertainties associated with portfolio transformation, a 12-year derogation for HFA-134a and HFA-227ea is required. Given the widespread use of these materials and the current lack of alternatives it will take a significant amount of time to evaluate potential replacements and make the substitution if at all viable. All changes made to a licensed medicine are reviewed and approved by the European Medicines Agency in accordance with their specific requirements. Performance must be compared between current and updated products (for example refer to `Q&A on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers', 30 March 2023, EMA/CHMP/83033/2023 Available at https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-datarequirements-when-replacing-hydrofluorocarbons-propellants-oral-pressurised_en.pdf). This will ensure that any updated products are fully assessed. The use of more reactive and softer materials in the construction of excipient production equipment may lead to contamination of the excipient and more frequent replacement of these alternatives increasing the waste coming from the industry. The new propellants HFA-152a and HFO-1234ze both have considerably lower GWP compared with currently used medical propellants (124 and <1 for HFA-152a and HFO-1234ze compared with 1430 and 3220 for HFA-134a and HFA-227ea respectively). These properties are of benefit in the context of climate change and will support regional net zero emissions targets and compliance with local and global HFA phasedown under the Kigali Amendment to the Montreal Protocol. Page 8 of 9 g) If substitution is not technically or economically feasible, information on what the socio-economic impacts As the current restriction proposal for medical HFA-134a and HFA-227ea would come into effect during the global portfolio transition period for European based MDI manufacturers and non-EU based MDI importers, this will impact the supply of currently marketed MDIs to both EU and non-EU patients who currently rely on these medicines. EU patients would not be able to access MDIs and supply of MDIs to non-EU patients would also cease until manufacturing could be relocated outside of the EU. Page 9 of 9