Document R22q60qw7GrvY8xNRRwEmMegX

2023 PQRI Comments to ECHA REACH on Annex XV Restriction Report for Per- and polyfluoroalkyl substances (PFAS) About PQRI The Product Quality Research Institute (PQRI) (www.pqri.org) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality, manufacturing, and regulation. 0 PQRI Comments on Annex XV Restricon Report Contents Glossary............................................................................................................................................................................2 Introducon .....................................................................................................................................................................4 Background - Medicinal product lifecycle ....................................................................................................................4 Scope of Evaluaon ......................................................................................................................................................5 Summary of Core Findings............................................................................................................................................6 ECHA Specific Informaon Requests.................................................................................................................................7 Request #1 Sectors and Sub-uses .................................................................................................................................7 Request #1 Summary - Sectors and Sub-uses.............................................................................................................13 Risk to supply of medicines in EU ...........................................................................................................................13 Regulatory Challenges ............................................................................................................................................13 Pandemic and Catastrophic Event Preparedness ....................................................................................................14 Future populaon...................................................................................................................................................14 Aging populaon ....................................................................................................................................................14 Societal Impact and Unintended Consequences .....................................................................................................15 Request #2 Emissions in the end-of-life phase - manufacture, use, end-of-life..........................................................15 Request #2 Summary - Emissions in the end-of-life phase - manufacture, use, end-of-life........................................18 Request #3 Emissions in the end-of-life phase - incineraon effecveness................................................................18 Request #4 Impacts on the recycling industry ............................................................................................................18 Request #5 Proposed derogaons - Tonnage and emissions......................................................................................18 Request #6 Missing uses - Analysis of alternaves and socio-economic analysis.......................................................18 Defining PFAS: Grouping, Properes and Hazard Assessment ................................................................................18 PFAS in the Pharmaceucal Supply Chain...............................................................................................................20 Raonale for Pharmaceucal Sector PFAS Usage and Sub-uses..............................................................................23 PFAS Used to Produce and Deliver Medicinal Products Alternave Potenal.........................................................29 Request #6 Summary Missing Uses Alternaves and substuon consideraons......................................................34 Request #7 Potenal derogaons marked for reconsideraon-Analysis of alternaves and socio-economic analysis. ...................................................................................................................................................................................34 Request #7 Summary - Potenal derogaons marked for reconsideraon current derogaons not feasible. ...........36 Request #8 Other idenfied uses - Analysis of alternaves and socio-economic analysis..........................................37 Request #8 Summary - Other idenfied uses Societal Cost of Ban for Pharma ..........................................................43 Request #9 - Degradaon potenal of specific PFAS sub-groups................................................................................43 Request #10 - Analycal methods..............................................................................................................................43 Closing Remarks: Bringing back points to consider and paent impact..........................................................................43 References......................................................................................................................................................................46 1 PQRI Comments on Annex XV Restricon Report Glossary AD API CCS COPD CSS DDS EC ECHA ECTFE EEA EiF EMA EPPA SEA ETFE EU FEP FFKM FIH FKM FVQM GMP HVAC IMPD IND IPAC IPAC-RS MAA Mab Mfg OECD OELs PFAS PFOA PLC pMDI PMT POC PPE PQRI PTFE PVDF QC R&D Alzheimer's Disease Acve Pharmaceucal Ingredient Container closure system Chronic Obstrucve Pulmonary Disease European Commission Chemicals Strategy for Sustainability Drug delivery system European Community European chemicals agency Ethylenechlorotrifluoroethylene European Economic Area Entry into Force European Medicines Agency European Public Policy Advisors Socioeconomic Analysis Ethylene tetrafluoroethylene European Union Fluorinated ethylene propylene Perfluoroelastomers First In Human Fluoroelastomers Fluorosilicones Good Manufacturing Pracce Heang, Venlaon, Air Condioning, Refrigeraon Invesgaonal Medicinal Product Dossier Invesgaonal New Drug Internaonal Pharmaceucal Aerosol Consorum Internaonal Pharmaceucal Aerosol Consorum on Regulaon & Science Markeng Authorisaon Applicaon Monoclonal Anbodies Manufacturing Organisaon for Economic Co-operaon and Development Occupaonal Exposure Limits Per- and Polyfluoroalkyl substances Perfluorooctanoic Acid Polymers of Low Concern pressurized Metered Dose Inhaler Persistant, mobile, toxic Proof of Concept Personal Protecve Equipment Product Quality Research Instute Polytetrafluoroethylene Polyvinylidene fluoride Quality Control Research and Development 2 PQRI Comments on Annex XV Restricon Report REACH Registraon, Evaluaon, Authorizaon and Restricon of Chemicals RO1 Restricon opon 1 in Annex XV Restricon Report on PFAS RO2 Restricon opon 2 in Annex XV Restricon Report on PFAS SBT Science-Based Targets SBTi Science-Based Targets iniaves TULAC Texles, Upholstery, Leather, Apparel and Carpets UK United Kingdom 3 PQRI Comments on Annex XV Restricon Report Introducon The Competent Authories of Germany, The Netherlands, Sweden, Denmark, and Norway submited a joint REACH Annex XV restricon proposal for a broad group of PFAS. The proposed restricon aims to limit the risks to the environment and human health from the manufacture and use of a wide range of PFAS for entry into REACH Annex XVII. Two restricon opons were proposed in consideraon of stakeholders' informaon [1]: A full ban with no derogaons and a transion period of 18 months from EiF A full ban with use-specific me-limited derogaons. (18-month transion period plus either a five- or 12-year derogaon period) It is acknowledged that a stakeholder call for PFAS evidence occurred in 2020 and 2021 which was reflected in the final proposal. Specific impact assessments for 14 sectors were documented in Annex E and PFAS data on human health and environmental hazards of alternaves was listed in Appendix E.2It was observed in the impact assessments that there were insufficient data for evaluaon of human health and environmental hazards in many cases. Further, there were cases in the Annex XV restricon report, where the available evidence base is considered weak. A derogaon is not supported at the moment, but derogaons could potenally be warranted [1]. There was no Pharmaceucal Sector included in the Annex XV restricon report. As the call for evidence took place during the height of the pandemic, the full scope and complexity of PFAS used throughout the medicinal product (pharmaceucal) supply chain was not enrely conveyed. The intenon of this paper is to provide regulators with informaon on the major impact that the proposed PFAS ban will have on the pharmaceucal supply chain and the risks that will be posed to the health and well-being of paents. The societal effects are expected to be severe should this restricon, as writen, become effecve. The European Medicines Agency (EMA) is responsible for the authorizaon of safe and effecve medicines [2]; however, medicinal products cannot be produced without access to PFAS and the arcles containing PFAS that are used to manufacture, store, transport and deliver medicines to paents. In an effort to beter understand PFAS sub-uses in the Pharmaceucal Sector, the Product Quality Research Instute (PQRI) conducted a survey among pharmaceucal companies and their suppliers. The survey was constructed in the form of a quesonnaire to obtain data on PFAS uses, alternaves, and the impact of a ban on medicinal products and diseases they are used to treat. The results from this survey are provided as evidence in this document. Background - Medicinal product lifecycle Background on the medicinal product lifecycle is necessary to understand the full effect that the PFAS restricon would have on the Pharmaceucal Sector, and therefore paents. The medicinal product scope encompasses pharmaceucals, biotechnology products, biological products, and vaccines. The approval of medicines requires significant me and substanal evidence for product safety and efficacy across the enre pharmaceucal supply chain prior to submission. There is a wide array of PFAS types, uses and suppliers throughout the pharmaceucal supply chain starng with the API, as well as arcles used to manufacture, package, store, transport, and deliver a medicinal product to paents. As shown in Figure 1, changes to any parts of the pharmaceucal supply chain, medicinal product manufacturing processes or delivery will trigger assessments of the impact of the change within the company responsible. In the case of suppliers, noficaon of their customers will prompt them to also consider the impact on their product/process (as evidenced via PQRI survey responses - refer to Request #7 secon of this document). 4 PQRI Comments on Annex XV Restricon Report Lifecycle/Change Management Impact to Unit Operaons Figure 1 Points of Change Impact on Medicinal Product Manufacture and Delivery All manufacturing and supply changes need to be evaluated and oen require tesng and data to be generated as part of the change. Depending on the change and the registered informaon, these changes could lead to the generaon of addional development data or the submission of post-approval changes for marketed products. It can take years to generate sufficient data to support a change that may delay development or require approval by regulatory authories before the change can be implemented. The lifecycle phases and esmated me frames for regulatory review and approval are illustrated in Figure 2. Figure 2 Medicinal Product Lifecycle Scope of Evaluaon The focus of the evaluaon presented in this document is on the societal impact on the European Union with respect to the proposed restricon submited to ECHA as a REACH Annex XV Restricon Report on Per- and polyfluoroalkyl substances (PFAS) [1]. Qualitave data was acquired by PQRI from mulnaonal pharmaceucal/ biopharmaceucal and vaccine companies (19 in total) and suppliers to pharmaceucal companies (15 in total) based on an anonymous quesonnaire that was open for entry for just five weeks. The quesons were formulated to provide informaon on the types, uses and interdependencies of PFAS across the pharmaceucal supply chain, the potenal for alternaves, substuon mes, supply of medicinal products and risk to paents who rely on lifesaving medicines every day. Addional informaon from literature and references to other consults already submited are included. 5 PQRI Comments on Annex XV Restricon Report Summary of Core Findings Below is a list of core findings and resultant recommendaons: Findings Recommendaons 1. Pharmaceucal producon and paent safety Include a Pharmaceucal Sector and their PFAS have unique requirements that are not missing uses/sub-uses. captured within the 14 sectors that are defined in the proposal. 2. Mulple types of PFAS are used in every phase Group PFAS to enable safety risk assessments as of pharmaceucal development and some are appropriate for the environment (emissions, known to have low toxicity and not expected to biota, workers, and consumers) and include have adverse effects on human health. safety risk assessments that are suitable for paent populaons. 3. Supply chain is complex, and it is difficult to Invest me to understand types of PFAS, correlate all types of PFAS to sources and emissions, and environmental contribuons from emissions. the Pharmaceucal Sector to enable 4. Potenal supply chain vulnerabilies exist with jusficaons for derogaons. highly uncertain data which can contribute to medicinal shortages. a. Shortages can drive demand for new sources of medicines and consequently, paents can be subjected to unapproved, illicit or counterfeit products compromising safety and efficacy. b. The societal cost of disconnuaon or shortages of medicinal products cannot be weighed against the environmental risks of their degradaon products. Lower environmental impact of medicines is increasingly in focus of pharmaceucal regulaons, and not limited to "PFAS" API. c. Nearly a quarter of the EU populaon, who have diabetes or respiratory diseases, could be impacted if the proposal, as it stands, moves forward. 5. The majority of PFAS applicaons used in the Pharmaceucal Sector have an essenal combinaon of properes that are unmatched by any other material. Reconsider me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability of connued PFAS supply from upstream and downstream supplier inventories. 6 PQRI Comments on Annex XV Restricon Report 6. Substuon of auxiliary PFAS across the pharmaceucal supply chain could have unintended consequences on human health and cause disrupon to the medicinal product supply. 7. The me to discover a PFAS alternave and implement it for each medicinal product can take anywhere from 20-60 years based on data that has been acquired from the PQRI survey of suppliers and pharmaceucal manufacturers. 8. There is a realisc possibility that mulple lifesaving or life-sustaining medicinal products would be disconnued. A large percentage of the EU populaon could be impacted if the proposed derogaon melines are kept. ECHA-Specific Informaon Requests The secons below address each of the specific informaon requests listed by ECHA for the purpose of organizing all consults with a similar structure. Request #1 Sectors and Sub-uses Although fourteen sectors were idenfied in which PFAS are commonly used, it seems that with respect to human health, only acve pharmaceucal ingredients and medical devices have been addressed in the proposed derogaons. As described in the introducon a survey of pharmaceucal manufacturers and suppliers to pharmaceucal manufacturers was conducted. The breakdown of the products represented in the survey results is shown in Figure 3 and Figure 4. 7 PQRI Comments on Annex XV Restricon Report Figure 3 Medicinal product types (routes of administraon) containing PFAS represented by pharmaceucal manufacturers in the PQRI survey Figure 4 Role of PFAS suppliers represented in the PQRI survey It was found from the PQRI survey that all pharmaceucal product types would be impacted in some way by a complete ban of PFAS. When compared to all of the diseases that these pharmaceucal products are used to treat (see Figure 5 and Figure 6) it is clear that all non-communicable disease treatments would be impacted at some level. Although there were fewer responses that indicated treatment for communicable diseases, all but one of the disease areas (measles, mumps, rubella) would be impacted in some way by a PFAS ban (see Figure 6). Due to the short meframe in which the survey data was collected, it is quite possible that pharmaceucal manufacturers of treatments for any missing disease areas had not responded to the survey. It is also possible 8 PQRI Comments on Annex XV Restricon Report that the results may not reflect the full scope of treatments and disease areas that might be impacted. This points to the fact that more me is needed to assess the impact on the Pharmaceucal Sector as a whole. In general, the results of the survey emphasize that many life-saving and life-sustaining treatments would be impacted by a PFAS ban. Figure 5 Product types (route of administraon) impacted by a PFAS ban and non-communicable diseases treated 9 PQRI Comments on Annex XV Restricon Report Figure 6 Product types (route of administraon) impacted by the proposed PFAS ban and communicable diseases treated To get a beter understanding of PFAS sub-uses in the pharmaceucal supply chain, the survey included both pharmaceucal manufacturers and their suppliers. Based on the results of the survey it can be seen that there are several uses and sub-uses of PFAS associated with medicinal product manufacture, storage/transport, delivery and disposal. As shown in Figure 7, the primary areas of use for the Pharmaceucal Sector include drug synthesis, drug product manufacturing, container closure/drug delivery systems (CCS/DDS) and storage. It is noted, that in the event of a PFAS ban, a direct impact on acve pharmaceucal ingredients (API) was indicated only for small molecule medicinal products that are administered by several routes (i.e., topical, oral, injectable). The proposed derogaon for medicinal products only applies to acve pharmaceucal ingredients and is a very small poron of the actual impact on pharmaceucal manufacturing and distribuon processes. Therefore, it is proposed that consideraon be given to the establishment of a separate Pharmaceucal Sector and that the scope of the proposed API derogaon be reconsidered to include all pharmaceucal uses and subuses. 10 PQRI Comments on Annex XV Restricon Report Figure 7 Proposed PFAS ban impact on pharmaceucal manufacturing and distribuon By looking at the PQRI survey results further granularity to PFAS uses and sub-uses can be understood. As shown in Figure 8, in addion to API, excipients and reagents are included when considering the drug formulaon. From a manufacturing perspecve in-process container closures, processing aids and lubricants were idenfied. From a packaging and delivery system perspecve, containers, closures, coangs and funconal/mechanical components as well as secondary and terary packaging were highlighted. Based on the noceable differences in perceived impact of a PFAS ban between the pharmaceucal manufacturer responses and the supplier responses to the survey it is clear that more informaon needs to be obtained on the various types and uses of PFAS in the Pharmaceucal Sector. Since uses/sub-uses of PFAS are not always obvious, it is possible there is a lack of awareness due to the broad PFAS definion; research has shown significant gaps in understanding types and sources of PFAS [1]. 11 PQRI Comments on Annex XV Restricon Report Figure 8 Proposed PFAS ban impact on materials supplied and uses in the Pharmaceucal Sector When consideraon is given to the sub-uses idenfied by both pharmaceucal manufacturers and their suppliers, it is possible to conceive that some of the sub-uses have already been accounted for in the 14 sectors idenfied in the Annex E Impact Assessment [1]. To invesgate that, the Pharmaceucal Sector uses and sub-uses were compared to the main uses and sub-uses idenfied in Annex E and Table 2 of the Annex XV Restricon Report. The details of that comparison are discussed in detail in the Request #6 secon (see Table 3). Aer consideraon of the detail provided in Annex E Impact Assessment [1] there is very litle direct overlap in uses, perhaps slightly with food packaging. Although there are some similar sub-uses, they are not the same. For example, the requirements for food contact may serve as a starng point but when materials that may be used in other consumer applicaons are used in medicinal applicaons there exist addional expectaons regarding consistency of supply and quality of materials and manufacturing processes [3, 4, 5]. To summarize the outcome of the comparison, the Pharmaceucal Sector uses and sub-uses were listed in order of progression from starng materials through delivery to the paent. To complete the summary shown in Figure 9, above each set of Pharmaceucal Sector sub-uses is a list of the relevant previously idenfied 14 sectors that had similar sub-uses for reference. Based on the lack of synergy between the pharmaceucal uses and sub-uses and those already described in the idenfied 14 sectors, it is highly recommended that a separate Pharmaceucal Sector be considered. 12 PQRI Comments on Annex XV Restricon Report PFAS mfr Mining Energy TULAC-PPE Electronics Energy TULAC-PPE Electronics Energy Lubricants Chemical mfr Biological processing Starting Materials API synthesis Excipient mfr Biological processing Active Pharmaceutical Ingredient/ Excipients Container/ closure Pharm mfg equipment Analytical equipment Formulated Drug TULAC-PPE Electronics Energy Lubricants Med Device Metal products Packaging Container/ closure Pharma mfg equipment Pharma Packaging Analytical equipment Packaged Medicinal Product Electronics Energy Fluorinated gases Transport Pharma Packaging Analytical equipment Storage/ Distribution Electronics Energy Fluorinated gases Transport Annex XV Report PFAS Identified sectors Pharma Packaging Pharma Waste Patient Use/ Disposal Pharmaceutical subuses Pharmaceutical Supply Chain Figure 9 Mapping of Pharmaceucal Sector sub-uses to relevant 14 Sectors idenfied in Annex XV report. Request #1 Summary - Sectors and Sub-uses Based on the informaon provided a Pharmaceucal Sector is jusfied. Unlimited derogaons are necessary due to the unique applicaons of PFAS use and sub-uses with respect to the pharmaceucal lifecycle and impact on the pharmaceucal supply chain. The intended use for PFAS in the pharmaceucal supply chain encompasses materials used from discovery through clinical studies to marketed product, for the purpose of manufacture, packaging and delivery to paents. Pharmaceucal discovery to product launch can take as long as 20 years or more. Changes over a medicinal product lifecycle can involve varying degrees of risk but could result in requirements for clinical studies adding to the me to idenfy and validate a replacement with the same properes. The regulatory change approval process can take 2-10 years, depending on the type and magnitude of change(s). Points to be considered regarding the health and well-being of paents include the following: Risk to supply of medicines in the EU 1. From the range of therapies and condions treated which have been highlighted by the survey responses, there is an opportunity to consider the potenal impact that the proposed PFAS ban may have. The impact would be not just to the EU but to the global healthcare system of a wide-ranging lack of access to medicaon due to shortages linked to PFAS restricons for arcles within the supply chain. Shortages of materials used in manufacturing processes or other areas of the pharmaceucal manufacturing supply chain would potenally be similar to shortages recently observed during the COVID-19 pandemic, where paents unable to access roune medicaons would default to the healthcare system for support. The healthcare systems would potenally be overloaded. There is also a significant risk to the availability of life-saving medicaon in an emergency situaon (medicaon has a shelf life and must be used or replaced by the expiry date, so a constant supply of medicaon is required to ensure that it is always available at the point of need). Regulatory Challenges 2. While the proposal to ban PFAS-containing materials is driven by ECHA, the EMA and country-specific regulatory authories are reviewing and approving submissions for new medicinal products and delivery systems, and are monitoring (via pharmacovigilance) all approved marketed pharmaceucal 13 PQRI Comments on Annex XV Restricon Report products. These are both branded and generic products. Some of these products may also be for rare diseases and may be under the orphan medicine process. All of these are at risk with the progression of the proposed PFAS ban. The generaon of significant amounts of data will be required to sufficiently support the changes. Preparaon of the required changes for review, and the performance of the review of the changes by health authories require significant amounts of me for the review cycle and approval to be completed. This will significantly increase workloads for regulatory agencies due to increases in variaons for changes and inevitably result in product withdrawals and shortages of medicines. Pandemic and Catastrophic Event Preparedness 3. There may be a serious public health impact if another global health emergency were to arise, and the pharmaceucal industry was not able to respond in the same way as it did to the COVID-19 pandemic due to the lack of crical materials within the supply chain, manufacturing process or other area of the pharmaceucal supply chain. Any restricons will have an impact on paents, whether this is immediate access to current medicines, future access to novel medicines, or pandemic and catastrophic event preparedness. The COVID-19 pandemic closed down supply chains/ countries/ borders/ facilies and effecvely stopped producon and shipping around the globe for a period; and natural disasters such as major weather events have disrupted and destroyed manufacturing facilies around the world that provide specialist products, leading to acute shortages of the medicines or materials. Future populaon 4. There is a risk to the future development of medicines as the products highlighted within the survey were both on the market and under development. Therefore, any restricons not only affect the current products but also future products and development, potenally liming the future availability of new life-saving medicaons, which could include vaccines, cancer therapies, and rare diseases. There may also be a reducon in the availability of veterinary medicines as indicated in the Animal Health EPPA SEA consult (Part 24-9530) where there is an impact on the resilience of the pharmaceucal industry. Some companies may go out of business if their sales are EU only or materials are sourced from the EU, which will reduce the quanty of medicine available in the global marketplace. Diseases that are currently well controlled may become a public health issue if there is a lack of available medicine in the EU due to restricons and/or companies going out of business or withdrawing products. Aging populaon 5. Populaons globally are aging, which brings with it the complexies of treang more diseases and oen mulple diseases in individuals. Neurodegenerave condions, such as Alzheimer's Disease (AD), are more common in older people. Therefore, the incidence of AD and other similar diseases will increase with the aging populaon. Age is the biggest risk factor [6] and as of 2020, there were approximately 50 million people worldwide with Alzheimer's disease [7]. Alzheimer's financial burden on society is large, with an esmated global annual cost of US$1 trillion [7]. In Europe, more than one fih of the populaon was aged 65 or over in 2020 (an increase of 3% compared to 2010) and the prevalence of demena in 2018 was around 1.6% and is ancipated to double by 2050 [8]. Other diseases will also have an increased probability with age. Therefore, the demands on research and the pharmaceucal industry for treatments will increase further - there are not yet cures for many diseases (AD included) but development work is ongoing with treatments to slow the disease progress. Restricons on the use of PFAS or fluoropolymers may have the consequence of reducing this research and the potenal for new therapies in many areas. 14 PQRI Comments on Annex XV Restricon Report Societal Impact and Unintended Consequences 6. The PFAS restricon can have a negave effect on the EEA due to 1) low or scarce inventory of medicinal products and 2) inhibited innovaon of new and improved treatments. There will be high demand for essenal medicines and shortages are known to give rise to alternave markets with inventories of unapproved, illicit or counterfeit medicinal products. This can result in serious consequences, causing hospitalizaons and even death for vulnerable populaons [9]. Addionally, this would contradict the EU's stated aim of shortening supply chains and bringing producon to the EU: "Europe supports research and innovaon in strategic areas where supply shortages persist, such as raw materials,....and increasing the resilience of industry." [10]. Request #2 Emissions in the end-of-life phase - manufacture, use, end-of-life Data were analyzed from the PQRI survey regarding both Pharmaceucal Manufacturers' and Suppliers' end-of-life treatments for materials used or supplied to support each stage of pharmaceucal producon. As shown in Figure 10 and Figure 11 there is no evidence of reuse for any of the materials. Recycling and on-site or off-site disposal are generally used by suppliers for starng materials, container closures and drug delivery systems. From the pharmaceucal manufacturers' perspecve, the primary mode of end-oflife treatment is offsite disposal. Offsite disposal is generally diverted from landfill to incineraon due risk and potenal impact of pharmaceucals on the environment and local regulaon requirements. 15 PQRI Comments on Annex XV Restricon Report Figure 10 End of Life treatment of materials containing PFAS at Pharmaceucal Manufacturers 16 PQRI Comments on Annex XV Restricon Report Figure 11 End of Life treatment of materials containing PFAS at Suppliers Risks to the environment and human health are a significant concern in the pharmaceucal industry, as are praccal approaches for risk management to protect paents. Net-Zero Standards adopted by many pharmaceucal manufacturers expect that companies invest above and beyond, but not instead of deep emission cuts in line with science [11]. Environmental priority connues to evolve, as evidenced in the 2023 SBTi Report. A total of 131 pharmaceucal and biotechnology companies set targets to reduce emissions consistent with the Paris Agreement goals [12]. Typically, pharmaceucal waste is incinerated based on current pracce to eliminate the inherent risk of medicinal products in the environment. Literature has shown potenal for recycling of materials from used paent medicines as evidenced by examples in the UK: recovery of un-used propellants from paent returned inhalers, (the Take-AIR 12-month pilot scheme in the UK accepted all inhalers and the recovered pressurized metered-dose inhalers (pMDIs) were dismantled and component parts recycled where possible; the remaining propellant gas was extracted for reuse in refrigeraon and air condioning industries. Other inhaler types were incinerated in an `energyfrom-waste' facility and recycling of empty medicine blister packs from medicines is also possible [13, 14, 15]. 17 PQRI Comments on Annex XV Restricon Report Feasibility studies for innovave waste management technologies for upstream suppliers and downstream users are ongoing. There is sll a lot of informaon to be gathered to support PFAS policy decisions to ensure the society would not be negavely impacted by banning all PFAS. Request #2 Summary- Emissions in the end-of-life phase - manufacture, use, end-of-life Manufacturers have requirements and controlled processes for disposal. Baseline emissions and waste in the Annex XV restricon report are highly uncertain. Also, there is no, or insufficient data on bioaccumulaon for the majority of PFASs. Safe concentraon limits are highly uncertain. Due to the risk of environmental contaminaon, most of the pharmaceucal waste is diverted from landfills and incinerated. New recycling technologies and design principles are emerging and signal a reducon of environmental PFAS in the near future. Request #3 Emissions in the end-of-life phase - incineraon effecveness Topic not addressed in this paper Request #4 Impacts on the recycling industry Topic not addressed in this paper Request #5 Proposed derogaons - Tonnage and emissions Several PFAS or PFAS containing arcles with long-term and short-term, exposures and use condions are used throughout development, manufacture, packaging and delivery of medicinal products. There are currently no rules or regulaons in place to monitor the PFAS proposed to be banned, which may number as many as 10,000. Emissions data is not also readily available and proxy data is not substanated. The Annex XV restricon report emphasizes the high uncertainty for baseline emissions data and environmental waste [1]. Tracking emissions with respect to PFAS (substances/precursors, gases, and polymers) across the pharmaceucal lifecycle for each medicinal product and all PFAS is not readily achievable due to the complexity of the supply chain. More me is needed to idenfy all PFAS sources, types and uses to enable a comprehensive esmate of tonnage and emissions. Request #6 Missing uses - Analysis of alternaves and socio-economic analysis Defining PFAS: Grouping, Properes and Hazard Assessment The restricon of PFAS must be substance-related and risk-based (Arcle 68 para. 1 of the REACH Regulaon [16]). The restricon must differenate between the different groups of PFAS and risks posed by their uses. Although various definions for PFAS exist, there is no consensus; PFAS scope for this proposal is aligned with the OECD definion. This is a very broad applicaon to define PFAS as, "any substance that contains at least one fully fluorinated methyl (CF3-) or methylene (-CF2-) carbon atom (without any H/Cl/Br/I atached to it" [1]. This scope would include a minimum of 10,000 PFAS that are grouped as per and polyfluoroalkyl substances, which can be categorized into 2 primary categories; polymers and non-polymers. These 2 categories are further simplified into 5 classes of PFAS: Perfluoroalkyl substances Polyfluoroalkyl substances Polymeric perfluoropolyether 18 PQRI Comments on Annex XV Restricon Report Side chain fluorinated polymers Fluoropolymers The non-polymer category includes perfluoroalkyl substances and polyfluoroalkyl substances, while the polymer category includes fluoropolymers, perfluoropolyethers, and side-chain fluorinated polymers. It is important to note that polymers generally have very different physical, chemical, and biological properes than do non-polymer chemical substances of low molecular weight. There are notable differences between the 5 classes of PFAS. For example, perfluorooctanoic acid (PFOA), a process aid, in the non-polymer perfluoroalkyl substances class, is mobile, and persistent and has been phased out. Subsequent to the phase-out, perfluoroalkyl substances with <8 carbons were substuted and consequently are now in the environment. Side-chain fluorinated polymer class compounds such as 8:2 fluorotelomer alcohol may degrade to form PFOA and therefore are subject to regulatory management. Finally, polymeric perfluoropolyethers represent a class of PFAS exemplified by oxygen linkages in the polymer backbone. The primary concern for PFAS and/or their degradaon products is the potenal for very high persistence in the environment and associated properes of long-range transport, mobility, accumulaon in plants, bioaccumulaon, ecotoxicity, endocrine acvity and effects on human health [1]. The proposed grouping approach to assess over 10,000 compounds for their effect on human health does not correlate to the presence of PFAS in the environment from industrial uses. An independent expert panel invesgated PFAS grouping for human health assessments and concluded that persistence is generally not deemed scienfically valid way to group "all PFAS" for the purposes of assessing human health risk [17]. Certain chemical-physical properes were considered potenal predictors of hazards and exposure for grouping PFAS when specific informaon was lacking, but not sufficient alone for informing exposure or potenal hazards or toxicological effects and dose response for risk assessment. The most crical data gaps idenfied were (1) exposure, (2) dose-response, and (3) mode of acon studies. It was also noted that there are crical gaps in understanding PFAS chemistries, mixture composion toxicity and handling overall uncertaines. Overgeneralized statements should be avoided and different strategies would be needed to support various risk management opons such as restricons in manufacture and use. The expert panel agreed that a broad definion, such as the OECD 2021 PFAS definion, may be a useful starng place, but that the definion needs to be refined for specific risk assessment goals. The OECD report also states this: "individual users may define their own PFAS working scope for a specific acvity according to their specific needs by combining this general definion of PFASs with addional consideraons" [18]. One possibility for subgrouping according to health hazard is to consider the OECD criteria for polymers of low concern (PLC) [19]. Fluoropolymers are inert, not mobile and can meet the criteria. The OECD definion of a polymer has been widely adopted and incorporated in the regulaon of many governments. However, this harmonizaon has not been reached for the criteria used to idenfy PLC. It was also noted that except in the EU system, all other jurisdicons integrate the concept of polymers of low concern into their regulaon. In March 2007, the OECD Task Force on New Chemicals Noficaon and Assessment organized an Expert Group Meeng on polymers in Tokyo, Japan. The recognion and acceptance of the PLC concept then constuted the basis for the discussions during the meeng. To reinforce this posion, a definion of a PLC was agreed upon. The proposed definion of a PLC emerged as the following: "Polymers of low concern are those deemed to 19 PQRI Comments on Annex XV Restricon Report have insignificant environmental and human health impacts. Therefore, these polymers should have reduced regulatory requirements."[19] The criteria for PLC may include polymer composion, molecular weight and molecular weight distribuon, weight % oligomer, electrical charge, reacve funconal groups, funconal group equivalent weight, low molecular weight leachables (including residual monomers), parcle size, water solubility and octanol/water paron coefficient, polymer stability (e.g., hydrolyc stability, thermal stability, photostability, oxidave stability), abioc stability and bioc stability. Examples of PLC are listed in Table 1. Table 1 OECD Polymers of low concern Fluoroplascs PTFE ETFE PFA FEP PVDF ECTFE Fluoro elastomers FKM FFKM FEPM FVQM PFAS in the Pharmaceucal Supply Chain As evident from the PQRI survey, major uses of PFAS in the pharmaceucal supply include drug formulaon, manufacturing processes, packaging, and delivery. Specific examples include API, excipients, propellants, manufacturing equipment, asepc processing equipment, reagents, cleaning agents, processing aids, flow agents, laboratory equipment, medicinal packaging, delivery system components, lubricants, electronics, storage and transport. Without all of these, medicinal products could not be made or tested. Any change to replace them (if it were possible to do so) could involve a complete redesign/rebuild of equipment and auxiliary materials. PFAS uses and sub-uses across the pharmaceucal supply chain are listed, but not limited to, those shown in Table 2. Table 2 PFAS Uses and Sub-uses in Pharmaceucal Sector and Potenal for Derogaons Uses Sub-uses* Drug Formulaon Excipients, Propellants, Solvents, Reagents Derogaon/ Recommended Derogaon Annex XV Report: API: me-unlimited derogaon Recommended Derogaon: reconsideraon of scope for meunlimited derogaons for coformulants, chemical intermediates, excipients and other PFAS used in the pharmaceucal supply chain. Clarity and alignment with EMA. Facilies Air Filtraon, Refrigerants, HVACR, Equipment, PPE, Seals, Pipes, Tubing, Water Purificaon, Gases 20 Annex XV Report: 6.5 or 13. 5 years aer EiF Recommended Derogaon: reconsideraon of me-unlimited derogaon for those PFAS used in the PQRI Comments on Annex XV Restricon Report Uses Sub-uses* Equipment: Manufacturing, Lyophilizaon and Asepc Processing Pipes, Valves, Gaskets, Seals, O-Rings, Filters, Tubing, Seals, Valves, Separaon Media, Ion Exchange Membranes, Filters, Sensors, Liners, Disllaon Systems, Capping/Sealing Systems, Reacon Vessels/Bags, Srrers, Tubes, Storage Containers, Coangs, Needles, Conveyor Belts, Vacuum Pumps, Water Purificaon Equipment, PPE, Cleaning Agents, Process Aids, Lubricants, Coangs, Engineering Fluids, Refrigerants, Compressors, Hydraulic Fluids, Coolants Laboratory Equipment Refrigerants, Filters, Membranes, Connectors, Seals Labware, Analycal Reference Materials, PPE, Coated Test Equipment, Tubing, Monitors/Sensors Medicinal Packaging Containment and Delivery Electronics Primary and Intermediate Vial, Stoppers, Seals, Syringes Barrels, Needles, Tip Caps, Coangs, Polymer Arcles, Drug Delivery Systems, Device Components Including (Tubing, Pumps, Bateries), Lubricants, Post Processing/Washing/Sterilizaon Equipment, Secondary Packaging, Labels, Inks, Adhesives, Solvents, Cleaning Agents, Terary Packaging, Outer Wraps, Polymer, Metal, Paper, And Cardboard Products Electronics, Semiconductors, Smart Devices, Computers, Temperature Monitors, Electronic Documentaon, Data Storage Systems, Analycal Data Capture, HVAC/Environmental Monitoring, Stability Chambers, Security Systems, Controlled Access, Payments, Ordering, Shipping, Electronic Safety Storage and Transport On Site Refrigeraon/Freezing for Manufacture/Distribuon Warehousing and In Transit, Controlled Temperature and Pressure 21 Derogaon/ Recommended Derogaon pharmaceucal supply chain and availability of upstream supplier inventory. Annex XV Report: 6.5 or 13.5 years aer EiF Potenal derogaon (silicone, PTFE, heparin) Recommended Derogaon: reconsideraon of me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability for upstream supplier inventory. Annex XV Report: 13. 5 years aer EiF with unlimited derogaon for PFAS analycal reference materials Recommended Derogaon: reconsideraon of me-unlimited derogaon for PFAS used in sample handling material and instrument operaon. Annex XV Report: 6.5 or 13.5 years aer EiF Recommended Derogaon: reconsideraon of me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability for upstream supplier inventory. Alignment with EMA approval requirements. Annex XV Report: Semiconductor mfg 13.5 yr aer EiF Recommended Derogaon: Reconsideraon of me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability for upstream supplier inventory. Annex XV Report: 6.5 years aer EiF Recommended Derogaon: reconsideraon of me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability for upstream supplier inventory. PQRI Comments on Annex XV Restricon Report Uses Sub-uses* Derogaon/ Recommended Derogaon *Uses and sub-uses include data from PQRI survey, other category and ECHA consult reviews As shown in Figure 12 and Figure 13, several types of PFAS are used in various types of drug products at each point in manufacturing, storage and delivery. If pharmaceucal manufacturers are unable to assure high purity raw materials and qualified manufacturing and containment materials, products will not meet label claims. Sequenal steps are necessary over the pharmaceucal lifecycle from the point of discovery to approval and change management. Figure 12 PFAS types used in pharmaceucal products - molecules and routes of administraon. 22 PQRI Comments on Annex XV Restricon Report Figure 13 PFAS types used in materials provided by suppliers to the Pharmaceucal Sector There may be some ancillary substances that are not recognized as containing PFAS that are also used in pharmaceucal applicaons. For example, cleaning agents can contain PFAS and some suppliers have already given noficaon for withdrawal of their products. Some substuon may be possible, but it takes me to idenfy an appropriate replacement, validate the process or qualify the material and implement the change. If a substute is available, the process of the change itself can be me consuming and may require data generaon and submission/approval of the change. The actual material may not contain PFAS, but a precursor or a process may include one or more PFAS. If these materials are banned in the EU, there may be an impact on the global supply as companies previously supplying to a global market may not have sufficient market share to sustain the manufacturing supply chain. If costs were to increase, this could also have an impact on connued supply as medicine prices in the EU are negoated and pharmaceucal companies may not be able to absorb cost increases incurred as a consequence of any PFAS restricon, which may lead to withdrawal of medicines and companies ceasing to supply markets. Raonale for Pharmaceucal Sector PFAS Usage and Sub-uses In each secon below a raonale is provided for PFAS use and sub-uses. 23 PQRI Comments on Annex XV Restricon Report Drug Formulaon The Pharmaceucal Sector manufactures a variety of APIs that contain at least one aliphac -CF2- or -CF3 group and fall under the current very broad scope of the PFAS group. Perfluoro-containing building blocks and raw materials are used to introduce the fluorine into the API and to manufacture specific groups of medicines (e.g., pepde synthesis). Fluorine, because of its small size and strong electron withdrawing properes, is widely used in the human and animal health pharmaceucal industries to improve medicinal products based on: molecule potency and permeability, pKa modulaon and lipophilicity, reduced rate of clearance, control of structural conformaon. The intenonal use of fluorine in the design of pharmaceucals has been proven to be safe for human and animal paents as assessed via extensive nonclinical, human, and environmental tesng as currently required by governing bodies for market authorizaon. The environmental impact of pharmaceucals is not limited to perfluoro alkyl groups and includes metabolites. In accordance with medicinal products direcve [Arcle 8(3) in Ref. 20], the potenal environmental impact of medicinal products is assessed. Since 2006, environmental fate and effects data with an API and an environmental risk assessment of that API are already required at the me of submission of a markeng authorizaon applicaon [21]. Due to the unique properes and funcon of fluorine, the use of alternaves has serious negave impact on both safety and desired effect of the drug molecule. The pharmaceucal intermediates used in the synthesis of the API if registered as intermediates according to REACH, will be handled under strictly controlled condions in closed systems. Intermediates are assigned to appropriate containment band on the basis of available health hazard data and pharmacology screening. To evaluate the effecveness of controls that are in place, exposure monitoring data is collected for APIs and compared to health based OELs derived by company toxicologists. Procedures used to establish in-house OELs for pharmaceucals have been described in the literature [22, 23, 24, 25, 26, 27]. The proposed restricon indicates a derogaon that only applies to API in human and veterinary medicinal products within the scope of Regulaon for pharmacovigilance [28] authorizaon of veterinary medicinal products [29] and medicinal products for human use Direcve [20]. In addion to APIs, the precedence of the use derogaon for medicinal products has already been established in the recently proposed Annex XV restricon report on intenonally added microparcles [30]. The use-specific restricon in the microparcle proposal applies to human and medicinal products inclusive of all drug components. PFAS substances can be present in the API precursors, and other components of the formulated drug product such as excipients, colorants, coang, adjuvants, etc. PFAS substances are also found in manufacturing and processing equipment and reagents, including equipment gaskets, protecve coangs, filters, tubing, and lubricants. In many cases, there are no known substutes for these items as they have unique properes, such as for corrosion prevenon and contaminaon control. If the ban becomes effecve it could cause disrupon to the enre pharmaceucal supply chain. Excipients enable the dose required (oen as low as a few micrograms) to be delivered to the paent in a stable and reproducible dosage form. Excipient properes are essenal for the formulaons they are included 24 PQRI Comments on Annex XV Restricon Report and approved within medicinal products. Propellants are one example as they must be safe, compable with the container closure used, not react with the acve ingredients, and deliver the required dose consistently to the paent. Each propellant has different physical properes (e.g., density) that enable appropriate selecon to generate a stable product for use by the paent. More informaon on medicinal propellants is found in the IPAC/IPAC-RS submissions to ECHA [31, 32, 33, 34]. Drug Formulaons Alternave Potenal More than 300 fluorinated compounds have been launched as drugs over the last decades and over 500 more are in late-stage clinical trials [35], which indicates the importance of fluorine in pharmaceucal compounds. Due to the unique properes of fluorine in API, alternaves are not available in most cases. There are other electron withdrawing groups similar to -CF2- or -CF3 such as carboxylic esters, amides, nitro, or cyano, but these carry various liabilies related to stability, permeability, and toxicity. Replacement of fluoro-alkyl by other haloalkyl groups such as chloro-alkyl will lead to reacve agents with serious toxicity issues. To improve oxidave metabolism of C-H bonds, instead of replacing it with a C-F bond, replacement with deuterium has been another strategy. However, this typically only results in modest improvements compared to the use of fluorine [36, 37]. The extensive applicaon of fluorine in drug research is related to the unique properes of this element. Fluorine is both small and has the highest electronegavity of all elements. To evolve a molecule into a potent and safe drug, many parameters need to be opmized in parallel. The introducon of fluorine is oen an essenal part of achieving an opmally balanced profile. The size of a fluorine atom is comparable to a hydrogen atom, but the stability of a C-F bond is higher than for a C-H bond and fluorine will change the lipophilicity and electron density of the molecule. The replacement of a hydrogen by fluorine will impact key properes required to make a drug efficacious and safe and lead to reduced clearance, and enhanced permeability. Due to fluorine's electronegavity, the molecule pKa will be decreased and subsequently impact key parameters for permeability and drug efflux, that can reduce undesired side effects, thereby increasing the therapeuc index. Medicinal products cannot be formulated without excipients, although these are inacve ingredients they possess crical funcons, e.g., stabilizaon of acve, distribuon and absorpon of the medicine. Excipients are necessary for medicine to funcon as intended and verified throughout the clinical development phases by studies that take years to complete before EMA approvals. Major drug formulaon changes could require costprohibive non-clinical and clinical studies to support safety and efficacy. A similar approach to that taken in the Annex XV report for intenonally added microparcles [30] is jusfied for the proposed PFAS restricon proposal to avoid significant market disrupon and drug shortages. Appropriate alternaves for medicinal product excipients may not be readily available at the me of implementaon of the restricon and in most cases, do not exist. Furthermore, there will be indirect consequences if a PFAS ban progresses for other industrial chemicals which are either used as excipients or are used to manufacture excipients, and which may not have derogaons. In many cases the amount of an excipient used in pharmaceucal applicaons is only a small percentage of the main volume of these chemicals produced by a manufacturer and may not be able to be sustained for pharmaceucal use if the materials are no longer available for use in other industries. There may not be any suitable alternaves for these excipients since they are already difficult to source. The lack of availability of these industrial chemicals could contribute to the lack of availability of medicines that could be considered to be life-saving or life-sustaining 25 PQRI Comments on Annex XV Restricon Report Facilies Pharmaceucal facilies/site systems must be designed for purpose according to GMP requirements, and with respect to local building codes and environmental laws. Facilies and maintenance pracces rely on related sector uses/sub-uses e.g., construcon materials, manufacturing materials, ulies, and supply (air, water, gases environmental controls). The facility requirements to install and qualify highly complex manufacturing and laboratory tesng equipment must be met for safe and efficient operaons. Examples of facilies requirements include clean rooms, biohazard rooms, venlaon, secured storage and access and other related funcons for manufacturing and tesng medicinal products. Medicinal product shortages can arise due to general capacity restraints already realized from the COVID-19 pandemic response. Other consideraons include updang aging facilies, or upgrades to accommodate new technologies. Various PFAS are used throughout pharmaceucal manufacturing facilies to enable producon of safe and effecve medicines. It is not feasible to idenfy, verify, substute, and eliminate all PFAS uses in a short period of me without experiencing some unintended consequences due to mulple changes in a highly controlled and complex facility. Manufacturing Equipment: Lyophilizaon, Asepc Processing The manufacturing and process equipment to produce medicinal products is designed specifically for each product to meet label claims, avoid cross contaminaon or external contaminaon. The same molecule moiees can treat mulple indicaons, and the API can vary in amount and formulaon, including excipients, dosage forms, routes of administraon, and delivery systems. The manufacturing equipment, operaons, and other materials used to contain, store, transport and administer medicinal products must also be qualified under pharmaceucal GMPs. Mulple PFAS are used throughout producon processes to ensure safety, enhance efficiency, reduce fricon, wear, degradaon, and energy consumpon. Fluoropolymers, coangs, lubricants, and processing aids are used for mulple purposes in precision manufacturing with equipment and filling operaons. If these materials were not available, unintended consequences could include malfuncon of equipment, increased maintenance and costs, increased downme, and low inventories. The me needed to maintain sufficient inventory would be exacerbated by substuon of mulple non PFAS alternaves (assuming they exist). It is possible equipment may need to be redesigned around alternave materials, including auxiliary materials to ensure new materials would not negavely impact the medicinal product and to be able to withstand the lyophilizaon, sterilizaon, filling, or other processes. A lack of materials for the manufacturing and processing equipment could therefore lead to a lack of medicinal products. Addionally, advanced manufacturing processes ulize microprocessors, sensor, computer vision and other semiconductorenabled electronic systems to ensure reliable, speedy, and effecve drug product manufacture and delivery of life-saving drugs to paents. Laboratory Equipment Laboratory equipment is necessary for the Pharmaceucal Sector to characterize medicinal products during development and release them per label claims. Tesng incorporates a multude of different methods, equipment and auxiliary materials depending on the atributes to be measured for each medicinal product. Release tesng of final product is required but is relavely simple compared to R&D evaluaons on chemical constuents and impuries of APIs, reagents, intermediates, excipients, and formulated drug products. The chemical, physical, funconal, and mechanical characteriscs of auxiliary materials must also be evaluated for use and introduces other types of test equipment, all of which use various PFAS. Addionally, advanced analycal instruments, automaon and controllers ulize microprocessors, sensors, and other semiconductor-enabled 26 PQRI Comments on Annex XV Restricon Report electronic systems. The implementaon of mulple advanced analycal technologies to meet performance and operaonal requirements for sophiscated measurements involves many PFAS materials for sample handling and equipment operaon. This is a much broader range of PFAS materials associated with tesng than the PFAS reference materials exempted in the Annex XV restricon report (see Ref. 1, proposed Restricon Opon 2). Medicinal Packaging, Containment, and Delivery Packaging for use in the Pharmaceucal Sector is approved together with the medicinal product. The primary packaging comes into direct contact with the medicinal product and must be shown to be compable with filling operaons and contact materials and verified to be stable over the shelf life. The primary packaging involves a container-closure system and can also be part of an administraon/delivery system with specific mechanical and funconal requirements. Product contact materials compability must be validated for use with the chemical, funconal, and physiochemical properes of the medicinal product. The primary packaging system must also protect the medicine to maintain quality atributes and sterility for each medicinal product and protect contents from microbial ingress or leaching of chemicals from materials for each intended use. Certain products can be extremely sensive to light, moisture, and air. In the case of biological products, there is a risk of adsorpon onto contact materials and the potenal to impact drug formulaon ingredient structural conformaon, which can result in paent adverse effects. Packaging materials are composed of glass, plasc, paper, metal, and elastomers which can be enhanced with fluoropolymers e.g., to reduce adsorpon and also create a barrier to chemical migraon. Another key atribute of fluoropolymers is low surface energy to minimize adherence of parcles onto surfaces during manufacturing to avoid risk of contaminaon of medicinal products. Fluoropolymers and other PFAS containing materials are used in secondary packaging for components and terary packaging for storage and shipping. Pharmaceucal packaging is essenal to assure drug product quality, efficacy, and paent safety. Each material must be validated for intended use with each drug product for approval as well as requalified based on changes post-approval. Various PFAS are used in nonproduct packaging components and to facilitate manufacturing processes. Alternaves for every type of PFAS used in packaging have yet to be idenfied, qualified, and approved for specific use. Substung all PFAS with non-PFAS packaging components will not be feasible unl alternaves are available and systemacally qualified for approval by EMA. Examples of melines are in Figure 1. There is a need for unlimited derogaon to contain, protect and deliver medicinal products. Environmental emissions informaon has been included for pharmaceucal packaging in the Food Contact Materials and Packaging Sector in Annex A Manufacture and Use and Annex B Informaon Hazard Assessment [1], however, the Pharmaceucal Sector has unique uses and requirements beyond food and feed applicaons. EMA evaluaon and approval of both medicinal products and any subsequent post-approval changes play a crical role throughout product lifecycle management. Electronics The electronics and semiconductor industries are crical to all aspects of discovery, development, manufacturing, deployment and lifecycle management for pharmaceucals. R&D automaon, high throughput screening, analycal instrumentaon and data systems, manufacturing systems, supply chain security and integrity controls, drug delivery systems, submissions, micro-electromechanical (MEM) systems, such as sensor chips and smart devices - everything ulizes computers/ microprocessors and related electronics. Any impact of the PFAS ban on the supply of electronics (as PFAS materials are essenal to the process of manufacture of semiconductors) would broadly impact many other areas of pharmaceucal producon. Current industry trajectory and regulatory expectaons are driving toward digital transformaon, "lights-out" automaon and manufacturing and AI/ML soluons to ensure digital data quality and integrity and greatly improve speed and 27 PQRI Comments on Annex XV Restricon Report effecveness of delivery of innovave and life-saving medicines for key therapeuc indicaons to crical paent populaons. Therefore, much informaon has been digized to expedite decision making and reduce the use of paper and prinng (resulng in reducon of energy, polluon, shipping and storage that was associated with paper usage). Submissions to regulatory authories are also electronic to facilitate improved processing of the submission and make the handling of the vast amounts of data and informaon contained within a single Markeng Authorisaon more manageable. The enre supply chain, manufacture, development, submission and monitoring are all impacted by electronics and a retrograde move to paper would be a significant impact and potenally stop many processes and impede or halt significant progress that has been made in health care. Even paent informaon can be accessed electronically. Storage and Transport Shipping and storage throughout the supply chain at cold, refrigerated, or deep freeze condions are required for many medicinal products to enable the full shelf life of the product to be achieved. Failure to store a product under appropriate condions can result in the product potenally being unacceptable and destroyed or assigned a much shorter shelf life (depending on the product requirements), which will impact product availability. Fluoropolymers are crical to containers used for ultracold storage, which must have flexibility and maintain integrity for shipping and freeze/thaw cycles required for biopharmaceucal bulk drug substances such as vaccines, monoclonal anbodies, and anbody drug conjugates. Storage and transport operaons include sophiscated means of ensuring supply chain security and integrity ulizing smart data soluons (e.g., blockchain) and other semiconductor-enabled electronic systems. If it is not possible to safely transport intermediate or finished medicinal products, due to extreme temperature fluctuaons, pharmaceucal companies and paents would experience a major loss and health risks. The Pharmaceucal Sector relies on the Transport sector as well as specialty pharmaceucal packaging to supply medicines to paents. Raonale for Missing Uses The Pharmaceucal Sector has disnct applicaons and quality standards for compliance to ensure safe and effecve medicines. It can be shown (see Figure 9) that PFAS use in the Pharmaceucal Sector are similar to PFAS uses that have been idenfied for other sectors already idenfied in the Annex XV restricon report. Although the requirements for these similar uses may serve as a baseline, they do not meet the needs of the Pharmaceucal Sector. (e.g., regulatory requirements for EMA approvals, lack of equivalent alternaves, and me involved for post-approval changes). Examples of these uses and raonales for classifying them as missing uses are provided in Table 3. Table 3 Raonale for missing uses in Pharmaceucal Sector Relevant Sector Related Use Pharma Sub-use TULAC Professional Apparel Food Packaging Food, Feed and Pharmaceucal Packaging (Annex A and B) Industrial Food Producon PPE, Sterile Gowning Packaging: Plasc, Elastomers, Metals, Paper, Paper Board Inadequacy to address Pharma Sub-use Parculates and sterile processing stringent requirements Pharmaceucal Packaging regulated under EMA stringent requirements for medicinal products. 28 PQRI Comments on Annex XV Restricon Report Relevant Sector Related Use Pharma Sub-use Metal Plang Consumer Mixtures Fluorinated Gases Chrome Plang, Metal Manufacture Cleaning Agents, Waxes Refrigeraon, Air Condioning, Heat Pumps, Solvents, Propellants Surface Corrosion Coang Delivery Systems Component Fabricaon Manufacturing Lines, Clean Room, Fill Finish Operaons, Storage MDI Propellants Deep Freeze Storage (-180C to -100C) Medical Device MDI Coang and Propellant Chronic Respiratory Disease Treatments Transport Electronics and Semiconductors Energy Sector Lubricants Petroleum and Mining Sealing Applicaons, Electrical Engineering, Informaon Technology, Hydraulic Fluids, Coangs, HVCAR Coang, Solvents, Cleaning Agents, Wires, Cables, Electronic Components, Heat Transfer Fluids Lithium-ion Bateries Low Viscosity, Film Lubricaon, Release Agents, Greases Anfoaming Agents, Water and Gas Tracers, Lining of Piping, Seals, Sensors. Raw Materials, Chemical Intermediates, Finished Products Shipments Facilies, Manufacturing Technologies and Operaons, Alarms, Stability Chambers, Delivery Systems, Communicaons, Tracking Systems Producon Records, Inventories, Finance Manufacturing, Delivery System Dosing Manufacturing, Processing, Laboratory Equipment Facilies, Manufacturing, Monitoring Inadequacy to address Pharma Sub-use Coangs for containers, delivery systems, manufacturing, and storage systems. Specific requirements under pharmaceucal GMPs and EMA Specific requirements under pharmaceucal GMPs Crical applicaon for inhalaon medicines and cell and gene therapies Device consideraons, not medicinal product consideraons, which are different Maintain temperatures and pressures for product quality, which may have ghter tolerances Specific applicaons for pharmaceucals crical to monitoring operaons, safety requirements, product quality, correcve/preventave acons pharmacovigilance, data integrity Crical to monitoring manufacturing and safe paent administraon Specific pharmaceucal GMPs for manufacturing operaons, packaging, and shipping Requirements for specific pharmaceucal use PFAS Used to Produce and Deliver Medicinal Products Alternave Potenal Fluorinated polymers were found to have the highest number of responses in the PQRI survey. These materials comprise a wide range of thermoplasc and elastomeric components ranging from semi-crystalline to totally amorphous with numerous applicaons in the Pharmaceucal Sector. Fluoropolymers have a unique 29 PQRI Comments on Annex XV Restricon Report set of properes that are unmatched and are described in Table 4. There are other polymers that have some of these properes but lack the complete set of atributes required to meet the needs of the pharmaceucal supply chain. These properes are all necessary within one product. There is no alternave material available that combines all these properes. Based on review of Annex XV restricon report Appendix E.2 Hazard Assessment [1], it was observed that the type of PFAS and usages were limited, and hazard informaon was listed as insufficient. There is no material possessing all these properes that has been idenfied or commercially available to evaluate. Another type of PFAS that is unlikely to have alternaves readily available are propellants used in pharmaceucal delivery systems. Metered dose inhalers (MDIs) for oral inhalaon use fluorinated propellants (e.g., HFA-134a and HFA-227) that fall under the broad Annex XV definion of PFAS. These propellants are small, low molecular weight, volale, two and three carbon fluorinated hydrocarbons. They are non-toxic, non-flammable, and of low chemical reacvity with the complex milieu of metal, plasc, and elastomer materials the MDI formulaon contacts. Their low reacvity beter assures uniform emited dosing and product stability over me. Further, their phase behavior at ambient temperatures makes it such that a balance between pressurized liquid / gas phase in the canister persists providing working pressures low enough to be safe and high enough to iniate forming the very small parcles / droplets necessary for successful inhalaon therapy (e.g., 1-5 micron sized) throughout the life of the MDI. The two-phase gas/liquid mix in the MDI canister allows the liquid to vaporize during the use-life to maintain the necessary equilibrium working pressure. There are no other known substances that possess all these properes; and the loss of these propellants for MDI use could iniate a public health crisis for paents with respiratory diseases such as asthma and COPD (chronic obstrucve pulmonary disease). As shown in Figure 14 and Figure 15 there is minimal chance that alternaves are currently available for PFAS used throughout the Pharmaceucal Sector. Table 4 Unique properes of fluoropolymers Specific Material Properes Temperature Stability Mechanical Strength Compressive Strength Dielectric Strength Low Surface Energy Low Fricon Low Abrasion Low Sffness Hydrophobic and/or Oleophobic Low permeaon Inert Barrier Durable Range of Melt Temperatures Funconality Tolerance of high temperatures for manufacturing and processing; low temperatures for cryogenic applicaons Toughness and resilient under stress and stress strain Withstand pressure and load without deformaon or cracking Reduced interfacial tension and liquid and gas flow Non-sck, non-adsorpve, hydrophobic, and resistant to hydrolysis Lubricious to impart slide properes, and increase fluid flow rates Withstand wear and parcle risks during manufacture and usage Resist fague and flexible for fluid processing equipment Non-weng and low chemical absorpon Low gas/vapor absorpon and chemical transport Chemically nonreacve Resist migraon of chemicals and moisture. Prevents chemical interacon of product with underlying material and inhibits corrosion Resistance to aging and oxidave stress, with a long service life Moldability for use in producon of arcles Ultra Clean Smooth surface, low stac charge 30 PQRI Comments on Annex XV Restricon Report Material Stability Resist chemical, biological, and environmental degradaon. Does not chemically react with or contribute leachables into products during use or storage. Figure 14 Availability of PFAS alternaves to Pharmaceucal Manufacturers 31 PQRI Comments on Annex XV Restricon Report Figure 15 Availability of PFAS alternaves to Suppliers to the Pharmaceucal Sector It is unlikely that all the potenal PFAS changes may be integrated seamlessly in one amendment (all done at once) - mulple changes are likely to be sequenal as all the input change aspects may not be available at the same me (as each will take different melines depending on the change required and the complexity). Also, the impact of each change on the product/process needs to be understood and if there is a product/process where several aspects are changed, locang the cause/reason for an unexpected result is essenal to enable this to be resolved. It may be possible to explore several changes in parallel, but atempng to change too many variables without understanding the impact of each could cause a program to fail. Should materials become unavailable, there will be a need to priorize the changing of products; as in the pharmaceucal industry and supply chain, each item is unique, and it is not possible to transfer the change from one product to another without undertaking studies on each specific product/item. The interacons with different products and formulaons are not the same - the soluon for one will not necessarily transfer to 32 PQRI Comments on Annex XV Restricon Report another (it is not a `drop in' replacement). Each needs to go through a rigorous change process to confirm whether the replacement is viable. Addionally, the resources required to update the items cannot be underesmated. The exisng medicines and devices have been developed and approved over decades - effecng a change on many at the same me (due to PFAS restricons) will overwhelm available capacity for development - experse is required to develop and change materials and products. Taking the example from the IPAC/IPAC-RS submission to ECHA, the atachment `IPAC Timeline Regulatory Milestone' indicates 6 years just to affect the transion to a new propellant for a single pressurized metered dose inhaler (pMDI) [32]. Even though there is a derogaon permited for the coated canisters ulized within pMDIs, there is not necessarily a replacement available - the coang provides several benefits to the system; reducing the likelihood for adhesion of the formulaon with the canister; protecng the container from being affected by the formulaon; protecng the formulaon from degradaon. These properes are conferred by the materials (which are fluoropolymers) which enable them to fulfill all the requirements. There will be some areas where alternaves are possible, and some of these may already be under development. For example, the use of non-fluorinated polymerizaon agents in fluoropolymers has been cited as an alternave for materials used in the Pharmaceucal Sector [38]. However, in most cases, it is not currently possible to match the properes and quality requirements for intended use to be suitable with every drug product. Alternaves must be proven safe and effecve for paents, qualified for use in materials and/or validated for use in processes to support regulatory approval. This can result in a long meframe before alternaves can be incorporated into medicinal products that are approved for paent use. While several patents on PFAS alternaves exist, it is not clear if there are sufficient inventories or commercialized products available. The interdependencies and complexity of the supply chain of the pharmaceucal supply should not be underesmated. There are numerous instances of PFAS usage at every level of the pharmaceucal lifecycle; any change will trigger a change control and may require EMA approval. There is potenal for mulple PFAS materials to change at the same me and decommission the producon of crical medicines and create an overwhelming regulatory burden leading to consequences for paents requiring treatments. Taking a closer look at the pharmaceucal supply chain (see Figure 16) clearly indicates that eliminaon of one PFAS compound used upstream could completely eliminate the availability of a medicinal product. The survey revealed that there may be PFAS compounds several levels upstream in the supply chain. The lack of starng materials could bring about an inability to innovate the development of new medicines to treat and even cure diseases. Consideraon should be given to the benefit of developing new medicinal products to treat disease versus the risk of allowing starng materials, some of which may be low environmental risk and needed at low volumes, to connue to be manufactured. 33 PQRI Comments on Annex XV Restricon Report Colorant Additive Carrier Master batch Ingredient #1 Ingredient #2 Filler Additive #1 Additive #2 Monomer Ingredient #1 Ingredient #2 Base polymer Precure Elastomer Postcure Treatment Packaging Component - Elastomer PFAS Identified in the following: Chemical ingredients Materials/ Intermediates Components Mfg processes In-process/finished Goods Ingredient #1 Ingredient #2 Ingredient #1 Ingredient #2 Ingredient #1 Ingredient #2 Glass stock Metal stock Coating Packaging Component - Glass Packaging Component - Metal Primary Packaging System Drug in primary packaging Secondary Package Marketed Drug Product Colorant Additive Carrier Additive #1 Additive #2 Monomer Master Batch Base Polymer Packaging Component - Plastic Secondary Packaging Insert Printed Label Ingredient #1 Ingredient #2 Solvent Excipient #1 Excipient #2 Solvent Active Pharmaceutical Ingredient Excipient Matrix Formulated Drug Figure 16 Pharmaceucal supply chain for medicinal product in a packaged container closure (Note: grey boxes indicate items unavailable; red diamonds indicate processes impacted) Request #6 Summary Missing Uses Alternaves and substuon consideraons The PFAS uses in the Pharmaceucal Sector are prevalent and not captured in the Annex XV restricon report Table 2 [1]. Disnguishing factors for pharmaceucal usage include strict requirements for treatment of disease and chronic illnesses, proven materials, and manufacturing processes for each medicinal product, conducng early to late phase clinical studies and meeng EMA requirements for approval and post-approval changes. The consequences for not considering the impact of a PFAS ban on the pharmaceucal supply chain could lead to shortages of medicinal products to treat diseases. PFAS alternaves either currently do not exist commercially or it is unknown whether there are substutes with the required properes that are safe to use and safe for the environment. Request #7 Potenal derogaons marked for reconsideraon-Analysis of alternaves and socioeconomic analysis. Evidence for underlying assessment of PFAS in the Pharmaceucal Sector is absent. The pharmaceucal supply chain encompasses a broad range of PFAS usages with significant reliance on other sectors to ensure paent 34 PQRI Comments on Annex XV Restricon Report accessibility to life-saving medicines (Illustrated in Figure 9). The derogaons outlined in the Annex XV restricon report ([1] restricon opon #2, paragraphs 1,2,5,6 and 7) have not been considered in the context of the Pharmaceucal Sector. The potenal derogaons marked for reconsideraon aer report consultaon are relevant to the Pharmaceucal Sector as well. The feasibility and praccality of proposed limits and test methods for medicinal products have not been considered. There are gaps in understanding PFAS identy and usage across the pharmaceucal supply chain, totality of emissions, or fate in the environment. The me limited derogaons of 6.5 years and 13.5 years (1.5 years transion plus 5 years or 12 years) aer EiF is not praccal for replacement (if an alternave exists) within the Pharmaceucal Sector. Pharmaceucal manufacturers have already received noficaons of materials containing PFAS, and the number of responses varied depending on the type of material (see Figure 17). When queried about the me it would take to substute an alternave both pharmaceucal manufacturers and suppliers indicated that several years would be required to idenfy alternaves, incorporate them into the design, build up inventory and commercialize the product. Figure 17 Supplier noficaons received by Pharmaceucal Manufacturers To implement a PFAS alternave that involves at least one supplier, the supplier will need to develop the material/component for the intended purpose first, assuming an alternave exists. The supplier would need to idenfy the alternave and incorporate it into the design, verify it for use and build-up commercial inventory. The pharma implementaon can start at the point the soluon is available to them; in some cases, the supplier may commercialize and start to build inventory in parallel with the medicinal product development. Alternavely, the commercially available alternave may be evaluated by the pharmaceucal manufacturer and, if found acceptable, it could be verified and used to build up commercial supply of a medicinal product. 35 PQRI Comments on Annex XV Restricon Report From the PQRI survey it was found that at least 1-3 years, and more oen 5-10 years, would be required to incorporate an alternave into the design, build inventory and commercialize the supplied material or medicinal product. Based on pharmaceucal manufacturer and supplier responses, the cumulave effect of these mes to implement a PFAS alternave was esmated to be a combined total of 20- 60 years as shown in Figure 18. The length of me for implementaon is longer than the meline reflected in Figure 1 for a new product because it is assumed that materials are already available. Therefore, the melines to generate products using alternaves (if one is available with the required properes) are much longer than the cumulave 6.5 or 13.5 years that the me-limited derogaons would allow. Exempons for PFAS used in the Pharmaceucal Sector and its supply chain are requested with unlimited derogaon due to the socioeconomic need for medicines (both exisng and future). Figure 18 Time to implement PFAS alternave. Request #7 Summary - Potenal derogaons marked for reconsideraon current derogaons not feasible. A current derogaon for the Pharmaceucal Sector does not exist but there are derogaons afforded to pharmaceucal upstream and downstream suppliers. It is essenal to have PFAS available for the pharmaceucal synthesis, formulaon, manufacturing, packaging, storage, shipment, and delivery of medicine to paents. The opportunies for EiF at 6.5 years and 13.5 years are not adequate to idenfy and address all the PFAS used throughout the pharmaceucal supply chain. This meframe is not sufficient for the idenficaon and implementaon of alternaves for most PFAS uses. Replacement of PFAS used, either directly or indirectly, for the producon of all medicines in development is not pragmac due to unique applicaons. A complete replacement requirement would also shut down the producon of marketed products. The numbers of affected medicines and paents are staggering (see Figure 20). The proposed PFAS targets, methods and limits for the environment do not directly correlate to the Pharmaceucal Sector usage, producon, waste, or emissions. Time is necessary to understand the usage in this sector and the societal effects, including the impact on the environment and innovaon of new technologies to combat PFAS polluon. 36 PQRI Comments on Annex XV Restricon Report Request #8 Other idenfied uses - Analysis of alternaves and socio-economic analysis Although the proposed restricon opons RO1 and RO2 are deemed proporonate to the risk, this assessment was done without consideraon of the unintended consequences to the Pharmaceucal Sector. As it currently stands, there are no cures for chronic diseases such as respiratory and diabetes among others that could result in death in Europe. As demonstrated from the survey results in Figure 5 through Figure 7, the enre supply chain for all drug types is dependent at some level on various PFAS. The proposed restricon is focused on new products being placed on the EU market and this will directly affect the medicinal products currently in development, which are many. As indicated by the survey results in Figure 19, more than half of the total number of products represented in the survey are in development. This is consistent with data obtained separately from PharmaCircle [39] that shows (see Figure 20) that, for most product types, there are many more products in development than the number of marketed products. According to PharmaCircle the top six indicaons that are currently targeted for pharmaceucal development programs include cancer, infecons, neurological disorders of the central nervous system, inflammaon/immune condions, endocrine/metabolic diseases, and cardiovascular disease (see Figure 21). Some of these indicaons were also idenfied as leading causes of death in Europe by the recent OECD report [40]. Figure 19 PQRI Survey responses indicang regulatory status of product types 37 PQRI Comments on Annex XV Restricon Report Figure 20 PharmaCircle informaon on regulatory status by product type Figure 21 PharmaCircle Top Six Indicaons by Molecule in Development The PQRI survey further queried acons respondents might take if the PFAS used in their products were to be banned in the EU. From the supplier perspecve (see Figure 22) it is quite likely that there would be disconnuaon, or at least modificaon, of their products that support drug formulaon, manufacturing, packaging, and delivery. The level of uncertainty regarding what acon might be taken was lower for the supplier than the pharmaceucal manufacturers. From the pharmaceucal manufacturer's perspecve (see Figure 23), across all product types, there were several responses indicang disconnuaon, modificaon, and uncertainty. With regard to PFAS use in pharmaceucal manufacturing materials or components (see Figure 24), across all product types, there were fewer responses that indicated the disconnuaon of the product, except for small molecules. In addion to a fair amount of uncertainty, there were indicaons that the manufacturing process might be changed or moved outside Europe. That same level of uncertainty was reflected regarding acon that might be taken if a PFAS ban were enacted that impacted storage facilies, equipment, or processes. The primary responses indicated that the products would be disconnued, or the 38 PQRI Comments on Annex XV Restricon Report storage facility would be modified (see Figure 25). From the supplier and pharmaceucal manufacturer responses, it was clear that there is a realisc possibility that several products would be disconnued in the EU market. Figure 22 Acon to be taken on Supplies to Pharmaceucal Sector in case of PFAS ban. 39 PQRI Comments on Annex XV Restricon Report Figure 23 Acon to be taken on Medicinal Products in case of PFAS ban Figure 24 Acon to be taken on Medicinal Product Manufacturing in case of PFAS ban. 40 PQRI Comments on Annex XV Restricon Report Figure 25 Acon to be taken on Medicinal Product Storage in case of PFAS ban. The disrupon of the medicinal products supply highlighted in the PQRI survey suggests that products will be disconnued/withdrawn from the EU market and that products may be modified. There are scenarios possible where the product will be withdrawn and not replaced. Products may also be disconnued at the point of the ban before replacement products are developed, as the melines for developing new products (see Figure 1) are longer than the melines for the proposed ban/withdrawal of PFAS materials from the market (18 months to 13.5 years). In fact, when queried on the topic of implementaon me for a PFAS-free alternave, pharmaceucal manufacturers' primary response across the majority of products was "unsure," emphasizing this uncertainty (see Figure 26). 41 PQRI Comments on Annex XV Restricon Report Figure 26 Time to implement PFAS-free Medicinal Product To beter understand the impact of a PFAS ban on paents suffering from life-threatening diseases the results from the PQRI survey were ploted alongside the PharmaCircle and OECD informaon. As shown in Figure 27, most of the life-threatening diseases were represented in the PQRI survey. The relave levels of responses from the PQRI survey are generally consistent with the relave numbers of programs idenfied in the PharmaCircle data for each disease area. Therefore, since the proposed restricon on PFAS has been demonstrated to impact all the drug product types used to treat these life-threatening diseases, it is possible that lifesaving medicines that are currently in development or placed on the market would not be able to be manufactured if the proposed restricon were to come into force. If the medicinal products are not available paents may suffer adverse effects from disease progression and even death. 42 PQRI Comments on Annex XV Restricon Report Figure 27 Impact of proposed PFAS restricon on treatment of life-threatening diseases Request #8 Summary - Other idenfied uses Societal Cost of Ban for Pharma The practical application of the results of the PQRI survey has shown that a restriction of PFAS in the Pharmaceutical Sector will likely result in the discontinuation of marketed life-saving medicinal products and the lack of ability to manufacture new life-saving medicinal products that are currently in development in Europe. In a similar way, the impact of the proposed PFAS restriction may result in a lack of maintenance medicinal products that are used to treat prevalent chronic diseases such as respiratory and diabetes (6% and 7% of the EU population respectively, [40]). Considering just these two diseases alone and the current population [41], over 96 million patients could be affected in the European Union. Request #9 - Degradaon potenal of specific PFAS sub-groups Topic not addressed in this paper. Request #10 - Analycal methods Topic not addressed in this paper. Closing Remarks: Bringing back points to consider and paent impact. The core concern for PFAS in the environment is their potenal to have persistent, mobile, and toxic (PMT) properes. We acknowledge that this is part of a larger iniave that was implemented in 2020. The European Commission Chemicals Strategy for Sustainability (CSS) is intended to increase innovaon for safe and sustainable chemicals while protecng the environment and human health [42]. This strategy incorporates the establishment of the chemical environmental footprint to enable the idenficaon of hazardous substances in the environment and the risk of exposure to biota and humans. This includes the phase-out of chemicals (e.g., PFAS) unless their usage is essenal. Pharmaceucal companies share the CSS's goals and are commited to the health and well-being of paents [11]. PQRI has taken this opportunity to provide qualitave data with 43 PQRI Comments on Annex XV Restricon Report supplemental literature references to ECHA to explain the essenal usage of PFAS across the pharmaceucal supply chain, the potenal for alternaves and risks to the supply of crical medicines in the EU. Historically, there have been other iniaves to ban specific types of fluorinated molecules based on scienfic data. Since the 1950s, PFOS and PFOA have been widely used and subsequently found in the environment based on thorough invesgaons. In early 2000, the producon of PFOS was phased out and at the end of 2015, PFOA was eliminated. Since the signing of the Montreal Protocol in 1987, the Pharmaceucal Sector has worked to reduce or eliminate certain types of fluorinated molecules used as propellants in MDIs for the sake of the environment [1]. Recently, other long chain PFAS and related substances have been restricted under REACH. Shorter chain PFAS have been substuted for the long chain PFAS over me and now these have also been detected in the environment. The enre group of 10,000 PFAS chemicals, as defined by ECHA, are suspected (but not proven) PMT and proposed to be banned. This definion of PFAS presents an unprecedented challenge for the methodical idenficaon of sources and PMT characterizaon for thousands of unique medicines in the EU. Although the PFAS ban is aimed at new enes, each marketed product will need some degree of requalificaon and approval for any and all changes that might result. In terms of paent safety and efficacy, a broad PFAS grouping structure is not appropriate for risk management and will inevitably add to medicinal product shortages. The complexity and interdependency of the pharmaceucal supply chain is substanal. The essenal properes and mulple applicaons of PFAS are currently irreplaceable. There are several obstacles to overcome across the pharmaceucal supply chain to achieve mely replacement of PFAS, including idenficaon of targets and all sources to be assessed in order to create a reliable footprint for usage and emissions. This will allow companies to build a PFAS acon plan to make science- and risk-based decisions. Taking a systemac approach will avoid disrupon of the pharmaceucal supply chain and ensure the accessibility of safe and effecve medicines in the EU. We can conclude we share a common goal of protecng the environment and human health. Our aim is to provide sufficient informaon on risks to the producon of medicines and the essenal usage of PFAS in the Pharmaceucal Sector. On behalf of PQRI, we request consideraon of the pharmaceucal supply chain to inform restricon decisions based on the following consideraons: 1. Include a Pharmaceucal Sector and their PFAS missing uses/sub-uses in addion to the other 14 sectors idenfied in the Annex XV restricon report. 2. Group PFAS to enable safety risk assessments as appropriate for the environment (emissions, biota, workers, and consumers) and include safety risk assessments that are suitable for paent populaons. 3. Invest me to understand types of PFAS, emissions, and environmental contribuons from the Pharmaceucal Sector to enable jusficaons for derogaons. 4. Reconsider me-unlimited derogaon for those PFAS used in the pharmaceucal supply chain and availability of connued PFAS supply from upstream and downstream supplier inventories. 44 PORI Comments on Annex XV Restriction Report Respectfully Submitted, Glenn E. Wright Chair, Board of Directors, PQRI PeRI Product Quality Research Institute Product Quality Research Institute 1500 K Street, N.W., 4th Floor, Washington, DC 20005-1209, USA , Fax: 45 PQRI Comments on Annex XV Restricon Report References 1. Registry of restricon intenons unl outcome: Per- and polyfluoroalkyl substances (PFAS) htps://echa.europa.eu/registry-of-restricon-intenons/-/dislist/details/0b0236e18663449b 2. European Medicines Agency, Human regulatory-- Markeng Authorisaon, htps://www.ema.europa.eu/en/human-regulatory/markeng-authorisaon 3. 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