Document a19vJ243nyrLavvqYRRQNxX4a

\ Bi. oPhorum JB et weseoanpussss wosaoas BioPhorum Response to the Annex XV report on the proposal for universal restrictions (Part Il) contact: J@biophorum com CCoolnlnaebcotrate AccelerateTM on Opening Statement: The Biopharmaceutical (BioPharma) industry, represented here by BioPhorum, acknowledge the concerns raised regarding the potential adverse effects of various Per- and polyfluoroalkyl substances (PFAS) materials on human health and the environment, and fully support efforts to minimise and mitigate the presence of these, and other potential substances of concern in our manufacturing processes and products. Our industry sector shares a responsibility to work with all relevant stakeholders to manage the transition away from materials of concern while maintaining our ability to ensure the safety and wellbeing of patients and the communities in which we operate. Any efforts to restrict usage and production of materials of concern by our industry must be pragmatically considered; the risk of drug shortages and therefore failure to supply medicines to patients must be evaluated against the risk the materials pose to the environment and that very same population. BioPhorum are a global biopharmaceutical manufacturing industry collaboration comprising all major manufacturers and their key suppliers (over 150+ companies, representing > 98% of all biopharmaceuticals manufactured worldwide); the 30 members of BioPhorum who participated in this collaboration included, but was not limited to: AGC Biologics, Bayer, Cobetter, Janssen, Lonza, NewAge Industries Inc., Pfizer, Qosina, Roche, Sartorius Stedim Biotech GmbH, Takeda, UCB, Watson Marlow Fluid Technology Solutions. While the Annex XV report includes consideration of the use of various PFAS in medical devices and some limited pharmaceutical applications, the BioPharma industry has not been specifically considered as a sector in the framework of the current proposal (refer to Table A.1 from the Annex XV report) and needs to be appropriately evaluated due to the considerable impact the proposal will have on our ability to supply safe and effective therapies to patients suffering from life threatening/debilitating illnesses. page 2 Biopharmaceuticals (or biologics), a subsector of the pharmaceutical industry, include biological therapies such as monoclonal antibodies, cell and gene therapies, mRNA and vaccines which treat a wide range of disease indications including immunology, neurology, infectious diseases, diabetes, oncology, cardiovascular conditions, and others. Advancements in biomedical science hold vast potential for growth of the Biopharma market and the ability of these drugs to treat chronic diseases that were earlier untreatable is increasing its demand enormously with newer therapies under development increasingly being in the biopharmaceutical category. Today, 50% of the top 100 drugs sold globally are biopharmaceuticals, with predications that this will increase to 55% of all innovative drug sales by 2027 [1], and the industry generates global annual revenues of USD 163 billion. A significant proportion of that revenue is generated in Europe (USD 48.19 billion in 2022[2]) with the European Biopharmaceuticals market estimated to be growing at a CAGR of 8.89% to reach USD 73.78 billion by 2027. 100% of the biopharmaceutical products currently being developed or already licensed for sale in the EU utilise PFAS somewhere in their development, manufacture, testing, storage of intermediates or in their drug delivery systems. If the ban is enforced, all those drugs would be removed from the market until PFAS alternatives could be developed, sourced, validated, and approved for use thus preventing access to life saving therapies. While the proposed restriction is intended for enforcement in the EU which will directly affect companies who manufacture and sell their products in that region, it will also have significant and wide-reaching impact on the export of drugs manufactured in the EU and supplied to the rest of the world, on global industries supplying materials to drug manufacturing facilities in Europe and to companies who import and sell their products into the European market. It would also limit the ability to develop new drug therapies since PFAS materials are also utilized directly and indirectly in drug discovery & preclinical development. For medicines which are still under patent or are orphan drugs there are no alternative drugs available for use if their production is prevented due to PFAS restrictions. Significant investment has been made in Europe to build and resource state of the art drug manufacturing facilities; an inability to manufacture product due to unavailability of PFAS materials would result in movement out of the region with potential closure of the facilities and resultant impact on the people, workforces (according to a European Commission report in 2019 the biopharma industry employs 2.4 million people [3] however this does not take in to account all suppliers and their suppliers across the supply chain) and revenues currently generated in the region with irreversible damage to the economy. The restriction on importing or placing on the market of both direct and indirect materials will impact the entire global supply chain and has the potential to shut down BioPharma manufacturing in Europe and the supply of critical drugs to patients within a very short timeframe. In time, this could lead to organizations outsourcing/relocating their manufacturing activities to locations without PFAS restrictions and impede plans for future investment in the EU with significant detrimental socioeconomic impact. While this specific response is focussed on the BioPharma sector, BioPhorum and its member companies recognise that the scope of PFAS use and resulting impact of the proposed restrictions on other industries is far wider across the Pharmaceutical and Healthcare industries and beyond. The biopharma industry is required by GMP legislation to use materials that are not reactive or additive to our product streams. Specific PFAS materials (PVDF, PTFE, FKM, FPM, FEP, etc.) have been chosen as they present negligible reactive properties and are particularly low in terms of adding anything to medicinal products either at drug substance or drug product manufacturing processes. It should be noted that the BioPharma Industry acts as downstream page 3 users of PFAS materials and does not own the technical solution outside of end-application qualification. Within the BioPharma sector there are multiple sub-uses and applications of PFAS materials (mainly fluoropolymers) across the value chain, the majority of which are not included in the restriction report, and which are therefore assumed to be subject to an immediate ban under the current proposal. These sub uses can be further categorized as: a) direct fluoropolymer materials used in BioPharma processing with critical quality attributes (i.e. with direct impact on drug product quality). b) other indirect PFAS materials used in BioPharma manufacturing processes (including manufacturing precursors/starting materials, intermediates, product testing and engineering & support system components). This collaboration of suppliers and end users of PFAS materials operating within the BioPharma industry and represented here by BioPhorum, are requesting full exemption (or time unlimited derogations) for: - fluoropolymer materials used in industry that are required for delivery of safe medicines. - other low risk, non-polymer PFAS materials used in BioPharma. - indirect materials used in supply chain, manufacturing, and quality control processes. A non-exhaustive list of PFAS applications across the BioPharma industry with indication of possible alternatives and an analysis of the complexity and anticipated cost of substitution is included in Appendix 1. Note: Appendix 1 was prepared in collaboration with BioProcess Solutions Alliance (BPSA). Further details of PFAS applications in the BioPharma industry are detailed in our response below. It should be noted here that if the BioPharma industry is granted an exemption from the restrictions and is permitted to utilise fluoropolymers/PFAS materials where no alternatives exist, there still remains a very serious concern that restrictions or removal of PFAS materials page 4 from the wider market will reduce or remove the availability of PFAS materials for BioPharma applications, resulting in a significant risk of disruption to the supply of critical medicines. When evaluating the impact of the proposed ban on the BioPharma industry 4 core categories of change are important to consider: 1. Where no suitable alternative is available 2. Where alternatives are available but are not suitable/fit for purpose in every application 3. Where alternatives are available and fit for purpose but there is no stable, reliable supply chain 4. Where alternatives are available and fit for purpose, but regulatory approvals will be delayed due to overload of the regulatory bodies who must evaluate and approve (or reject) every submitted change Below is our collaboration's response to the request from ECHA for more information on Missing uses - Analysis of alternatives and socio-economic analysis (Q6): a. The annual tonnage and emissions (at sub-sector level) and type of PFAS associated with the relevant use. With a multi-tier, complex supply chain that is nearly impossible to evaluate and quantify, any number we could suggest would be an estimate. PFAS usage by the biopharma industry and subsequently their suppliers make a miniscule contribution to the total annual usage and emissions from other industries (around 45 million tonnes of PFAS is supplied to the EU market annually with a global figure likely to be at least 3 times this), the impact of a ban on our industry is disproportionate to the risk and would be very detrimental to the patient population as well as the European BioPharma manufacturers and suppliers. Sector-based estimates, shared by the BioProcess Systems Alliance (BPSA), indicate that the single-use biotech/biopharma industry accounts for approximately 0.1% of PTFE production and 0.5% of PVDF production. b. The key functionalities provided by PFAS for the relevant use. PFAS materials have been selected for use in the BioPharma industry for their core properties, some of which are listed in Annex A of the restriction report (refer to the below table copied from the report): inertness, chemical resistance, oleo- and hydrophobicity, cleanliness, lack of chemical interaction with drug products, lubricant, and heat resistance/cryogenic properties etc. All these unique properties of PFAS provide key functionality in assuring integrity of drug product quality in the multiple applications they are used in across the end-to-end manufacture and supply of drugs. This includes ensuring quality of production page 5 processes, assurance of sterility and stability throughout product shelf life, axenicity and safe delivery/dosage to the patient. c. The number of companies in the sector estimated to be affected by the restriction. 100% of the approximately 830 BioPharma manufacturers in Europe, their global suppliers (and in turn their intermediate material suppliers) including 3rd party testing and validation service providers would be impacted across the complex and multi-tiered supply chain. This supply chain has yet to fully recover from the pandemic shortages. Additionally, where alternatives to PFAS are available, any changes to drugs manufactured in Europe which are filed and distributed in Europe and/or in regions beyond must be submitted for approval to the European Medicines Agency and other global regulatory authorities; this is required to maintain license to operate and market authorisation. The volume of changes requiring review and approval resulting from the proposed restrictions will out-pace capacity of the authorities and put the supply of critical therapies at risk with drug stock-out situations becoming a reality. The exact number of companies impacted is extremely difficult to quantify due to the complexity of the supply chain however there are at least 830 BioPharma companies with facilities in Europe alone. Every biologic drug currently licensed for sale in Europe and those in development but not yet licensed will be manufactured and packaged using PFAS materials somewhere in the process and will be impacted by these restrictions. If drug manufacturing is moved out of the region to other geographies which do permit the use of PFAS, availability of these drugs may be impacted; an example of this is the current challenge in accessing some antibiotics in certain member states of the EU due to sourcing outside of the region. Movement to other less well-regulated regions where raw material quality is lower and regulatory compliance is less regulated may also impact drug quality resulting in a risk to patients. Any such external manufacturing locations will still require significant time to secure the appropriate licensing (as indicated for the case where alternatives exist). d. The availability, technical and economic feasibility, hazards, and risks of alternates for the relevant use, including information on the extent (in terms of market shares) to which alternative-based products are already offered on the EU market and whether any shortages in the supply of relevant alternatives are expected. The proposed timeline for consultation and implementation of the restrictions, if the proposal is accepted, has not permitted the biopharma industry sufficient time to fully identify, qualify and implement suitable non-PFAS alternatives for all applications. In this highly regulated industry sufficient time is required to perform several activities when making changes to the manufacturing process of drugs currently licensed for sale: 1. Research & development of potential alternatives with functional equivalence by the suppliers. 2. Perform development work to demonstrate "equivalence" of the products (characterization) to demonstrate suitability and safety of the materials in the specific biopharmaceutical processes. Note: a functionally equivalent product is not necessarily suitable in all end user applications. 3. Validate the biopharmaceutical product manufacturing process. One critical application of PFAS is in the filtration of drug intermediates to ensure sterility of page 6 final drug product using e.g., fluoropolymer (Polyvinylidene fluoride, PVDF) filter membranes. Factors such as different drug adsorption to different membrane materials can significantly affect yield and quality, and therefore availability of and cost to manufacture drugs. Exposure to solvents, surfactants and chemical mixtures throughout the drug manufacturing, packaging, and storage process (which will be specific to each drug) will have variable impact on the stability and durability of the materials and may result in leaching of substances during the manufacturing processes which pose a risk to patient safety if not fully tested and validated. Significant effort has been made during drug development to demonstrate that all materials currently used are safe and non-toxic for patients, switching to new non-PFAS materials would require significant time and cost investment to ensure no new risks are introduced. Currently, there are few (if any) alternatives to PFAS that encapsulate the required chemical and physical properties to fully emulate the performance of the components currently in use. 4. Generate stability data for the drug substance/product for its required shelf-life - this is a critical rate limiting step and will vary from product to product. 5. Update product licences for review and approval by regulatory authorities in every country that the product is marketed in (likely 3-6 years after time taken to complete steps 1-4). This is also a critical, rate limiting step- Regulatory authorities are likely to be overwhelmed by applications for license updates therefore the time required to complete this step is currently unknown and entirely unpredictable; every drug manufacturer globally is likely to be submitting additional license updates (1:1 submission for every biologic drug currently licensed for sale in the EU market). This will be applicable to licenses held for drug substance and drug product, without an exemption or at least an appropriate derogation this restriction will cause drug shortages in countries where the alternative material has not yet been approved. Note: This does not account for drugs currently being developed and not yet licensed. Therefore, availability of new drugs will also be critically impacted by the proposed restrictions. Nor does it reflect the severe disruptions placed on supply chains that would be observed during any future pandemic situation; the BioPharma supply chain is still recovering from the impact of Covid and has not yet established pre-Covid stability. Even if the industry were granted the current maximum derogation of 12 years (plus 18-month transition) there is no guarantee that alternatives could be sourced, tested, and approved in that timeframe; if PFAS materials are removed from the supply chain while alternatives (where they are available) are being sourced there is a significant risk of interruption to the supply of critical drugs. Mapping of PFAS use applications across the biopharma value chain (both direct and indirect uses) and indication of known, available alternatives is described in Appendix 1. Note: this information was prepared in collaboration with Bio-Process Solutions Alliance (BPSA). We must also be cognisant of another dimension to finding alternatives to PFAS, they have been chosen in drug manufacturing processes because of their unique properties provided by their chemical composition and there is a risk of regrettable substitution i.e., replacing PFAS components with alternative materials which have properties that may impact the quality of the drug. page 7 e. For cases in which alternatives are not yet available, information on the status of R&D processes for finding suitable alternatives, including the extent of R&D initiatives in terms of time and/or financial investments, the likelihood of successful completion, the time expected to be required for substitution (including any relevant certification or regulatory approvals) and the major challenges encountered with alternatives which were considered but subsequently discarded. The sourcing of and switching to non-PFAS alternatives needs to be considered from four critical perspectives- the design and manufacture of novel chemistries, adoption into plastic resin and intermediate articles, incorporation into Bioproduction equipment and processes including qualification and validation of the alternative material in its specific application (including safety evaluation to protect the ultimate user, the patient) and finally the regulatory review and approvals. For suppliers to develop non-PFAS alternatives (if alternatives can be identified and developed), it will take up to or possibly more than 20 years of Research & Development followed by 2-3 years of validations to get to commercial availability for use in biopharmaceutical processes. However this is just the start of the substitution journey for biopharmaceutical end users who must then complete their own evaluation and validation in every application plus submit any changes under regulatory filings and await approval before implementation post-approval of the impacted licenses (refer to point d). Drug product packaging such as PFAS lined closures for glass vials/syringes and vial stoppers (drug delivery systems) are likely the most difficult materials to change due to the lack of suitable alternatives in this application. The manufacturers of certain primary drug product packaging systems have failed to identify any viable alternatives. Fluoropolymers (such as ETFE) laminates on rubber closures provides the best protection to sensitive drugs and no suitable alternatives have been identified or become commercially available over the last 20 years. Vent and gas filtration in equipment requiring in-place steaming/sterilization is performed using PVDF/PTFE based filters for which no robust alternatives were developed over the last 20 years either. The fluoropolymer membranes exhibit unique characteristics providing resistance to the chemical and thermal environment that other membranes could not so far sustainably provide. No PFAS free alternatives for membranes used in venting and gas-filtration applications are available today. Restrictions in the availability of PFAS based air- and vent filters would result in an inability to manufacture biopharmaceutical drug products. Alternatives with the necessary specific properties that PFAS fulfil in drug packaging applications (such as high purity solvent resistance), are not currently available. f. For cases in which substitution is technically and economically feasible but more time is required to substitute: The biggest risk is the time required to a) develop alternatives, b) test alternatives and then c) obtain regulatory approval to switch to new materials in every single country where each product is marketed (refer to point d above). This process will take several years (easily beyond 20 years) for each change and each product under consideration. Without a sufficiently long derogation for the industry and the health authorities to adapt (beyond 20 years), this legislation could cause drug shortages in countries where the new material has not yet been approved. page 8 For drug manufacturing processes which utilise PFAS at multiple stages and in multiple applications across the end-to-end value chain (essentially all drug manufacturing processes) there are two possible scenarios: 1. Best Case: every component part or ingredient which contains PFAS has an alternative which can be "dragged and dropped" into the process and where comparability studies show that the substitution does not impact product quality and Regulatory Authorities have no additional barriers to change. 2. Worst Case: any or all identified alternatives fail the comparability studies and cannot be substituted thus requiring continued use of the current PFAS material- if PFAS is removed from the market under the current proposal the ability to manufacture that drug would be at significant risk. There is no regulatory alignment with the change and every asset needs to be approved (essentially the process detailed above would be multiplied by the number of drugs and countries impacted). In both cases the exercise in completing the required studies will require significant investment in resource, materials and time and would be required for every drug manufactured by each company in both development efforts and in commercial production. If critical resources are diverted to address the multiple changes resulting from a ban this will compete for vital and limited R&D resources, thus delaying introduction of new life saving technology and therapeutics. A specific example of substitution requiring more time is for viral filters used in recombinant therapeutic protein purification processes, where demonstration of viral retention must be executed today for each process/product synthesised in mammalian/insect cell lines and be conducted in facilities that are accredited for virus manipulation. The availability of such facilities is low and conducting an industry wide change of viral filtration technology will result in a huge bottleneck and delay of the availability of support data to submit to regulatory authorities. The supply and qualification of the fluoropolymer materials currently used in the biopharma industry has been evolving over the last 30 years to fully support their safe and effective use in drug manufacture, it is not inconceivable that finding and transitioning to alternatives (if they can be found and safely and sustainably produced) could take another 30 years. i. The type and magnitude of costs (at company level and, if available, at sector level) associated with substitution (e.g., costs for new equipment or changes in operating costs). For pharma/biotech manufacturers, the biggest impact is the time, cost and (human) resources required to a) test alternatives and then b) obtain regulatory approval to switch to new materials in every single country where each product is marketed. This process can take several years for each change and product under consideration. When determining the cost of substituting PFAS materials with alternatives there are multiple factors to consider: the time and resource for research and development, qualification and validation of their use in existing manufacturing processes (studies which may ultimately fail and require sourcing and testing of another alternative), the capacity of 3rd party test labs to evaluate extractables and leachables of the alternatives and which could quickly become a bottleneck at industry level, the resource required within health authorities to review and approve changes (again this is not a guaranteed process and may result in page 9 rejection of changes). This applies to all impacted drugs and registrations around the globe which would result in additional burden on resources at suppliers, biomanufacturer and regulatory authorities to complete all required activities. In the proposal there is no derogation for the Biopharma industry, and we would be subject to an immediate ban. A key consideration is also the capacity of the suppliers to support increased demand for the alternative materials, there are currently still some supply issues with existing materials following a rapid increase in demand during Covid, is the supply chain in place and robust enough to support new demand for new materials? The cost of completing all the above noted points is anticipated to be vastly disproportionate to the impact of the small quantity of stable fluoropolymers sent for incineration (consumable parts) or retained as components of long-life instrumentation. It is difficult to estimate due to the complex, multi-tier supply chain and the requirement for regulatory scrutiny of changes within our highly regulated industry. ii. The time required for completing the substitution process (including any relevant certification or regulatory approvals). In the best-case scenario where an alternative is known, it is functionally equivalent and commercially available, requiring only process validation by the drug manufacturer and assessment and approval by regulatory authorities - estimated 5-8 years. In the worst-case scenario-a full cycle of material identification and functionality assessment at the supplier, process validation in specific processes and assessment and approval by regulatory authorities- will take an estimated 20+ years. A non-exhaustive summary of key steps and timelines for finding and approving alternatives is described in the table below. page 10 Anticipated steps for substitution if alternatives are available. 5a re lE = RaA 2 Eram-I eere [[ = e Emre {EF--sT----rf f --" Tm] " i Tn ElTa =zRaArma.t ZI downstream users and consumers (e.g. estimations of expected early A may be suitable/applicable for some applications but not others. LSA aiLA a Et 8 A risk for the patient and may include reduced stability of biopharmaceuticals and a assuring product and therefore patient safety, and biologic drugs are typically fstieuroirliozpeodlybmeyr fPiVltDrFat.ionThuesimngembmermabnreamnaetesricalomismohniglhyly cdounrsatbrleu,ctaenddftrhoemdrtuhge. from cellulose acetate (CA), Nylon and polyether sulphone (PES), which constitute different limitations e.g. PES is also highly durable but shows higher LL a ar: `adsorfoprtceirtoainn drugs andconstitusuecnhtas excipients and surfactants. wr iv. Information on the benefits for alternative providers. ` On the basis that our industry has not identified suitable alternatives in most of the applications no further comment is appropriate. g. For cases in which substitution is not technically or economically feasible, information on what the socio-economic impacts would be for companies, consumers, and other affected actors. If available, please provide the annual value of EU sales and profits of the relevant sector, and employment numbers for the sector. The European Biopharmaceuticals Market is projected at USD 48.19 billion in 2022 and estimated to be growing at a CAGR of 8.89%, to reach USD 73.78 billion by 2027 [3]. As detailed in the response above there are many applications of PFAS across the Biopharma industry where no technically suitable alternatives exist; if alternatives do exist there is a risk that the time required to qualify and approve those alternatives would exceed any maximum derogation period currently proposed by ECHA. Removal of the impacted drugs from the market (either to allow for qualification and approval where alternatives exist or complete removal when no alternatives with comparable performance attributes are available) would result in significant economic impact to the global manufacturers of these drugs and their suppliers resulting in facility closure, loss of employment and reduced revenue in Europe. Those organizations with alternate manufacturing provisions outside the EU would likely move manufacturing to that region with detrimental impact on future investment within the EU and potentially delaying the supply of therapies (including those in development) due to lack of capacity in the alternative facilities. It is also important to note that the non-EEA production capacity would not be able to cope with the current EEA demand. There is negligible readily available production capacity at biotechnology manufacturing facilities outside of EU-27. If global capacity is not available, shortages in life saving and life prolonging medicines would become a realistic possibility. Indeed, the most critical impact would be to the patients who would have no access to current and developing lifesaving and life prolonging therapies resulting in needless suffering and potential mortality. References: 1. europeanpharmaceuticalreview.com) 2. Marketdataforecast.com 3. 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