Document GK6KeMZVV76yN884DM9Y2nZVx

Use of Fluoropolymers and Fluoro-Elastomers in Medicinal Product Manufacturing Facili9es ISPE (the Interna-onal Society for Pharmaceu-cal Engineering) is a nonprofit associa-on serving its members by leading scien-fic, technical, and regulatory advancement throughout the en-re pharmaceu-cal lifecycle. This document was prepared in good faith by an ISPE interested par-es working group for the purposes of preparing the public consulta-on response submiCed by EFPIA to the PFAS Restric-on proposed under Title VIII of the REACH Regula-on. The informa-on is not intended in any way to serve as promo-onal material for any of the products men-oned there-in. TABLE OF CONTENTS: Executive Summary ............................................................................................................................ 3 Abbreviations...................................................................................................................................... 4 6(a) - Annual Tonnage and Type of Fluoropolymers / Elastomers ..................................................... 5 6(b) - Key Functionalities Provided by Fluoropolymers and Fluoro-Elastomers ............................... 24 6(c) - Number of Companies in the Sector Estimated to be Affected by the Restriction ................. 25 6(d) - Information on the Availability, Technical and Economic Feasibility, Hazards and Risks of Alternatives for the Relevant Use ..................................................................................................... 25 6(e) - If Alternatives are not yet Available, Information on the status of R&D Processes for Finding Suitable Alternatives......................................................................................................................... 26 6(f) - Cases in which substitution is technically and economically feasible but more time is required to substitute...................................................................................................................................... 27 6(g) - If substitution is not technically or economically feasible, information on the potential socioeconomic impacts for companies, consumers, and other affected actors....................................... 27 Appendix 1 ........................................................................................................................................ 29 Page |2 Execu1ve Summary Medicinal product manufacturing facili2es are heavily dependent upon fluoropolymer components present in u2li2es, piping, equipment (process/u2li2es), & single use systems. While some alterna2ves exist, these materials are widely used to maintain safe working environments and enable the produc2on of safe and effec2ve medicines. Chemical Synthesis Manufacturing Chemical manufacturing requires materials that are chemical and corrosion resistant. In certain applica2ons, rather than use PTFE lined pipework and process equipment high nickel alloys and glass lined carbon steel pipe work could be used instead. However, flanges on pipework will require PTFE sealing and gasket material. A poten2al replacement that provides all key func2onali2es provided by fluoropolymers in par2cular PTFE will be hard to find. Any alterna2ve with comparable chemical stability, may also be persistent in the environment, resul2ng in regreNable subs2tu2on. Bioprocessing & Sterile Manufacturing Manufacturing biologics requires highly controlled environments that fluoropolymers support in various ways. It is very important to thoroughly evaluate risks to product quality, including extractables and leachables, from any change in the equipment used. There are some alterna2ves in certain aspects of manufacturing already widely in use (i.e. EDPM gaskets, silicone tubing) but depending on the applica2on, they come with other risks (worker safety, product protec2on) that need careful management. PES is cited in the literature as a poten2al alterna2ve filter MOC (material of construc2on) to PVDF, which is used in all low bioburden and sterile manufacturing processes. If re-execu2on of filtra2on studies was successful, ISPE member companies surveyed indicated that a complete replacement program could be in the order of 20 years. Impact of Proposed PFAS Restric>on An alterna2ve that exhibits all the proper2es of the fluoropolymers used in medicinal product manufacturing facili2es is not available at this 2me. If the proposed PFAS restric2on prohibits the supply of these cri2cal raw materials, manufacturing opera2ons at EU facili2es will cease when con2ngency stock levels are depleted. A recent industry survey indicates that the number of ac2ve substances associated with manufacturing opera2ons that are dependent on fluoropolymer components in equipment and single-use systems is es2mated to be at least 1,794. These ac2ve substances are intended to treat condi2ons such as cancer, cardiovascular disease, diabetes, mental health disorders. Therefore, a 2me unlimited deroga2on for the industrial use of fluoropolymers in medicinal product manufacturing facili2es is a necessary medicine shortage mi2ga2on measure. Close partnership across medicinal product supply chain is needed to iden2fy all sources of PFAS, to sufficiently manage emissions from waste streams, and where possible, to develop suitable alterna2ves that maintain the highly controlled environment required for efficacy and pa2ent safety. A response to Ques2on 6 of the Annex XV REACH proposal on PFAS is presented in the document that follows. Page |3 Abbrevia1ons API BAT CEWEP CIP ECHA ECTFE EEA EDPM EFPIA EMA EPDM ETFE EURTIS EWC FEP FDA FIBC FKM GC GMP HPLC ICH ISPE LPPS MOC NMR P&ID PCTFE PCV PE PES PFA PFAS PRV PTFE PVDF PWEC QC RP SIP SPPS TFM WFI AcZve PharmaceuZcal Ingredient Best available technologies ConfederaZon of European Waste to Energy Plants Clean in pace European Chemicals Agency Ethylenechlorotrifluoroethylene European Economic Area Ethylene propylene diene monomer rubber European FederaZon of PharmaceuZcal Industries AssociaZon European Medicines Agency Ethylene propylene diene monomer Ethylene Tetrafluoroethylene European Union for Responsible Treatment of Special Waste European waste catalogue fluorinated ethylene propylene Food & Drugs AdministraZon Flexible intermediate bulk container Fluorine Kautschuk Material Gas chromatography Good manufacturing pracZce High performance liquid chromatography InternaZonal Council for HarmonisaZon InternaZonal Society for PharmaceuZcal Engineers Liquid phase pepZde synthesis Materials of construcZon Nuclear magneZc resonance Piping and InstrumentaZon Diagram polychlorotrifluoroethylene PosiZve Crankcase VenZlaZon Polyethylene Polyethersulfone Perfluoroalkoxy alkane Per and polyfluoroalkyl substances Pressure relief valve Polytetrafluoroethylene polyvinylidene fluoride Purified water for endotoxin control Quality control Reverse Phase Chromatography Steam in place Solid phase pepZde synthesis Modified PTFE Water for injecZon Page |4 6(a)- Annual Tonnage and Type of Fluoropolymers / Elastomers Medicinal product manufacturing facili2es are governed by a GMP (good manufacturing prac2ce) cer2ficate, issued by global health authori2es. Opera2on of these facili2es are heavily dependent upon fluoropolymer use in u2li2es, piping, equipment (process/u2li2es), & single use systems. Fluoropolymer materials are widely used in the pharmaceu2cal manufacturing industry because of their corrosion resistance and are deemed to be inert by most regulatory agencies and are considered desirable to produce medicinal products, e.g. they are EMA cer2fied. Examples of Polymers Used in Pharma Manufacturing Examples of Fluoropolymers: PFA = perfluoroalkoxy alkane PTFE = polytetrafluoroethylene FEP = fluorinated ethylene propylene TFM = modified PTFE ETFE = ethylene tetrafluoroethylene PCTFE = polychlorotrifluoroethylene PVDF = polyvinylidene fluoride Non-fluorinated Polymers: PEEK = polyether ether ketone PET = polyethylene terephthalate PC = polycarbonate PP = polypropylene LDPE = low-density polyethylene HDPE = high density polyethylene PETG = polyethylene terephthalate glycol Prepara2on of a quan2ta2ve es2mate of all fluoropolymer materials used in plant, equipment and consumables in a typical pharmaceu2cal manufacturing facility will be a challenge if not impossible because: There are kilometres of lined piping (millimetre thickness), valves, check valves and sight glasses in GMP process systems and u2lity systems. Fluoropolymers are also found in the component parts of valves - gasket, joints, sealants, seal rings, pumps, filters and it would be impossible to reliably catalogue each of these very specific applica2ons. Fluoropolymers are also found in many single-use items, such as process bags, engineered tubing sets, and process filters. The amount of fluoropolymer cons2tuents present in these ar2cles is in most cases regarded as business confiden2al informa2on by the supplier, and not accessible to the downstream users of such ar2cles. An explana2on for the widespread use of fluoropolymer types associated with the manufacturing opera2ons is provided for: Small molecule & pep2de manufacturing - chemical synthesis of an ac2ve substance Bioprocessing facility - manufacture of an ac2ve substance using biological processes Sterile manufacturing - asep2c processing of a parenteral medicinal product Table2ng process - formula2on of a solid dosage form Page |5 (i) a Manufacture of a Small Molecule by Chemical Synthesis Small Molecule APIs (ac0ve pharmaceu0cal ingredients) are low molecular weight (1000 Daltons) organic compounds Molecules are built by a series of chemical reac0ons (or steps) conducted in a broad set of organic solvents as well as strong acids or bases. Equipment needs to withstand a wide range of opera0ng pressures and temperatures (i.e. from-80 to +180C) QC analysis of raw materials, synthesized intermediates & APIs is a mandatory step to ensure the product meets the required specifica0ons PreparaZon of a Small Molecule API by Chemical Synthesis Page |6 (i)b Manufacture of a Pep9de Therapeu9c by Chemical Synthesis (Solid or Liquid Phase Pep9de Synthesis; SPPS or LPPS) Therapeu0c pep0des are a unique class of pharmaceu0cal agents composed of a series of well-ordered amino acids, pep0des are usually with molecular weights of 500-5000 daltons. Amino acids act as the building blocks in a defined set of unit opera0ons along with coupling agents, organic solvents and deprotec0on reagents. ASer the progressive build of pep0de on resin or in the solu0on, the crude pep0de is cleaved (only for SPPS) and precipitated. Purifica0on is then achieved by chromatography followed by precipita0on or lyophiliza0on to produce ac0ve pharmaceu0cal ingredient (drug substance). Page |7 GMP & U'lity Systems in Chemical Synthesis Plants - Types of Fluoropolymers Used The following are examples of typical fluoropolymer materials found in the GMP and u2lity equipment systems of a mul2-purpose chemicals synthesis manufacturing plant: Chemical Synthesis Facili1es - type of equipment & consumables containing fluoropolymers Mechanical seals on process equipment- vessels, pumps, fans Valve seats on ball Valves, bugerfly & gate valves Gaskets on pipework & vessels O-ring seals on vessels & pipework PTFE lined pipework & hoses Scrubber linings Flexible tubing chemical synthesis flow reactors Fluoropolymer Type PTFE PTFE/PVDF/PFA PTFE FEP/PTFE PTFE PVDF/PFA PFA A chemical manufacturing plant is a system of individual parts (reactors, pipework, condensers, receivers, valves, pumps etc). All parts must be compa2ble with the opera2ng condi2ons (temperature, pressure, pH) and the materials (solvents, reagents) being handled. Chemical reac2on vessels are typically made of Glass-lined (enamelled) Steel, Stainless Steel, or Hastelloy, and can range in size from 10 to 10,000 litres and are usually equipped for hea2ng and cooling via a jacket. Fluoropolymers are used in sealing of (mul2purpose) manufacturing equipment including reac2on vessels to prevent leakages between equipment (flanges, valves etc.) components. Hence the need for a MOC (Materials of Construc2on) evalua2on when building a new facility, and when introducing a new process into exis2ng equipment. This process safety requirement is intended to minimise the risk of leakage/release of aggressive substances/materials from closed manufacturing systems, thus minimising the risk of injury to employees. Compared to the other types of pharmaceu2cal manufacturing facili2es (sterile and biological processes), fluoropolymer materials used ofen have long life2mes within equipment (or are replaced less infrequently). Structural long-life2me equipment such as PTFE lined pipework could have an in-service lifespan of up to 20 years. A gasket once fiNed could have a life2me as long as the pipe work it seals, provided it's lef undisturbed. Quality control analysis depends heavily on the presence of fluoropolymers in analy2cal equipment such as HPLC, GC, NMR instrumenta2on. The analy2cal detectors employed are extremely sensi2ve to impuri2es. PFAS materials are used in this context e.g. to seal samples, protect tubes because they are inert to other chemicals and do not leach out during their life2me. Conversely, leaching out of contaminants from alterna2ve equipment parts would lead to false results. Yet, replacing these equipment parts with fluorine-free alterna2ves would disable a vast number of the aforemen2oned analy2cal models and analyses. Page |8 Internal surfaces of glovebox are PFAS lined Valves with PTFE internal components Glove ports have PTFE o-rings PTFE liners on access port into glovebox Valves & rotary valves with PTFE internal components Glovebox for Contained Transfer of Solid Materials into Reac1on Vessel Page |9 PTFE Agitator belts, manway gaskets, mechanical seals, outlet valve, reactor seals - inlets / outlets PTFE filter and seals on housing PTFE lined pipework PFAS compressed air filters and instrumentaIon Pipework on top of a glass lined reac1on vessel (front & rear) PCVs, PRV, instrumentaIon, all with PTFE seals PFAS agitator belts, manway gaskets, mechanical seals PTFE lined glovebox on an inline sampler Control valves with PTFE internal components Valves with PTFE internal components P a g e | 10 Working PlaKorm on Top of Filter Dryer PTFE agitator belts, manway gaskets, mechanical seals, valves, instrumentaIon PTFE coaIng on process control monitor PTFE lines PTFE vent lines P a g e | 11 Pack off staIon PTFE seals and instrumentaIon, control staIon, liners P a g e | 12 Pep1de Synthesis - Reac1on Vessel PTFE, FEP reactors seals, gaskets, fiPng Clean Room Protec1on Equipment PTFE glovebox/protecIon screens seals P a g e | 13 (ii) Manufacture of an Ac9ve Substance by Biological Processes Biological acZve substances are produced by complex manufacturing processes using living cells, examples include: Monoclonal an0bodies, fusion proteins Live/aVenuated vaccines Cell-based Therapies, Gene Therapies Blood / Plasma deriva0ves Pep0des manufactured using Bacterial/Yeast Fermenta0on Common Unit OperaZons in the Manufacture of a Biological AcZve Substance P a g e | 14 TYPICAL PFAS USAGE THROUGHOUT THE VACCINES MANUFACTURE, RELEASE AND SUPPLY CHAIN CELLS AND RAW MATERIALS PRODUCT RECOVERY AND FILTRATION LABEL, PACK STERILISE, FILL VIALS, LYOPHILISE, CLOSE STORE, TRANSPORT AND SUPPLY CELL BANKS FORMULATE AND POOL BULKS VACCINES MANUFACTURE (STERILE PRODUCTION) Equipment: fluoropolymers in production equipment (e.g., reactor lining, seals, gaskets, piping, anti-stick coating, surfaces, filtration units) contact and quality impact): fluoropolymers in filters bioreactors production equipment: fluoropolymers in complex equipment, such as: insulation material mechan' fluoropolymers with product contact and quality impact, including spare or replacement parts. bags tubes, etc. Fluoropo VACCINES PACKAGING duct contact. 1 Independent OMCL release in the EU ( see QC release) Laboratory equipment/consumables: PEAS fluoropolymers (e.g., Teflon tubing, valves, gaskets, filters) including product contact and quality impact electrical components diagnostic laboratory testing refrigerants in laboratory equipment (temperaturecontrolled centrifuges) Laboratory reagents: PFAS materials and reagents used in quality control activities are mandated by product licenses or regulations such as European Pharmacopoeia monographs. Examples: trifluoro acetic acid (TFA) in the mobile phase of high-performance liquid chromatography (HPLC) perfluoro butanoic acid (PFBA) as ion pair reagent in chromatography N-methyl-bis(trifluoroacetamide) (MB-TFA), N,0-bis-trimethylsilyl-trifluoroacetamide (BS-TFA), and N-methyl-N- trimethylsilyl-trifluoroacetamide (MS-TFA) to derive silyl derivatives in gas chromatography or other methods. Independent NCL release on import for non-EU countries (see QC Release). Local QC release on import by manufacturer (see QC Release) Manufacturing, storage and transport: polymeric (e.g., filters, seals) and no transport, including spare or replacement parts. Cred images and graphics taken from www.canva.com and usaNw.freeplk.com created by usertrmk, rawpixel.com, aleksanclarlittiewoli and Marta Borreguero. ctrical components, refrigerants in HVACR equipment and low temperature refrigeration, refrigerants in storage anc P a g e | 15 Bioprocessing Facili'es & Asep'c Processing - Types of Fluoropolymers Used The following are examples of typical fluoropolymer materials found in the GMP and u2lity equipment systems of a bioprocessing and asep2c processing facility: Bioprocessing Facili1es & Asep1c Processing - Fluoropolymer Type type of equipment & consumables containing fluoropolymers O-rings/gaskets/seals on vessels & pipework PTFE Filters PVDF, PTFE Pump heads/fijngs PVDF, PTFE Hoses and tubing PTFE Chromatography Column Equipment PTFE EU Annex 1 guidance1 applies to low bioburden and sterile manufacturing techniques used to produce biological acZve substances which are typically administered to the paZent as parenteral medicines. Fluoropolymer components are found in single use consumables, as these materials are deemed to be inert by most regulatory agencies and are considered desirable to produce medicinal products. Extractables and leachable study requirements apply to single use materials which have direct contact with a parenteral product.2 To maintain the required equipment cleanliness, strong acids and bases as well as high temperatures and pressures are needed to CIP (clean in place) and SIP (steam in place) producZon vessels, as well as to produce WFI (water for injecZon). The areas of faciliZes that distribute these criZcal uZliZes to the main producZon suites must be closely monitored and maintained with the right equipment to prevent corrosion and ensure a safe working environment. Therefore, PTFE is commonly used in seals, gaskets, hoses, and diaphragm valves due to their resistance to corrosion and mechanical properZes. Other known fluoropolymers used include PVDF, found in components needed for manufacturing such as filters, which supports the product quality. Biologics are sensiZve to product quality impact, e.g. adsorpZon, aggregaZon, degradaZon, etc. when using non-fluoropolymer containing filters, which also pose higher risk of leachables which puts paZent safety at risk. Fluoropolymers may also be present in single-use systems such as bags and connectors, which are criZcal to enable future "next generaZon" conZnuous bioprocessing, which enable a much smaller producZon footprint, therefore significantly decreasing the energy and freshwater demands of manufacturing these medicines3. AddiZonal data 1 20220825_gmp-an1_en_0.pdf (europa.eu) 2 Regulatory guidelines and regula=ons for leachables from the US Food and Drug Administra=on (FDA), the European Medicines Agency (EMA), and the Interna=onal Council on Harmonisa=on (ICH): 21 Code of Federal Regula=ons (CFR) 211.65(a) specifically states: "Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reac8ve, addi8ve, or absorp8ve so as to alter the safety, iden8ty, strength, quality, or purity of the drug product beyond the official or other established requirements." Sec=on 6.1.3 of the European Medicines Agency's 2016 Guideline on process valida=on for the manufacture of biotechnology-derived ac=ve substances and data to be provided in the regulatory submission states: "When single use equipment is used in evalua8on studies, considera8on should be given to leachables and extractables. Informa8on should be provided on the nature and amount of poten8al leachables, and the removal of such impuri8es. Besides data, this normally includes a risk assessment. 3 Streamlined life cycle assessment of single use technologies in biopharmaceu=cal manufacture - New Biotechnology (2022) P a g e | 16 gathered indicates that single-use systems manufactured from fluoropolymers are resistant to carbon dioxide ingress during shipping on dry ice4. Another advantage of fluoropolymers is that they exhibit very low coefficients of fricZon. That means that they do not adhere biological materials to process surfaces, have inherent resistance to bioburden and endotoxin, and can be easily cleaned when required. A low coefficient of fricZon also means that liquids will drain fully from fluoropolymer-based systems because they will roll off container surfaces. While there are sources of fluoropolymers used throughout a bioprocessing facility, there are alternaZves used widely where the mechanical strength and corrosion resistance is not necessary, such as EPDM gaskets and silicone tubing. The following images illustrate typical uses of both fluoropolymers as well as their commonly used alternaZves in typical manufacturing sejngs: Upstream Processing - Bioreactor Bioreactor with internal PTFE seals Pumps with potenIal PVDF fiPngs / tubing and/or PTFE lubricants 4 BioProcessing Ar=cle, 22 August 2022 Advanced Materials in Bioprocessing P a g e | 17 FiltraIon unit containing PVDF components. Downstream Processing - Buffer Make Up Buffer soluIon is transferred through the filtraIon unit from an adjacent fixed vessel into a hold bag, located inside a stainless-steel support unit Buffer soluIons are made up to adjust pH of the process soluIon. The buffer soluIon must be filtered to protect the process soluIon from microbial contaminaIon - an important step in ensuring the sterility of the medicine product. Equivalent filtraIon is required for process intermediates prior to hold duraIons. PVDF filter membranes are widely used in filtraIon units within bioprocessing. Each filter in the industry has specific surface area, pore size and MOC (material of construcIon). MOC properIes are not readily interchangeable. Changing MOC with equivalent surface area and pore size requires re-execuIon of filtraIon studies. PVDF filter membranes have higher oxidant resistance and mechanical strength compared to PES (polyethersulfone) filters Downstream Processing - Nanofiltra1on PVDF Tube Connector FiPngs on top of a NanofiltraIon Skid P a g e | 18 Downstream Processing - Chromatography Column Chromatography column with internal PTFE seals and frits Chromatography columns are criZcal to purify the AcZve PharmaceuZcal Ingredients. In order to funcZon properly, they must be opZmally packed to specified column bed heights using large, fine mesh screens lined with PTFE, which has a low coefficient of fricZon. P a g e | 19 (iii) Formula9on - Sterile Dosage Form Parenteral Medicines Parenteral drug administraIon refers to medicinal products administered by routes other than the digesIve tract, parIcularly by injecIon or infusion. Water acts as an excipient in parenteral formulaIons of a medicinal product and must meet WFI (water for injecIon) quality standards. PTFE coated stoppers were introduced over 20 years ago to avoid cases of pure red cell aplasia associated with leachates from uncoated rubber syringe stoppers P a g e | 20 (iv) TableFng process -formula9on of a solid dosage form PTFE components - tablet dedusIng equipment PTFE components - tablet compressing equipment PTFE components - within the turret of a rotary tablet press P a g e | 21 PTFE ] components SBV valve powder inlet PTFE components SBV valve granules outlet P a g e | 22 (v) Waste Management Use of Fluoropolymers in Medicinal Product Manufacturing FaciliZes occurs in an industrial sejng, so worker protecZon and environmental legislaZon applies. Waste streams generated from the operaZon of medicinal product manufacturing faciliZes is disposed of as per local legislaZve requirements as well as locally available disposal treatment. Non-hazardous waste streams will contain non-product contacZng arZcles such as discarded mechanical seals, valves, gaskets, O-rings, cartridges, single use containers, which are likely disposed of either via incineraZon or licenced landfill facility based on local waste treatment opZons. Waste classified as hazardous, will be treated at an industrial incineraZon facility which must be permiged for the disposal of the parZcular waste streams as idenZfied by EWC (European Waste Catalogue) code. Experts in the waste sector federaZons (CEWEP, EURITS) are best placed to provide informaZon on the effecZveness of incineraZon units operated as per best available technologies (BAT). Compared to other polymers, recycling of fluoropolymer containing waste is not common pracZce5. Recycling processes must avoid emissions of PFAS break down products or accumulaZon in the recycled material returned to the supply chain. As PFAS waste treatment technology and analyZcal methods are evolving, transiZon to the use of recycled fluoropolymer materials will take Zme. 5 Recycling and the end of life assessment of fluoropolymers: recent developments, challenges and future trends - Chemical Society Reviews, (2023) P a g e | 23 6(b)- Key Func1onali1es Provided by Fluoropolymers and Fluoro-Elastomers Chemical Synthesis Facili1es - Fluoropolymer Key Func1onality Provided type of equipment & consumables containing fluoropolymers Type Mechanical Seals on Process Equipment- Vessels, Pumps, Fans Valve Seats on Ball Valves, Bugerfly & Gate Valves Gaskets on pipework & vessels O-ring seals on vessels & pipework PTFE Lined Pipework & Hoses Scrubber Linings Flexible tubing serving chemical synthesis flow reactors PTFE PTFE/PVDF/PFA PTFE FEP/PTFE PTFE PVDF/PFA PFA Chemical / Corrosion Resistance Temperature resistance, Mechanical strength Reasons for using fluoropolymer over an alterna1ve material / technology Performance (incl. lifeZme of equipment) Health, safety & environment GMP RegulaZons and standards Less spare parts management Fewer opZons reduce mistakes when replacing parts Biological ac2ve substances are more labile and sensi2ve to product quality impact, e.g. adsorp2on, aggrega2on, degrada2on, etc. when using non-fluoropolymer containing filters. Addi2onally, other filter materials have higher leachables which pose a greater risk to pa2ent safety. Bioprocessing Facili1es & Asep1c Processing - type of equipment & consumables containing fluoropolymers O-rings/gaskets/seals on vessels & pipework Filters Pump heads/fijngs Hoses and tubing Chromatography Column Equipment Fluoropolymer Type PTFE PVDF, PTFE PVDF, PTFE PTFE PTFE Key Func1onality Provided Temperature resistance, Chemical/Corrosion resistance Repellence properZes Mechanical strength, Low coefficient of fricZon Temperature resistance, Chemical/Corrosion resistance Mechanical strength, Low coefficient of fricZon Reasons for using fluoropolymer over an alterna1ve material / technology GMP RegulaZons and standards for paZent safety Performance (incl. lifeZme of equipment) Health, safety & environment P a g e | 24 6(c)- Number of Companies in the Sector Es1mated to be Affected by the Restric1on A survey of ISPE members (see Appendix 1) conducted in August 2023 indicated that at least 157 companies have manufacturing and/or packaging opera2ons in the EU. Due to the short 2meframe in which the survey data was collected it is quite possible that pharmaceu2cal manufacturers have not responded to the survey. Based on the membership of the trade associa2ons represen2ng actors in the human pharmaceu2cal sector, there at least 200 companies who depend on the use of fluoropolymers in manufacturing opera2ons and are affected by the proposed Restric2on. 6(d)- Informa1on on the Availability, Technical and Economic Feasibility, Hazards and Risks of Alterna1ves for the Relevant Use (i) Chemical Synthesis Manufacturing There are some alterna2ves to PTFE that are used in lined pipework and process equipment, such as glass or certain metals. Transi2oning to alternate materials like high nickel alloys and glass lined carbon steel pipe requires the use of the inert, stable and very high purity gasket material and flexible expansion bellows on the main connec2ons. In such applica2ons PTFE would be required in the sealing and gasket materials used in pipework connec2on points. Also taking sealing applica2ons as an example, ceramic seals can also be very inert, but contain fibres that can be released into the medicinal product. Similarly, graphite seals (e.g., gaskets) are not suitable for pharmaceu2cal processing due to the risk of carbon debris in the final medicinal product. Other materials, such as tantalum or gold can be used in connec2ons between equipment parts but are extremely expensive (many orders of magnitude more expensive than PFAS). Fundamentally these alterna2ves, however, are not compa2ble with a mul2purpose manufacturing facility. In general, none of the alterna2ves provide a broad-spectrum corrosion resistance and their mechanical proper2es are limited. Chemical compa2bility for non-PFAS-made equipment may be very limited, bringing safety and quality issues into a mul2purpose manufacturing facility. Ul2mately, other alterna2ve materials would limit the use of solvents, chemicals, and process condi2ons (temperature range, pH values). P a g e | 25 (ii) Bioprocessing Manufacturing Single-use systems were introduced to reduce the environmental footprint of biopharmaceu2cal manufacturing plamorms. In the 1990s the industry started to move away from stainless steel equipment trains to single-use systems6 that contain some fluoropolymer components to op2mize yield and decrease waste from cleaning. Rigorous cleaning standards are applied to reusable stainless-steel equipment to avoid microbial contamina2on of produced material. The required equipment cleanliness is provided by CIP (clean in place) and SIP (steam in place) systems which require significant energy and water usage. Lifecycle assessment studies indicate that single use technology exhibits a lower environmental impact due to a reduc2on facility size, drama2cally reducing the energy demand as well as demand for WFI, process water, steam and less requirement for cleaning and sani2za2on in place7. Therefore, fluoropolymers materials used are essen2al for "next genera2on" con2nuous bioprocessing, to enable a much smaller produc2on footprint, therefore significantly decreasing the energy and freshwater demands of manufacturing biomedicines. 6(e) - If Alterna1ves are not yet Available, Informa1on on the status of R&D Processes for Finding Suitable Alterna1ves Research conducted so far indicates that a poten2al replacement that provides all key func2onali2es provided by fluoropolymers in par2cular PTFE will be hard to find.8 The C-F chemical bond is one of the most stable bonds in organic chemistry leading to superior chemical resistance against acids, caus2cs, solvents, oxidizing materials etc. It is possible that any future alterna2ve with the comparable chemical stability and corrosion resistance could be very persistent in the environment, leading to cases of regreNable subs2tu2on. 6 BioProcessing Ar=cle, 22 August 2022 Advanced Materials in Bioprocessing 7 Streamlined life cycle assessment of single use technologies in biopharmaceu=cal manufacture - New Biotechnology (2022) Single-use technology and sustainability: quan=fying the environmental impact in biologic manufacturing - Cy=va (2020) 8 University of Warwick, collabora=on to find alterna=ves (Nature: Vol 620 3 August 2023) P a g e | 26 6(f)- Cases in which subs1tu1on is technically and economically feasible but more 1me is required to subs1tute PVDF filters are used in all asep2c and sterile manufacturing processes. The reason PVDF is used in filters over selected alterna2ves is beNer oxidant resistance and mechanical strength. In some publica2ons PES (polyethersulfone) is cited as a poten2al alterna2ve filter MOC (material of construc2on) to PVDF. Changing MOC with equivalent surface area and pore size will require re-execu2on of filtra2on studies, including extractables and leachable study data. In some applica2ons the equivalent PES filter may not be suitable for the process applica2on or require repeat execu2on of studies to iden2fy a suitable filter size for the applica2on. The change management process can require process op2miza2on work, equipment requalifica2on and valida2on, and regulatory approval by all global health authori2es. Es2mated change over 2me to successfully replace a filtra2on unit in a single manufacturing process could take 2 years. As parenteral medicines are marketed interna2onally each product depending on the filter cri2cality may require re-registra2on in each individual target country, and standard 2mes for this are 3-5 years. Many companies will have a significant variety of PVDF filters with some being used in several processes. Depending on the applica2on of the filter, some of the above work will have to be completed for each individual product and each filter type. In total, ISPE member companies surveyed indicated that a complete replacement program may therefore be in the order of 20 years. These 2mescales consider a single change, however, mul2ple changes for a company would create produc2on capacity constraints. Thus, pupng the supply of medicinal products to pa2ents at risk. 6(g) - If subs1tu1on is not technically or economically feasible, informa1on on the poten1al socio-economic impacts for companies, consumers, and other affected actors. An alterna2ve that exhibits all the proper2es of the fluoropolymers used in medicinal product manufacturing facili2es is not available. If the proposed PFAS restric2on prohibits the supply of these cri2cal raw materials, manufacturing opera2ons at EU facili2es will cease when con2ngency stock levels are depleted. Transfer of manufacturing opera2ons to non-EEA facili2es to ensure con2nued supply of many medicinal products may not be possible. It is incorrect to assume that there is readily available manufacturing capacity at biotechnology and chemical synthesis produc2on facili2es outside of the EEA. Non-EU producers would require sufficient idle produc2on capacity at a drug substance, drug product formula2on and packaging facili2es to meet the demand created by the unavailability of medicines manufactured in the EEA. It is unlikely that there is surplus idle capacity at non-EU facili2es as underu2lisa2on of produc2on capacity is not good business prac2ce. P a g e | 27 Should suitable non-EU produc2on capacity become available, 2me is required to complete the technology transfer of the manufacturing process to a new facility. In the case of the manufacture of a biological ac2ve substance, this could take 4 to 8 years: Iden2fica2on of a suitable facility & comple2on of necessary due diligence 1-2 years Carrying out technology transfer process including stability studies 2-3 years Comple2on of global regulatory submissions plus wait 2me for approval 1-3 years Commission working document9 describes vulnerabili2es in the global supply chains of medicinal products, including produc2on capacity constraints. The COVID-19 pandemic highlighted vulnerability in global manufacturing capacity for sterile and biological processes. These processes are complex, and therefore must comply with addi2onal quality and regulatory requirements. The length of 2me required to build new facili2es to manufacture biological substances is significant. Recent real-world examples indicate that the amount of 2me required to design, construct, commission, qualify and obtain regulatory approval for a new biologics manufacturing facility is 5 years. Annex 2 describes the cross-industry survey undertaken to evaluate the impact to pa2ents if the proposed PFAS Restric2on is implemented without a deroga2on for industrial use of fluoropolymers in pharmaceu2cal manufacturing. The number of ac2ve substances associated with manufacturing opera2ons that are dependent on fluoropolymers used in plant, equipment was consumables was 1794. These ac2ve substances are intended to treat condi2ons such as cancer, cardiovascular disease, diabetes, mental health disorders. In addi2on, considering the wide-spread impacts from a changing climate on water and biodiversity, shifing the burden of the global supply of medicines away from one major region of the world would place undue burden elsewhere, including in areas that may face more pressures on nature. In short, a 2me unlimited deroga2on for the industrial use of fluoropolymers and fluoroelastomers in medicinal product manufacturing facili2es is a necessary medicine shortage mi2ga2on measure. 9 mp_vulnerabili=es_global-supply_swd_en.pdf (europa.eu) P a g e | 28 Appendix 1 Output from an ISPE Survey on the Impact of a Proposed Ban on Per- and Polyfluoroalkyl Substances (PFASs) P a g e | 29 Output from an ISPE Survey on the Impact of a Proposed Ban on Per- and Polyfluoroalkyl Substances (PFASs) EXECUTIVE SUMMARY The conclusion from an ISPE survey conducted in August 2023 is that extensive derogation in the form of actions and timescales are required by the pharmaceutical industry and its suppliers resulting from PFAS restriction. Without such derogation there is a very high probability of many drug products required critically by patients becoming unavailable. Timescales for replacement strategies and actions by companies will be long and uncertain given that substantial studies will be required to support replacement. The majority of responses indicated a range of 3 to 10+ years to complete the technical change. In addition, there is the time taken to obtain regulatory approval, which in many cases will include the need to seek approval in other regions of the world. Evidence suggests this additional regulatory time could be 3 to 5 years. A complete replacement program may therefore be in the order of 20 years total. For nearly 30% of all impacted cases, technically there is currently no substitution feasible. Such situations may require major redesign of the drug product or its associated process (including drug substance process) or withdrawal from the market. This technical and regulatory change management process will require substantial resources from marketing authorization holders. In addition, there will be a proportionately high resource needed from regulatory agencies in the EU, and elsewhere to review and approve these changes. SUMMARY OF RESPONSES FROM ISPE SURVEY ISPE conducted a survey in August 2023 with the objective of identifying the impact of the European Chemicals Agency (ECHA)'s proposed ban on PFAS on various sectors of the pharmaceutical industry during the production and packaging stages. Responses were received from 130 companies of varying sizes with a very wide spread of activity such as supply of materials and manufacture of drug substance (small molecule and biologics), supply of materials and manufacture and package drug product (sterile and non-sterile), provision of analytical and manufacturing materials and equipment. The main messages of this survey are: 75% of the companies surveyed have factories in Europe. They all are very concerned about the potential impact of a potential PFAS ban or restriction. For 30% of the affected entities (chemicals for active ingredient manufacturing or analytics, products, manufacturing processes, equipment, utilities as well as primary packaging materials) there are not technical alternatives, in certain cases not even P a g e | 30 after longer development work. For example, no alternatives are available for coated stoppers, which are used in almost all aseptically or sterile manufactured products. The times mentioned in the survey for the re-registration of all entities concerned do not include the times needed on the part of the registration authorities. For example, internationally marketed products must be re-registered in each individual target country, and standard times for this are 3-5 years, which must be added. A complete replacement program may therefore be in the order of 20 years total. These timescales consider a single change, however, multiple changes for a company may lead to capacity restraints. SURVEY DEMOGRAPHICS Responses from 130 small, medium-sized and large pharmaceutical companies as well as suppliers of starting materials, excipients and production aids were received in the survey on PFAS related activities. Among those were manufacturers of Active Pharmaceutical Ingredients (APIs), non-sterile drug products, sterile products, biotech drug substances, packaging material, equipment, analytical material, production material, excipients and facility construction companies. 60% of all companies supply or import APIs or drug product into the territory of the European Union, 40% of all companies produce material and excipients. 50% of responses are from companies with more than 5000 employees. (see Fig 1) Fig 1. Demographics of ISPE survey on PFAS. P a g e | 31 IMPACT OF PFAS RESTRICTIONS 74% of all companies have facilities in the European Union. (see Fig 2), ALL of them are concerned by the impacts of a potential PFAS restriction. (see Fig 4). Fig 2. Companies with facilities in the EU. P a g e | 32 The activity of these companies is distributed as follows (Fig 3): Fig 3. Surveyed companies' activities in the EU. Fig 4. Surveyed companies concerned with the potential PFAS ban. P a g e | 33 The highest impact is expected for production material, 30% for container closure system, i.e., vials and stoppers, followed by 29% for packaging materials (bottles and blisters). The second relevant group are fluorinated drug substances 19.5%, followed by fluorinated reagents 13% and fluorinated excipients 8.5%. (Fig 5). As a pharmaceutical drug is registered with all components included specified packaging material and with the manufacturing process for the API and for the drug product or biological, each change of a component must undergo a regulated change management process with regulatory authorities. This change management process is based on a long list of questions requiring development activities, stability studies and even sometimes new clinical investigations. Fig 5: Impact of a potential PFAS ban on substances and packaging materials in direct contact with the product. P a g e | 34 In processing equipment there is an equal impact for single use systems (disposable containers, bioreactors, bags, pouches and tubing), equipment gaskets, coated valves and filters. Utility systems, (e.g., manufacturing of sterile water for injection) are all affected (Fig 6). The concerned processing equipment is essential and affects almost all production steps in a manufacturing process. Substitution requires development activities, tests, optimization, trial runs, qualification, validation - in addition and as a pre-requisite to start a regulated change management with regulatory authorities. The kind of interaction given between polyfluoropolymers and equipment which has direct contact with the product is material compatibility (leachables and extractables) with potential alternate materials of construction. This requires additional qualification and validation studies and subsequent regulatory approval in the change management process with regulatory authorities. Fig. 6. Impact on a potential PFAS ban on production materials and equipment in contact with the product. For utilities there is a similar picture. The extent of work is even higher as buildings need to be re-constructed. P a g e | 35 CHANGE MANAGEMENT TIME For 26% of cases, the change over time including all technical preparations with 3-5 years is expected, followed by 15.8 % with 6 to 10 years and for 15% even more than 10 years (Fig 7). Fig 7. Estimated change over time, where substitution of PFAS components is feasible. This survey does not include time and capacity constraints for EMA and National Competent Authorities to generate change approvals. A PFAS ban will generate a huge amount of drug product modifications in product components, causing regulatory authorities a bolus of submissions with a short timeline for approval. Another multiplier is given for internationally registered products as each product is registered in its country of destination and the national competent authority there. Global change over times, just for the registration part, usually takes 3-5 years. This needs to be calculated as an additional time frame. P a g e | 36 Highlighting the workload of changes: Example 1: A regulatory requirement to use product-specific filters additional resources required for each product depending on the manufacturing process, there are several filtration steps per product needed. Filter vendors - if they have alternative solutions - must make challenges tests for the filters linked to each product for change management purpose and application changes. Example 2: PFAS will not concern only APIs, but every product that requires filtering. Nearly 100% of all aseptic and sterile manufactured products require filtering, meaning that all sterile products will be impacted by PFAS restriction. Even with filter alternatives and if filter materials are available, a full validation work will be needed with several runs of Aseptic Process Simulation which will have a huge impact on pharmaceutical operations, including personnel qualification. ALTERNATIVES For nearly 30% of all impacted cases, technically there is no substitution feasible. Example: Coated stoppers have a PFAS based safety barrier in order to protect the product from extractables and leachables from the stopper material. Years of research have not resulted in a safe alternative to the coating material. There are other examples available. For alternate substances, excipients, production aids, construction material deeper investigations per product and per process and per factory are needed in order to calculate the resource as needed for a change. For the cases where substitutions are technically not feasible and unavailability of drugs (more severe than temporary drug shortages) is expected, a derogation for these cases is requested in order to ensure patient health and safety. The highest impact of PFAS restriction for the health world and patients is the likelihood of generating additional drug product unavailability due to product temporary or definitive disruption. P a g e | 37