Document jMRjZ326wewx4x51Rkj9wBpQ

== AKT 8358484 == [ VB: Possible meeting in Stockholm - PFAS V1 ] == Dokument 5 == [... == Socio-Economic Assessment for the use of PVDF in Biopharmaceutical Manufacturing Final Report prepared for V1 23 August 2023 Socio-Economic Assessment for the use of PVDF in Biopharmaceutical Manufacturing August 2023 Final Report Date of issue P1 23 August 2023 Disclaimer The views and propositions expressed herein are, unless otherwise stated, those of Risk & Policy Analysts and do not necessarily represent any official view of V2 , Ltd or any other organisation mentioned in this report. Recommended citation: RPA (2023): Socio-Economic Assessment for the use of PVDF in Biopharmaceutical Manufacturing, report for V1 , August 2023, Norwich, Norfolk, UK Executive Summary F1 V1 The filters are F2 and used throughout the EU in the manufacturing process of biopharmaceuticals, an important class of medicines derived from biological sources of human or animal origin. These filters contain a fully enclosed, engineered membrane made from the PFAS1 material polyvinylidene fluoride (PVDF). The PVDF polymer is inert and meets the OECD criteria to be considered a Polymer of Low Concern. Based on its characteristics it is unlikely to have any intrinsic toxicological hazards (not related to particle size). The available information indicates that the only property of concern is persistence. Biopharmaceuticals Biopharmaceuticals represent a significant part of the pharmaceutical market and include important therapeutic proteins such as immunoglobulin/monoclonal antibodies, which are used to treat a number of prevalent, serious diseases for example primary immunodeficiency (PID) syndromes and haemophilia. Immunoglobulin therapies for PID and Kawasaki diseases are on the WHO List of Essential Medicines. 2 , 3 Monoclonal antibodies are used in targeted cancer therapies. Biopharmaceuticals are expected to increase in importance as trends in demographics imply that for example cancer, predominantly a disease of old age, will increase in prevalence. Additionally, with ongoing research and development it is expected that a proportion of the biopharmaceutical products currently at the clinical trials stage will achieve marketing authorisation (licencing/approval), and new types of biopharmaceuticals will be developed. It is expected that biopharmaceuticals contribute to meeting the intentions of Europe's Beating Cancer Plan.4 F3 manufacturing process used for safety and quality assurance of biopharmaceutical Undesirable viruses may be present in the source cells used to manufacture biopharmaceuticals or may be unintentionally introduced into the process as contaminants. Such viruses can have serious clinical consequences and must be removed from the process. The F4 filters are one technology that is used for virus removal, and as such are integral to the safety and quality assurance of the biopharmaceuticals that are manufactured. F5 F4 F6 filters are used for clarification/purification to separate the biopharmaceutical product of interest from cell debris and other impurities. As such they are integral to the quality assurance of the 1 Per- and polyfluoroalkyl substance. 2 WHO 22nd model list of essential medicines (2021), https://www.who.int/publications/i/item/WHO-MHP- HPS-EML-2021.02. 3 WHO 8th model list of essential medicines for children (2021), https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.03. 4 https://commission.europa.eu/strategy-and-policy/priorities-2019-2024/promoting-our-european-way- life/european-health-union/cancer-plan-europe_en ; https://www.ipaac.eu/news-detail/en/53-europe-s- beating-cancer-plan-a-new-eu-approach-to-prevention-treatment-and-care/ F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | i biopharmaceuticals that are manufactured. At present these filters are in the market entry/market development stage and are being trialled by some EU drug manufacturers. PFAS restriction puts the use of F4 and F6 at risk In January 2023, competent authorities from five EU Member States5 submitted a REACH Annex XV restriction proposal to the European Chemicals Agency (ECHA) proposing to restrict or ban the manufacture, use, and placing on the market of all PFAS within the EU, unless a use-specific, time- limited derogation of either 5 or 12 years6 is granted, although no derogation was recommended for this specific use (PVDF for virus removal filtration). This restriction proposal puts the use of F4 and F6 filters at risk. F56 assesses the impact of a ban on suppliers, manufacturers and patients Risk & Policy Analysts Ltd (RPA)7 have been contracted by V3 to carry out a socio-economic analysis ( F56 ) to assesses the expected impact of the proposed restriction and the potential ban of F4 and F6 filters. The F56 also assesses the expected consequential impact on the ability of EU drug manufacturers that rely on these filters to produce the important biopharmaceuticals that use them (or are expected to use them for biopharmaceuticals currently in development at clinical trials stage), and the consequential impact on the health and wellbeing of current and future patients in the EU. The F56 quantitatively compares a continued use (baseline) scenario against a non-use scenario (NUS). The continued use scenario assumes that F4 and F6 filters containing PVDF can continue to be placed on the EU market and used in the filtration stages of biopharmaceutical manufacturing processes. The NUS assumes a ban on the use of F4 and F6 filters in the EU for use in biopharmaceutical manufacturing. The F56 comprises an Analysis of Alternatives (AoA), which assesses the technical and economic feasibility, availability, and suitability of potential alternatives to PVDF used in F4 and F6 . Alternative substances to PVDF as a membrane used in filtration, and alternative technologies other than filtration have been assessed. The AoA can be considered as a determinant of the extent to which the impacts identified in the NUS will be felt. Alternatives may provide lower performance There are two main approaches for ensuring virus levels in biopharmaceutical products are sufficiently low to meet the required industry standards, these are virus removal, and virus inactivation. Virus removal technologies physically separate the virus from the biopharmaceutical product and include filtration methods by size exclusion - this includes both PVDF-based filtration ( F4 ) as well as non- PFAS based filtration using materials such as non-PFAS polymeric materials, or engineered cellulose. Other virus removal methods are chromatography, and precipitation. Virus inactivation technologies reduce virus infectivity by chemical or physical modification and include heat treatment, use of solvents or detergents, acid/alkali treatment, and irradiation. Each of these technologies have advantages and disadvantages and their relative effectiveness and performance depends on the type of virus, the type of cell, and other operating parameters. All these virus removal and virus inactivation technologies are currently used in biopharmaceutical manufacturing processes. 5 The Netherlands, Germany, Norway, Denmark, and Sweden. 6 Plus an 18 month transition period beyond the date of entry into force of the restriction. 7 https://rpaltd.co.uk/. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | ii Several metrics are used to assess the performance of virus removal and virus inactivation technologies. The most important metric is viral clearance, which is a measure of the extent to which a virus has been removed from the feed stream during the virus removal stage of biopharmaceutical manufacture. Other parameters are also important, such as protein throughput. Performance metrics must be considered collectively, rather than in isolation, to assess the relative performance of virus removal technologies. Drug manufacturers need to demonstrate adequate virus removal performance in their manufacturing process. EMA guidance recommends the use of orthogonal technologies for virus removal; to use at least two independent virus removal technologies that use different modes of action. Any switch to an alternative to F4 must retain this orthogonality requirement. In practice this may mean that F4 would need to be replaced by another virus filtration technology, rather than another virus removal or virus inactivation technology. Profits are generated in the EU from the use of F4 and F6 filters V3 V3 F7 F4 F4 F6 F6 The non-use scenario places this revenue and profit at risk, as a restriction would mean a ban on the placing on the market of F4 and F6 filters in the EU from 2026. The study team assessed these losses over an assessment period between the years 2026 to 2030. F8 F4 F6 It may be possible for V3 to offset some of these expected losses by converting some or all their F4 and F6 customers to alternative, non-PFAS F9 virus removal filters sold by V3 , but the ability to do this is uncertain and even if technically possible will require the switching costs discussed below. Switching to alternatives will take time and be costly to implement Limited data from V3 's customers (i.e. biopharmaceutical manufacturers) was obtained in the consultation, and these data consequently represent only a small fraction of the F4 market. It has therefore not been possible to prepare a robust estimate of the potential impacts on V3 's customers of a ban on the use of F4 . F10 F4 F4 This assumes that it would not be possible for biopharmaceutical manufacturers to switch to alternative virus removal technologies while maintaining orthogonality. It is expected that many customers would be able to make this switch, however the switching process will require revalidation and the completion of a new viral reduction study to assure acceptable virus removal. F11 F4 , the cost of them switching to an alternative virus removal technology would be in the range of F12 over three to five years. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | iii Development of a new PFAS-free filtration product is expected to take 10 years, including viral clearance study, the entire process can take a total of 15 years. Potential supply interruption for important biopharmaceuticals with impacts on patients Given the limited data from V3 's customers, estimates on the impacts of the NUS on the final users of the biopharmaceuticals been difficult to calculate precisely. Clearly the risk is due to potentially interrupting the manufacturing process for biopharmaceuticals on which many patients suffering from serious diseases relies. Such patients include those undergoing treatments for cancer, immunodeficiency diseases, or cardiovascular diseases. While it is theoretically possible that the NUS would mean that biopharmaceuticals currently manufactured using F4 and F6 would no longer be able to be produced, with severe consequences for patients, it is thought the more likely scenario would be the requirement for a transition period as drug manufacturers switch their virus removal technology to an alternative and complete the necessary revalidations and viral reduction studies. If this cannot be completed within the proposed 18-month transition period beyond the Entry into Force of the restriction, there is a risk of interruption of supply of important biopharmaceuticals. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | iv Glossary Terms in bold are cross-referenced in the glossary. API Adventitious virus AEX Antibody AoA Batch operation Biopharmaceutical Bioreactor Capture step Cell cultivation Cell harvesting CEX Clarification Coagulation factor Active Pharmaceutical Ingredient. Undesirable contaminant viruses that are unintentionally introduced into a biopharmaceutical manufacturing process. Such viruses could have serious clinical consequences and must be removed from the process. Anion exchange, used as a separation/purification step in the biopharmaceutical manufacturing process. A type of protein that is produced by the body's immune system in response to the presence of harmful substances, called antigens. Antibodies are an important group of products which are produced in the commercial biopharmaceutical production process. Also known as immunoglobulins. Analysis of Alternatives. A mode of manufacturing where pre-determined amounts of products are produced in a pre-determined amount of time. See perfusion. An important class of drugs manufactured or extracted from biological sources of human or animal origin. Biopharmaceuticals treat, prevent, or alleviate the symptoms of a disease. Virus removal is an essential part of the biopharmaceutical manufacturing process. Reaction vessel in the biopharmaceutical production process that provides a supportive environment for cell growth. An example of a process that occurs in the bioreactor is the inoculation of cells generated in the seed train to produce antibodies of interest. Recovery of the biopharmaceutical product of interest after the cell harvesting step. Process to grow and maintain cells of interest that are subsequently used to produce the target biopharmaceutical. Cell cultivation happens in the seed train and the bioreactor. First separation/purification process after the bioreactor cell cultivation step. The biopharmaceutical product of interest is separated from cells and cell debris. Cation exchange, used as a separation/purification step in the biopharmaceutical manufacturing process. Removal/separation of cells or cell debris from the biopharmaceutical of interest. A class of proteins that cause the blood to clot. Coagulation factor disorders include haemophilia. Recombinant protein biopharmaceutical products include coagulation factors used to treat such disorders. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | vii Depth filtration ECHA Endogenous virus Enveloped virus Flexural strength Flux GMP/cGMP Heat distortion temperature Immunoglobulin Inoculation LRV Master cell bank Microfiltration F6 Filtration in which the primary flow of the feed stream is at 90 to the plane of the filter membrane. A matrix of fibrous or granular material retains particles within it. Typically used for removal of larger impurities and used as a primary clarification step. See tangential flow filtration. European Chemicals Agency. An undesirable virus which is present in the source cells used for biopharmaceutical manufacture. Such viruses could have serious clinical consequences and must be removed from the process. See adventitious virus. A virus with an outermost layer ("envelope"), such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. Not all viruses are enveloped (see "non- enveloped virus"). Enveloped viruses can be less challenging to remove from biopharmaceuticals than non-enveloped viruses. The ability of a material to resist deformation under stress. Relevant to the performance of filtration membranes. A metric used in filtration operation, calculated as litre per m2 per hour (L/m2/hr), or LMH. (Current) Good Manufacturing Practice. The temperature at which a material deforms under load. A performance metric for filters used in biopharmaceutical manufacturing where high temperature may be used as a sterilisation method - the filter should not be adversely affected by the high temperature. An important group of plasma-derived medicinal products. Immunoglobulins (Ig) include polyclonal/polyvalent immunoglobulin (IgG), and hyperimmune immunoglobulin (H-IgG). They are used for treating e.g. primary immunodeficiency syndromes and are on the World Health Organisation List of Essential Medicines. Also known as antibodies. A process carried out in the bioreactor stage of the biopharmaceutical manufacturing process. Inoculation of the cells in the bioreactor stimulates the production of antibodies of interest. Logarithmic reduction value. A measure used to express the proficiency of virus removal, by comparing the viral loading in the feed stream with the viral loading of the filtrate (permeate). LRV=4 means the permeate has 10,000 times less virus than the feed stream. A pool of cells of human or animal origin prepared under defined conditions and used as the feedstock for biopharmaceutical manufacture. Filtration method primarily based on size exclusion with pores sizes from 0.1 to 10 micrometres (m). Typically used for removal of larger particles (e.g., cells, cell debris, aggregates). V3 F16 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | viii Monoclonal antibody Nanofiltration Non-enveloped virus NUS OECD Oligomer Pathogen Perfusion Permeate PFAS F9 F4 An antibody produced from a single type of cell (monoclonal) such that all antibodies trace back to an original parent cell. Monoclonal antibodies are an important type of biopharmaceutical used in, for example, targeted cancer therapy. Filtration method primarily based on size exclusion at the nanometre scale (10-9 meters), although commercial nanofilters have nominal pore sizes of tens of nanometres. In the biopharmaceutical industry, this is also referred to as "virus filtration" or "virus removal filtration". Viruses which are more resistant to extreme pH, heat, dryness, simple disinfectants, and detergents. Examples include norovirus, enterovirus, adenovirus, rhinovirus, Hepatitis A, and parvovirus B19 (B19V). These viruses are more challenging to remove in the biopharmaceutical manufacturing process. Non-use scenario. In the F56 , a description of the expected consequences of a ban of PVDF, and consequently, a ban on the use of F3 in biopharmaceutical manufacturing processes. Organisation for Economic Cooperation and Development A molecule consisting of a few repeating units. An organism that can cause a disease. Refers to a biopharmaceutical production process where the culture step is operated in continuous mode (in contrast to batch mode). The term "perfusion" only relates to the culture step. For other parts of the process e.g. filtration, the term "continuous" is used. Solution that is recovered from a filtration process. The feed stream contains particles that are captured on the filter, and the resulting permeate stream contains a significantly lower (or zero) concentration of the particles. Per- and polyfluoroalkyl substance, defined by the OECD as a fluorinated substance that contains at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it). The definition of PFAS in the restriction dossier is aligned with the OECD definition. F17 V3 Plasma Plasma-derived medicinal product Protein A component of blood, which is sourced from either whole blood donation by separating from blood cells, or by direct plasma donation through a process called plasmapheresis. Plasma is used for a range of important plasma-derived medicinal products. A biopharmaceutical product manufactured from plasma. An example is immunoglobulin. An important class of biomolecule responsible for an extensive range of functions in living organisms. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | ix Protein concentration Protein throughput/ protein throughput rate PVDF A metric used in biopharmaceutical manufacture. There is a trend towards higher protein concentrations which places higher demands on clarification and virus removal processes. Protein throughput is one of the metrics used to assess performance of virus removal filters. It is calculated as the mass of protein product in the filtrate (kg) divided by the filter area (m2) and expressed in units of kg/m2. Protein throughput rate is protein throughput per unit time, kg/m2/hr. F18 F3 REACH Recombinant protein F56 Seed train SIP Small molecule TFF Tensile strength Therapeutic protein Totally synthesised Viral clearance Virus Virus filtration / virus removal Registration, evaluation, authorisation and restriction of chemicals. EU Regulation. Proteins formed using laboratory methods of combining genetic material from one or more sources. Important examples of recombinant protein biopharmaceuticals include coagulation factors. Socio-economic analysis. The purpose of a seed train is to generate an adequate number of cells for the inoculation of a production bioreactor. Steam-in-Place. A sterilisation method to inactivate viruses. A pharmaceutical that is not derived from living organisms but instead is fully synthesised, typically through multiple steps, from simpler precursors. Also known as totally synthesised. Tangential flow filtration (also known as cross flow filtration). The primary flow of the feed stream is parallel to the plane of the filter membrane. The maximum stress a material can withstand before breaking. Affects the maximum pressure that a filter can withstand, which is a performance metric for filters used in biopharmaceutical manufacturing. A broad class of biopharmaceutical products, including for example monoclonal antibodies. A pharmaceutical that is not derived from living organisms but instead is fully synthesised, typically through multiple steps, from simpler precursors. Also known as small molecule. A measure of the extent to which a virus has been removed from the feed stream during the virus removal stage of biopharmaceutical manufacture. Typically measured as LRV, logarithmic reduction value. An infectious microbe that cannot replicate by itself; instead it needs to infect a cell and use the cell's existing mechanisms to replicate. A virus may be pathogenic or non-pathogenic. The removal of viruses from biopharmaceutical products using nanometre-scale size exclusion. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | x Virus inactivation Yield strength The reduction of virus infectivity caused by chemical or physical modification. The point at which a material begins to deform. Affects the maximum pressure that a filter can withstand, which is a performance metric for filters used in biopharmaceutical manufacturing. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | xi 1 Introduction 1.1 Background and motivation V1 (hereafter referred to as V3 ) manufacture a range of filtration products which are used throughout the EU/EEA as key components in the biopharmaceutical manufacturing process. Biopharmaceuticals are an important class of medicines, used for example in cancer therapies and treatments for immunodeficiency syndromes, which are derived from biological sources of human or animal origin. Two of V3 's products, F3 8, are used for purification and virus removal in the biopharmaceutical manufacturing process, and as such are integral to the safety and quality assurance of these medicines. F4 and F6 filters contain a fully enclosed, engineered membrane made from the PFAS9 material polyvinylidene fluoride (PVDF), which is within the scope of the proposed PFAS Restriction (see Section 1.2). This restriction proposal puts the use of F4 and F6 filters at risk. Risk & Policy Analysts Ltd (RPA)10 have been contracted by V3 to assesses the expected impact of the proposed restriction and the potential ban of F4 and F6 filters in the EU. Impacts on V3 , its downstream customers, and patients that benefit from the biopharmaceuticals manufactured using the filters, are considered. The objective of this study is to develop a socio-economic analysis ( F56 ) for the continued use of F4 and F6 filtration products and compare with a "non-use scenario" (NUS) which assumes a ban on PVDF, and consequently a ban on F4 and F6 products in the EU from 2025. 1.2 PFAS Restriction In January 2023, five European countries (Germany, The Netherlands, Sweden, Norway, and Denmark) submitted a REACH restriction proposal to the European Chemicals Agency (ECHA) proposing that all per- and polyfluoroalkyl substances (PFAS) be restricted within the EU unless a derogation is granted. PFAS substances are defined in the restriction proposal and by the OECD as "any substance that contain at least one fully fluorinated methyl or methylene carbon atom (without any H/Cl/Br/I atom attached to it)".11 The definition includes many long chain fluoropolymers which typically are less hazardous than shorter chain compounds. PFAS substances are widely used throughout society due their useful physical and chemical properties. Because of the very strong carbon fluorine bond, PFAS have high resistance to UV, temperature, corrosive chemicals, oils, and biological degradation making them durable in a range of extreme environments. This durability results in exceptionally long lifetimes and has led to PFAS being considered as very persistent. The restriction proposal highlights the need to address the inherent persistence of PFAS, as some PFAS are biologically available and bioaccumulative and lead to a progressive increase in human/organism exposure "until such levels are reached where effects become inevitable."12 8 Hereafter referred to as F4 and F6 respectively. 9 Per- and polyfluoroalkyl substance. 10 https://rpaltd.co.uk/. 11 OECD (n.d.), About PFASs. Information found here - https://www.oecd.org/chemicalsafety/portal- perfluorinated-chemicals/aboutpfass/ accessed July 2023. 12 https://echa.europa.eu/documents/10162/f605d4b5-7c17-7414-8823-b49b9fd43aea, Accessed: Feb 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 1 The restriction proposal highlights two potential restriction options (ROs) referred to as RO1 and RO2. RO1 outlines an approach in which all chemicals meeting the classification as PFAS would have their manufacture, use, and placing on the market restricted in the EU. This would occur following an 18-month transition period from the entry into force of the restriction. RO2 proposes the same scope of restriction but includes a selection of use-specific time- limited derogations. These would be in addition to the 18-month transition period and would be granted for either 5 or 12 years. After consideration, it has been agreed by the dossier submitters that the most appropriate RO to implement is RO2 as this allows for mitigation of unwanted societal effects due to the sudden removal of products from the EU market. Should companies wish to continue using PFAS substances it is therefore highly important that evidence relating to alternatives, emissions, and socio-economic impacts are shared as a part of the consultations relating to the PFAS restriction13. 1.3 Methodology The present study comprises an F56 , including an analysis of alternatives (AoA), and a high level emissions/exposure overview. RPA have gathered information on: The importance, functionality, and economics of PVDF filtration products in the biopharmaceutical manufacturing industry; Suitability of alternatives to the PVDF-based filtration products; and Responses of businesses and society to a restriction, to quantify impacts and compare to other regulatory measures. The F56 quantitatively compares a continued use (baseline) scenario against a non-use scenario (NUS). The continued use scenario assumes that F4 and F6 filters containing PVDF can continue to be placed on the EU market and used in the filtration stages of biopharmaceutical manufacturing processes. The NUS assumes a ban on PVDF and hence a ban on the use of F4 and F6 filters in the EU for use in biopharmaceutical manufacturing, with the ban coming into effect in 2025. Data to inform the study were gathered through desk research, and through consultation with V3 and their downstream customers. Desk research included analysis of scientific journal articles, regulatory agency guidance documents, marketing materials, company websites, and other relevant literature. Consultation with V3 and their customers was organised using targeted questionnaires (separate questionnaires for F4 and F6 ) and follow-up interviews. Consultation with V3 's customers was carried out independently of V3 to encourage quantity and number of responses, under the assurance that customer responses would be aggregated and anonymised. Responses to RPA from V3 's customers were not made available to V3 . This was facilitated by hosting the questionnaires on the EU Survey platform14. Statistics for the consultation are shown in Table 1-1. 13 The first consultation will be in relation to the proposed restriction set out in the submitted Annex XV dossier. This consultation opened on 22 March 2023 and will remain open for six months, until 25 September 2023. ECHA also advise that `more substantial comments should be submitted at the latest 1 month before the final deadline' (i.e. around 25 August). 14 https://ec.europa.eu/eusurvey/home/welcome. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 2 Table 1-1: Downstream user consultation statistics Metric Number of companies F19 As input from only a small proportion of F4 and F6 users was obtained, calculation of the expected downstream impacts of the NUS has been carried out using a semi-quantitative approach. The impact on the AoA is discussed in Section 5.2.3 and Section 5.3.2. Further details on the methodology used in the F56 and AoA can be seen in Sections 5.1, 6.1, and 7.1. 1.4 Structure of this report In addition to the Executive Summary and Section 1, the remainder of the report is structured according to the following: Section 2 Substances and Products in Scope of the Study: describes the structure, properties, and regulatory context of PVDF, its use in F4 and F6 , the biopharmaceutical manufacturing process, and the role of F4 and F6 ; Section 3 Value Chain of F9 F4 and F20 Products: describes the processing activities and value chain of F9 F4 and F6 in the biopharmaceutical industry; Section 4 The Pharmaceutical Market: discusses the importance of drugs and the role F9 F4 and F20 play; Section 5 Analysis of Alternatives: alternative materials to PVDF containing F4 and F6 filters are examined in their ability to replace PFAS in the use cases within scope of this study; Section 6 Continued Use Scenario: assesses the socio-economic landscape within V3 and its downstream users under a business-as-usual scenario; Section 7: Non-use Scenario: assesses the socio-economic landscape within V3 and its downstream users should a PFAS restriction prohibit the use of F4 and F6 containing PVDF in the use cases within the scope of this study; and Section 8 Conclusions: information gathered in this study is collated and a final commentary is made on the availability of alternatives and the overall effects of a PFAS ban versus the continued use scenario. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 3 2 Substances and Products in Scope of the Study 2.1 Fluoropolymers The polymer within the scope of this study is polyvinylidene fluoride (PVDF), a fluoropolymer that falls within the OECD definition11 of PFAS. Polymers are currently not subject to registration under REACH. As such, a full picture of the production volumes of these substances in the EU is not complete. Fluoropolymers are considered as a lower toxicological concern than non-polymeric substances due to their very high molecular weights. This makes transport across biological membranes, such as the skin or gut-lining, unlikely (see Section 2.2). Additionally, fluoropolymers comprise less than one percent of global polymer production15. The presence of very stable carbon-fluorine bonds provides fluoropolymers with outstanding chemical properties, making them a high-performance group of substances. Fluoropolymers have a set of properties that when considered in combination make them unique, these include durability, stability, mechanical strength in harsh conditions, as well as chemical inertness, permeation resistance, non- wetting, non-stick and high resistance to temperature, fire, and weather 16 . Consequently, fluoropolymers are used in many sectors17 and are often not easily replaceable with other substances or technologies. 2.1.1 Polyvinylidene fluoride (PVDF) Polyvinylidene fluoride (Figure 2-1), CAS 24937-79-9, EC 607-458-6, is a non-reactive thermoplastic fluoropolymer. PVDF is synthesised from the monomer vinylidene fluoride (VDF) (CAS 75-38-7, EC 200-867-7). VDF, also known as 1,1-difluoroethylene, is a flammable gas, is slightly soluble in water and soluble in alcohol and ether. Figure 2-1: Structure of polyvinylidene fluoride (PVDF) PVDF has physico-chemical properties that make it suitable for use in applications requiring resistance to solvents, strong and weak acids, weak bases, ionic and salt solutions, halogenated compounds, hydrocarbons, aromatic solvents, aliphatic solvents, oxidants, resistance to high temperature and 15 Based on 2.44 million tonnes of fluoropolymers produced in 2020 https://www.chemanalyst.com/industry- report/fluoropolymer-market-315 and 367 million tons of polymers produced in 2020 https://plasticseurope.org/knowledge-hub/plastics-the-facts-2021/ . Accessed July 2023. 16 https://fluoropolymers.plasticseurope.org/application/files/5416/5104/8333/20211104_FP_RMOA_Final_ 3.pdf accessed July 2023. 17 Including automotive, aerospace, environmental control, energy production and storage, medical, pharmaceutical, chemicals production, and electronics. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 4 pressure, and UV. It also has mechanical stability and is suitable for use in high purity environments. PVDF demonstrates compatibility in relation to other thermoplastic materials. The properties of PVDF that make it especially suitable for use in F4 and F6 filters is shown in Table 2-1. These physico-chemical properties are directly linked to the functionality and performance of the F4 and F6 filters, such as being able to operate at high pressure. This will be discussed further in Sections 2.3.1, 5.2.1 and 5.3.1. Table 2-1: Properties of PVDF and link to performance of F4 and F6 Property Value Link to F4 and F6 performance CAS No. 24937-79-9 - EC No. 607-458-6 - Density 1780 kg/m3 - Heat Distortion Temperature Service Temperature 145C Up to 150C Ability to withstand sterilization using heat Tensile strength (23C) 35 - 50 MPa Ability to operate at high pressure Flexural strength (23C) 11165 MPa Yield strength (23C) 53 - 57 MPa Source documents: https://www.fluorotherm.com/technical-information/materials-overview/pvdf- properties/ accessed July 2023 2.2 Hazard properties of PVDF 2.2.1 Introduction PVDF is inert and based on its characteristics is unlikely to have any intrinsic toxicological hazards (not related to particle size). It meets the criteria to be considered a polymer of low concern. The available information indicates that the only property of concern is persistence. This section outlines the hazards introduced into the EU by the PVDF that is used in F4 and F6 filter products. The primary concern of PFAS substances as stated in the restriction dossier is their persistence. This persistence is due to the very stable C-F bond18 which also gives PFAS many of their desirable properties. F4 F6 F21 The PVDF remains enclosed in the housing throughout the filters' use in the drug manufacturing process and through delivery to the end-of-life incineration process. Fluoropolymers are PFAS that are high molecular weight polymers and can be assessed according to criteria described by Henry et al (2018) to determine their hazard level19. Due to their high molecular weight, they are considered too large (>1,000-10,000 Dalton) to cross biological membranes and therefore to exhibit hazardous properties. Molecular weight is the most commonly used criteria when 18 The C-F bond has an average bond energy of 453kJ/mol; the carbon fluorine bond is the strongest single bond in organic chemistry. 19 Henry, B. J., Carlin, J. P., Hammerschmidt, J. A., Buck, R. C., Buxton, L. W., Fiedler, H., Seed, J., & Hernandez, O. (2018). A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers. Integrated Environmental Assessment and Management, 14(3), 316-334. https://doi.org/10.1002/IEAM.4035 accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 5 assessing polymers19. Polymers that present the highest potential health concerns have a number average molecular weight (Mn) of less than 1,000 Dalton and an oligomer20 content greater than one percent19. Monomers, oligomers, and degradation products from the polymerisation process are smaller and may therefore potentially cross biological membranes and therefore have the potential to be hazardous. It is important that any residual oligomer and monomer content is considered to assess the leachability of the polymer. V3 F22 The presence of Reactive Functional Groups (RFGs) can be associated with adverse human health effects and ecotoxicology19. The Functional Group Equivalent Weight (FGEW) determines if the RFGs are diluted by polymeric material and is used as an indication of how reactive the polymer is19. The polymeric charge is important to consider because charge can influence a polymer's properties and how it behaves. For example, cationic polymers have been associated with aquatic toxicity19. In summary, according to Henry et al. (2018)19 and the OECD21, the properties affecting a polymer assessment include the following: Molecular Weight (MW): A polymer with a low molecular weight could indicate a potential for health and ecotoxicological concerns; Polymer composition: This relates to the residual presence of monomers, oligomers and processing aids used during polymerisation. These will have lower molecular weights potentially making them more hazardous; Polymer charge: Charge can influence a polymer's properties and how it behaves, including its physical properties, fate, ecotoxicity, and human toxicity; Structural features: This includes the polymer's RFGs and particle size; and Solubility and stability: Low solubility of the polymer in water and n-octanol demonstrate the inability of fluoropolymers to cross cell membranes and bioaccumulate. Stability shows the durability of the polymer and likelihood of breaking down into smaller molecules. Each of these properties are assessed for PVDF in Section 2.2.3. The CARACAL (Competent Authorities for REACH and CLP) sub-group CASG-Polymers has been mandated by CARACAL to advise the Commission, amongst other issues, on which types of polymers will require further assessment (Polymers Requiring Registration, PRR) and potential risk management based on their characteristics22. In a recent CARACAL meeting23, the criteria to identify PRR were outlined. These criteria included if the polymer was fluorinated, cationic, contained certain RFGs, MW, polymers with severe hazard classes, active surface area, and degradation products suspected of concern. Whilst PVDF meets the previously used polymer of low concern criteria, under the new PRR criteria it would require registration because it is fluorinated. 20 A molecule consisting of a few repeating units. 21 Joint Meeting Of The Chemicals Committee And The Working Party On Chemicals, Pesticides And Biotechnology Data Analysis Of The Identification Of Correlations Between Polymer Characteristics And Potential For Health Or Ecotoxicological Concern JT03258707 Document complet disponible sur OLIS dans son format d'origine Complete document available on OLIS in its original format. (2009). https://www.oecd.org/env/ehs/risk-assessment/42081261.pdf accessed July 2023. 22 CARACAL CA/53/2021 Brussels 10/11/2021 42nd Meeting of Competent Authorities for REACH and CLP CARACAL). Open session 17-18 November 2021 Online. 23 CARACAL-48 (28-29 March 2023), AP4_1_REACH_Revision_overview_CARACAL-48_presentation - found here https://circabc.europa.eu/ui/group/a0b483a2-4c05-4058-addf-2a4de71b9a98/library/d950d2a7- 3d37-40c2-bce9-bc03c60a21ba/details. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 6 2.2.2 Classification and labelling PVDF does not have a harmonised classification and labelling according to Regulation (EC) No. 1272/2008 (CLP Regulation). ECHA report a total of 51 notifications of classification and labelling24, of which 37 indicate that insufficient information is available to classify, 13 indicate no classification and labelling and one reports skin and eye irritation category 2 (H315, causes skin irritation and H319, causes eye irritation, respectively), as well as STOT SE 3 (H335, Specific target organ toxicity single exposure) in relation to lung irritation. Given the inert nature of the polymer, it is possible that the irritation classifications relate to the release of hydrogen fluoride upon decomposition, or to exposure to the powder. Neither of the notified classifications report severe hazards (i.e. there is no notification as carcinogenic, mutagenic or reprotoxic, respiratory sensitisation or equivalent concern). 2.2.3 PVDF homopolymer characteristics Table 2-2 presents the characteristics of PVDF homopolymer. PVDF meets the criteria to be considered a polymer of low concern according to the OECD criteria. Substances with a molecular weight greater than 1,000 Da are not expected to be absorbed through the skin and from the gastrointestinal tract and are therefore not considered to be a hazard when ingested orally or through dermal exposure. PVDF has an average molecular weight of more than 1,000 Da (70,000-300,000 Da), and oligomer content that is considered negligible. These values indicate that PVDF does not present a potential hazardous concern25. The data in the study for the PVDF discussed in Table 2-2 concludes that Up to 50 ppb of the monomer are present in the PVDF, the ratio of residual monomer to Mw is negligible (10-12 to 10-13), there is no PFAS polymerisation aid is used in the process of making the polymer, and the polymer has no charge and does not have any reactive functional groups. These characteristics indicate that the polymer is of low toxicological concern25. The particle size of the powder form of PVDF used in the study is approximately 5m, which is at the limit for a polymer to be considered of low concern25. V3 F23 Thermal decomposition above 375C generates hydrogen fluoride. Therefore, thermal decomposition during use is not a risk for PVDF used in F4 and F6 . The other physico-chemical properties reported in Table 2-2 do not indicate that PVDF is potentially hazardous (i.e. no water or lipid solubility and no degradation). 24 See ECHA C&L inventory entry at https://echa.europa.eu/information-on-chemicals/cl-inventory-database/- /discli/details/132980, accessed July 2023. 25 Korzeniowski, S. H., Buck, R. C., Newkold, R. M., kassmi, A. el, Laganis, E., Matsuoka, Y., Dinelli, B., Beauchet, S., Adamsky, F., Weilandt, K., Soni, V. K., Kapoor, D., Gunasekar, P., Malvasi, M., Brinati, G., & Musio, S. (2023). A critical review of the application of polymer of low concern regulatory criteria to fluoropolymers II: Fluoroplastics and fluoroelastomers. In Integrated Environmental Assessment and Management (Vol. 19, Issue 2, pp. 326-354). John Wiley and Sons Inc. https://doi.org/10.1002/ieam.4646. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 7 Table 2-2: Polymers of low concern assessment for PVDF Criteria Value Molecular Weight Characteristics: Number average molecular weight (Mn) (Mn > 70,000-300,000 Da 1000 Da and oligomer content <1%) Molecular Weight Distribution (MWD) 2 - 3 Wt% oligomer (<5% for <1000 Da oligomers, <2% Negligible for <500 Da oligomers) Polymer composition: Residual monomer <50 ppb Ratio of residual monomers to MW ~10-12 to ~10-13 Polymer charge Neutral Reactive functional groups (RFGs) None Low molecular weight leachable No active leachable by USP class V1 (121C) Physico-chemical properties: Water solubility Insoluble at 20C Lipid solubility Insoluble Stability Inert polymer, not biodegradable and chemically stable Thermal stability and normal maximum operating 150C temperatures Particle size Powders: 5 to 300 m Pellets: 2 to 4 mm Source documents: Korzeniowski, S. H., Buck, R. C., Newkold, R. M., kassmi, A. el, Laganis, E., Matsuoka, Y., Dinelli, B., Beauchet, S., Adamsky, F., Weilandt, K., Soni, V. K., Kapoor, D., Gunasekar, P., Malvasi, M., Brinati, G., & Musio, S. (2023). A critical review of the application of polymer of low concern regulatory criteria to fluoropolymers II: Fluoroplastics and fluoroelastomers. In Integrated Environmental Assessment and Management (Vol. 19, Issue 2, pp. 326-354). John Wiley and Sons Inc. https://doi.org/10.1002/ieam.4646 2.2.4 Environmental properties There is no PVDF data on toxicity to aquatic, sediment or soil organisms available. The substance has a high molecular weight distribution (Table 2-2), therefore uptake from organisms is not expected. PVDF homopolymer is not soluble in water (Table 2-2), therefore aquatic toxicity studies are not considered to be relevant. Overall, there are not many data on the environmental properties, but toxicity appears to not be of concern, as well bioaccumulation, due to the inherent properties of the polymer. While persistence is an issue, that alone cannot be used to determine adverse effects or rationalize the need for risk management25. REACH combines persistency with other factors such as toxicity and bioaccumulation potential to determine risk management measures25. 2.2.5 PBT/vPvB assessment PVDF does not meet the PBT/vPvB criteria. REACH Annex III and XIII present the persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative (vPvB) criteria, and the information requirements that can be used in the PBT/vPvB assessment. P/vP - persistency: the half-life of PVDF has not been measured but is expected to be in the order of years, exceeding the vP criteria. Therefore P/vP criteria are met. B/vB - bioaccumulation: the data to establish the bioaccumulation potential of PVDF homopolymer have been predicted. The modelling confirms that PVDF with a molecular F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 8 weight between 70,000-300,000 is not expected to bioaccumulate (Log Kow >10, based on Figure R.11-4 of the ECHA Guidance R. 1126). T - toxicity: the substance is not classified as carcinogenic (category 1A or 1B), germ cell mutagenic (category 1A or 1B), or toxic for reproduction (category 1A, 1B or 2), nor is there other evidence of chronic toxicity, as identified by the substance meeting the criteria for classification: specific target organ toxicity after repeated exposure (STOT RE category 1 or 2). No long-term toxicity studies according to Table R.11-3 of ECHA Guidance R.11 (2017) are available. The long-term no-observed effect concentration (NOEC) or EC10 for marine or freshwater organisms needs to be less than 0.01 mg/l for a substance to be classed as T, but no data are available on long-term toxicity to aquatic organisms. While no data are available to conclude on T, based on the characteristics of the polymer (Table 2-2) and its lack of water solubility, it is likely that the substance is not T. Based on the available information, it is possible to conclude that PVDF homopolymer is P, not B and likely not T according to Annex XIII to the REACH Regulation. Similarly, it is possible to conclude that PVDF homopolymer is vP and not vB. Overall, PVDF does not meet the PBT/vPvB criteria. 2.2.6 Conclusions The polymer is inert and based on its characteristics it is unlikely to have any intrinsic toxicological hazards (not related to particle size). The available information indicates that the only property of concern is persistency. 2.3 Products manufactured by V3 biopharmaceutical manufacturing using PVDF used in V3 produce a range of products that are used in the biopharmaceutical manufacturing process. Products include virus removal filters, clarification and purification filters, chromatography equipment, testing and analysis equipment, and ancillary equipment such as filter assemblies and controllers27. The importance, role, and position of these products in the manufacturing process is discussed in the following sections. 2.3.1 Biopharmaceutical manufacturing process Biopharmaceuticals are an important class of drugs manufactured or extracted from biological sources of human or animal origin. The manufacturing process for biopharmaceuticals is complex and must follow strict safety and quality guidelines, for example those set out in the European Medicines Agency "Guideline on plasma-derived medicinal products"28 and "Guideline on virus safety evaluation of biotechnological investigational medicinal products".29 While the latter document discusses clinical trials (rather than full commercial production), the production process for clinical trials and full commercial production are (and must be) the same. Also, unlike other types of pharmaceutical product (known as "small molecule" or "fully synthesised" pharmaceuticals), the active agent of interest, derived from human or animal cells, is present from the start of the manufacturing process, 26 ECHA (2017) Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB assessment. Version 3.0. June 2017. European Chemicals Agency. 27 F24 28 EMA/CHMP/BWP/706271/2010, https://www.ema.europa.eu/en/plasma-derived-medicinal-products- scientific-guideline . 29 EMEA/CHMP/BWP/398498/2005, Virus safety evaluation of biotechnological investigational medicinal products - Scientific guideline | European Medicines Agency (europa.eu) . F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 9 and subsequent process steps are designed to clarify, purify and concentrate the agent of interest. Undesirable contaminant viruses (known as adventitious viruses) can be unintentionally introduced into a biopharmaceutical manufacturing process. Additionally, endogenous viruses may be present in the source cells used to manufacture the biopharmaceutical, and the risks from this may be higher when using animal-derived cells. Such viruses could have serious clinical consequences and must be removed from the process. The biopharmaceutical manufacturing process is illustrated in Figure 2-2 and Figure 2-3. These processes must be carried out under good manufacturing practice (GMP), which describes the minimum standard that a medicines manufacturer must meet in their production processes. The European Medicines Agency (EMA) coordinates inspections to verify compliance with these standards and plays a key role in harmonising GMP activities at EU level.30 F25 The seed train is a critical step in the process, it ensures the availability of a sufficient volume of cells in order to produce the volume of the desired therapeutic protein31. The main purpose of a seed train is to increase cell population from a small seed culture to a large working volume suitable for the bioreactor31. F26 The product of interest, typically a protein-based therapeutic active pharmaceutical ingredient, is separated from the particulate matter in the bioreactor: the cells and cell debris.32 The harvesting method of choice depends on the type of source cells, scale of manufacturing, and product properties. Typical unit operations include centrifugation, expanded bed chromatography, depth filtration, and tangential flow filtration (TFF).32 30 https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good- manufacturing-practice . 31 Hernndez Rodrguez, T., Prtner, R., & Frahm, B. (n.d.). Seed train optimization for suspension cell culture From 23rd European Society for Animal Cell Technology (ESACT) Meeting: Better Cells for Better Health. https://doi.org/10.1186/1753-6561-7-S6-P9. 32 Zhang et al, "Modelling tangential flow filtration using reverse asymmetric membranes for bioreactor harvesting". Biotechnol Progress. 2021;37:e3084 https://doi.org/10.1002/btpr.3084 . F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 10 In batch operation (see "Trends" section below), both centrifuge and depth filtration are used in the clarification step. For large volume production, both techniques are used together. For smaller volume production a depth filter alone is used. In perfusion mode centrifuges are not used as they are designed for short term filtration only (for example less than three hours). Perfusion filtration is carried out over days or weeks.33 Under controlled conditions the cells used are grown in the bioreactor. Once the target cell density and therapeutic protein is reached it will be harvested. Harvesting involves many steps, such as clarification, centrifugation, filtration and chromatography (affinity, ion exchange and size exclusion) to separate the cell and remove viruses and impurities. The harvesting and purification steps (seen in the above Figures) are described in Table 2-3. 33 V3 consultation. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 11 Table 2-3: Main process steps in biopharmaceutical drug manufacturing shown in Figure 2-2 and Figure 2-3 Step Technique Materials present at that Importance/Role step Culture Seed Host cell and cell-derived Growth and maintenance of source cells train/bioreactor materials, active from which the biopharmaceutical of pharmaceutical interest is derived. ingredient (API), impurities (aggregated or inactivated API) and media components (sugar, vitamins, amino acid, proteins Clarification Centrifugation API, media components, Separation of protein of interest from impurities cells and cell debris. Clarification Depth (DF) or Separation of protein of interest from microfiltration cells and cell debris. (MF) Polishing Protein A API, impurities Affinity chromatography (contrasted with chromatography ion exchange chromatography) - binds only the target protein of interest, to separate it from impurities. Polishing Cation exchange API, impurities Primary role: removal of impurities. (CEX) Secondary role: removal of some viruses. Polishing Anion exchange (AEX) API, impurities Unlike the virus removal step, ion exchange is less robust for virus removal. Virus Low pH treatment API, impurities Reduction of virus infectivity inactivation (ph4) Heat treatment Solvent/detergent Irradiation Virus removal Filtration API, Ionic salts used for Virus removal CEX or AEX Concentration Filtration API Increase concentration of dilute protein (target drug). Benefits include the smaller volume needed to inject into the patient (taking less time) and allows injection into muscle instead of vein (less painful). Source: V3 consultation July 2023 Trends - higher concentration, and perfusion production Due to process and technology improvements, there is a trend towards higher protein concentration solutions (ca. 30mg/mL). Higher concentration has been achieved from the beginning of the process, with each subsequent process step being improved so the concentration is higher in all process steps. Higher concentration provides several benefits including a smaller volume needed to inject into the patient (taking less time and a shorter duration stay in hospital) and allows injection into muscle instead of vein (less painful). Some performance metrics of certain types of virus removal filtration membrane F27 are reduced when used with high concentration solutions (see Section 5.2.2). There is also a nascent move towards continuous instead of batch production, initially with a focus on the seed train and bioreactor. Biopharmaceuticals are typically manufactured in a batch process, F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 12 although there is a small but growing trend towards continuous operation of the culture step (also known as "perfusion") manufacturing. Perfusion is one aspect of process intensification. The main difference between batch and perfusion is that for a perfusion process the cell cultures are constantly being monitored, changed out and given growth media to maintain optimum conditions over an extended period resulting in maximum cell growth to generate the required antibodies. When compared to a batch process the constituents are not changed out during the batch run. There are advantages and disadvantages to both processes, but this depends on the intended outcome. For example, the batch process is more cost effective for manufacturing smaller volumes of active pharmaceutical ingredients. In general, conditions of growing and maintaining the cells in the perfusion process are much better because there is less variation and less disruption to the cells and therefore it is possible to reduce the volume. In continuous/perfusion process you continuously monitor, check and adjust process parameters to maintain optimal conditions. This approach requires a lot of process control with resulting cost. Continuous process is carried out over e.g., one month, batch process is carried out over e.g. one week. The batch process is less cost effective in the long run than the continuous process, but this depends on the volume. Role of filters in the manufacturing process Filtration plays an extremely important role in the manufacturing process. As previously demonstrated in the above figures, there are various methods of separation in the process, filtration being one of these methods. Filtration methods are used at the beginning and end of the process (clarification and virus removal). It is important to note that there are different modes of filtration that is dependent on the specific requirements of the manufacturing process. Typically, a combination of different filtration modes will be used in a sequential manner to achieve the desired purification product. Terms used in filtration, and filtration methods, are summarised below: Depth filtration (DF):34 Depth filters are made from a matrix of fibrous or granular material, with no specific pore size that retains particles within it. Typically used for removal of larger impurities and used as a primary clarification step. Mechanism is size exclusion and adsorption. Used for batch operation only. Membrane filtration:34 Membranes have very specifically engineered pore size and structure. Tangential flow filtration (TFF): Also known as cross flow filtration, a continuous mode of filtration uses a recirculating flow of the process stream across a filter membrane. Typically used for concentration, diafiltration and buffer exchange of products. Dead-end filtration: also known as direct filtration, the product flows perpendicular into the filter. The filtered material typically builds on the filter surface, clogging the membrane. Microfiltration (MF): uses filters with pores sizes from 0.1 to 10 micrometres (m). Typically used for removal of larger particles (e.g., cells, cell debris, aggregates) by size exclusion. Typically used for perfusion, but also used for batch although is less cost effective in batch mode. Nanofiltration (NF): uses filters with pore sizes from 1 to 100 nm. Typically used to selectively separate molecules based on their size and charge (e.g., remove viruses while allowing the passage of desired components). Microfiltration can be used to remove cells, debris and large particles. Tangential flow filtration (TFF) is used to separate and concentrate the target protein based on molecular weight or size. The removal 34 V3 consultation. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 13 of cell debris and aggregates can affect the quality and safety of the end product. Most importantly, nanofiltration methods (used in dead end mode) are critical for viral clearance to ensure product safety and protect end users from virus contamination. A schematic of tangential (cross flow) filtration is shown in Figure 2-4. F28 EMEA guidance recommends the use of orthogonal technologies for virus removal; to use at least two independent virus removal technologies that use different modes of action29,35. While the guidance document discusses clinical trials (rather than full commercial production), the production process for clinical trials and full commercial production is (and must be) the same. Also, while the guidance "recommends" using orthogonal technologies, consultation with V3 confirmed that in the pharmaceutical industry this "recommendation" is considered as a requirement. The virus removal method must be validated by real-life data to ensure it is robust and effective. Viral clearance validation studies are carried out to achieve this. One database36 was assessed in 2021 to determine if clearance methods continue to remain robust and effective. Within this study it was stated that an effective virus removal efficiency is 4 log1036. This figure was also validated within a document by the Committee for Proprietary Medicinal Products (CPMP) discussing the guidance on virus validation studies37. The most robust and effective virus removal methods are viral reduction filtration, low pH inactivation and AEX Fourier Transform chromatography. Virus removal filters should have the following properties to deliver the functionality required, this can be seen in Table 2-4. 35 Chmp/Bwp (Committee Abbreviation) Guideline On Virus Safety Evaluation Of Biotechnological Investigational Medicinal Products Draft Agreed By Bwp Adoption By Chmpfor Release For Consultation Guideline On Virus Safety Evaluation Of Biotechnological Investigational Medicinal Products. (2006). http://www.emea.eu.int. 36 Ajayi, O. O., Johnson, S. A., Faison, T., Azer, N., Cullinan, J. L., Dement-Brown, J., & Lute, S. C. (2022). An updated analysis of viral clearance unit operations for biotechnology manufacturing. Current Research in Biotechnology, 4, 190-202. https://doi.org/10.1016/j.crbiot.2022.03.002. 37 Revised. (1995). Transmission To The Cpmp 11-13 July 1995 Transmission To Interested Parties 12 July 1995 Deadline For Comments 1 November 1995 Re-Submission To The Biotechnology Working Party 5-6. http://www.eudra.org/emea.htmlLondon,14February,1996CPMP/BWP/268/95. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 14 F29 The properties in the above table are critical to the functioning and effectiveness of filtration techniques for virus removal. Any new virus removal methods would need to be validated to ensure product safety is maintained. A more in-depth illustration of the manufacturing process, including upstream and downstream process steps, is illustrated in Figure 2-5. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 15 2.3.2 F9 F4 for virus removal F9 F4 is a type of filter trademarked by V3 and used for virus removal in the biopharmaceutical drug manufacturing process. F31 38. The virus removal membrane in the filter is made of PVDF which offers mechanical stability and homogeneity enabling high protein yield ( 6.0 kg/m2/3hr) and viral clearance of LRV 4.39 The PVDF used in these filters is made by thermally induced phase separation techniques creating a dense homogenous structure38. The filters are then hydrophilized through graft polymerisation achieving the desired filtration rate and virus removal capacity38. The filter housing and connections are made from polycarbonate, silicone, polysulfone, and polypropylene. Virus removal of these filters is based on size exclusion, i.e., viruses larger than the pore size of the filter will remain within the filter. Therefore, F9 filters are offered in varying pore sizes to target the viruses that need removal for particular products. The size range of known viruses in human blood/plasma and recombinant products are shown below in Figure 2-6. Figure 2-6: Size range (nanometres) of viruses known to be present in human blood/plasma products and recombinant products (in red) as well as some model viruses used for process validation (in blue) Source : Inouye and Burnouf, "The Role of Nanofiltration in the Pathogen Safety of Biologicals: An Update", Current Nanoscience, 2020, Vol. 16, No. 3 The solution containing the cell cultures, protein and potentially viruses is introduced into the hollow fibres of the F9 filter and as it is pushed through the walls of the filter, the dense homogenous structure effectively captures viruses whilst retaining low levels of the target protein. Figure 2-7 illustrates the virus filtration method using F4 filters. 38 F32 F4 39 V3 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 17 F33 F4 filters have high logarithmic reduction values (LRV) to deliver maximum virus removal. A LRV is used to measure the effectiveness of a process or treatment in reducing the number of microorganisms or contaminants, in this case, viruses40. It represents the logarithm (base 10) of the ratio between the initial number and the remaining number after treatment40. For example, a LRV of 2 means the number of viruses has been reduced by a factor of 100 (102)40. F4 filters can remove the smallest known virus found in nature, porcine parvovirus (PPV)38. These filters have been proven to remove > 4.0 logs (> 104 or 10,000) of PPV38. F4 filters come in a variety of effective surface areas that can be used for commercial purposes and research and development purposes. This study will focus on the filters that are used for commercial purposes; these can be seen below in Table 2-5. F34 The varying effective surface areas of F4 filters are shown in Figure 2-8, this includes smaller filters typically used for R&D purposes. After use, the filters are disconnected from the filtration line and remain fully self-contained with any separated virus particles safely enclosed within the filter housing. 40 https://www.endurocide.com/news/log-reductions-a-beginners-guide-2/ accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 18 F35 2.3.3 F20 F6 filters for cell culture clarification F20 F103 are a type of membrane filter trademarked by V3 for separation of the produced target protein from the cell culture solution in the bioreactor. These filters comprise PVDF hollow fibre membranes, separation is achieved by passing the feed stream through uniform pores on the membrane surface.41 The PVDF makes them particularly suitable to be used under the long-term operating conditions used in perfusion processes. In the production process illustrated in Figure 2-3, F20 filters are highlighted yellow. F36 F20 F20 filter products enable an increased yield of antibodies to be separated from mammalian cells.42 The PVDF of the membrane allows for antibody permeability in perfusion processes due to the uniform pore structure.42 F37 4 V3 F38 42 V3 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 19 F40 F3 V3 F4 F6 V3 F4 F6 F4 V3 F9 V3 F4 F6 filters are used by professional users only in a highly controlled GMP environment. They cannot be purchased by the public. 43 Jung et al, "Understanding the non-solvent induced phase separation (NIPS) effect during the fabrication of microporous PVDF membranes via thermally induced phase separation (TIPS)", Journal of Membrane Science vol. 514 pp250-263 (2016), https://www.sciencedirect.com/science/article/abs/pii/S037673881630309X . F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 21 4 The Pharmaceutical Market 4.1 Introduction This section provides a general overview of the pharmaceuticals industry in the European Union, making the distinction between the biopharmaceuticals market and the non-biopharmaceutical market. A high-level assessment of disease prevalence and demographics in the EU is included, to demonstrate the impacts European society could experience under the non-use scenario which is expected to interrupt the supply of biopharmaceuticals in the EU, which are used to treat prevalent and burdensome diseases such as cancer. This section will also illustrate emerging industry trends and their impact on the future in the continued use scenario, as well as quantifying what is at stake in the event of a restriction of PVDF in the non-use scenario. The section highlights the most prevalent diseases in the EU, how demographics will change over time and the expected link to disease prevalence, and an insight to the drugs that can be manufactured using F3 filters. The pharmaceutical market is a complex industry that encompasses the development, production, and commercialisation of drugs and pharmaceutical products. According to the European Medicines Agency, "a pharmaceutical or medicinal product is a substance or combination of substances that is intended to treat, prevent, or diagnose a given disease, or to restore, correct, or modify physiological functions by exerting a pharmacological, immunological or metabolic action."44 Ultimately, the goal of these products is to cure, vaccinate or alleviate symptoms of the prescribed user. 45 The pharmaceutical market consists of biopharmaceuticals and non-biopharmaceutical or small molecule drugs that are manufactured through chemical synthesis and are the most common medication in the market.46 In 2022, the global pharmaceutical market had a revenue of $1.48 trillion.47 There is a strong and competitive pharmaceuticals market in the European Union compromised of 1,900 companies of all sizes as estimated to be represented by the European Federation of Pharmaceutical Industries48 directly employing 840,000 people whilst also supplying indirect employment upstream and downstream.49 The EU pharmaceutical market is a vast complex industry which not only serves public health needs but is also a key driver of international trade and job creation in the EU economy. Its importance is magnified now more than ever given the demographic changes seen in society, with an ageing population susceptible to chronic disease and increased disease prevalence; the reliance on medicinal products is increasing.50 These factors have driven the European pharmaceutical market to grow from $296 billion at a compound annual growth rate (CAGR) of 5.4% from 2021 to 2028 reaching a market 44 https://www.ema.europa.eu/en/glossary/medicinal-product accessed July 2023. 45 https://www.pharmaceuticalonline.com/doc/are-you-asking-too-much-from-your-filler-0001 accessed July 2023. 46 https://pharmanewsintel.com/news/key-differences-in-small-molecule-biologics-drug-development accessed July 2023. 47 Revenue of the worldwide pharmaceutical market from 2001 to 2022 - https://www.iqvia.com/insights/the-iqvia-institute/reports/the-global-use-of-medicines-2023accessed July 2023. 48 The EFPIA Newsletter - https://www.efpia.eu/news-events/newsletter/efpia-newsletter-external/efpia- newsletter-27-april-2023/. Accessed July 2023. 49 The Pharmaceutical Industry in Figures. (n.d.). www.efpia.eu. 50 Europe pharmaceutical market size -https://www.researchandmarkets.com/reports/5457655/europe- pharmaceutical-market-size-share- and#:~:text=What%20is%20the%20estimated%20value,at%20%24296.3%20billion%20in%202021. Accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 22 size of $432 billion in 2028.50 With a 109.4 billion trade surplus, the EU is the second largest market in the world for pharmaceuticals. 51 According to the European Federation of Pharmaceutical Industries and Associations (EFPIA), "during a two decade time frame, EU pharmaceutical companies have more than doubled production, increased exports to the rest of the world by a factor of six and recorded a trade balance that puts it far ahead of other high-tech sectors in Europe resulting in 162 billion in gross value added to the economy."52 These statistics illustrate the significance this industry has on the European economy. According to Eurostat 53 , Germany and Belgium were the largest exporters and importers of pharmaceutical products in 2022. This suggests that in the event of a non-use scenario, Germany as the largest producer and one of the main consumers of pharmaceuticals in the EU would likely feel the most impact. As seen in Figure 4-1, Germany employs the largest number of people in the sector in the EU. Impacts under a non-use scenario will be discussed in more depth in Section 7. Figure 4-1: Pharmaceutical industry employment in selected European countries Source: https://efpia.eu/media/rm4kzdlx/the-pharmaceutical-industry-in-figures-2023.pdf Accessed 4th July 2023 4.2 Biopharmaceutical Market The pharmaceutical market comprises biopharmaceutical and non-biopharmaceutical products (sometimes called "small molecule" or "fully synthesised" products). A biopharmaceutical is a drug that is derived from living organisms such as mammalian cells, virals, or bacteria54 and includes 51 European Commission (2020) - https://health.ec.europa.eu/system/files/2021-02/pharma- strategy_report_en_0.pdf. Accessed 20th July 2023. 52 EFPIA (2021) -https://www.efpia.eu/more-than-medicine/economic- impact/#:~:text=In%20the%2021%20years%20from,high%2Dtech%20sectors%20in%20Europe. Accessed 20TH July 2023. 53 Trade in medicinal and pharma products: new peak in 2022 - https://ec.europa.eu/eurostat/web/products- eurostat-news/w/ddn-20230424- 1#:~:text=Between%202002%20and%202022%2C%20EU,represented%20an%20increase%20of%2022%25 accessed July 2023. 54 F41 V3 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 23 proteins, sugars, nucleic acid, and tissues55. These drugs include proteins such as antibodies that are used for therapeutic purposes56. Due to the specific antibodies being produced, these drugs can target a range of diseases affecting the EU population. The manufacturing process is complex and requires conformity to standardised methods and regulations to maintain quality and safety of the product (see Sections 2.3.1 and 5.4). Since the emergence of the first biopharmaceutical product, Humulin57, approved by the Food and drug and administration (FDA) in 1982 the biopharmaceutical industry has quickly expanded55. In 2017 the biopharmaceutical industry had a global revenue of $163 billion and comprised 20% of the total pharmaceutical market and was expected to grow by 8% each year 58 . In 2022 the global biopharmaceutical market revenue was estimated to be $472 billion59 representing just under 32% of the entire global pharmaceutical market. The European biopharmaceuticals market was estimated to be $48.2 billion in 2022 with CAGR of 8.89%60. The emergence of these drugs treating diseases that previously could not be treated has largely driven the increase of the market along with the prevalence of chronic diseases and increasing elderly population61. Biopharmaceutical drugs are extremely important to the proportion of the population with a unique disease, such as plasma protein deficiencies, that cannot be treated by any other method62. Plasma derived medicines originate from substances found within human plasma such as immunoglobulins. The biopharmaceutical market can be broken down into product types, including e.g.: Monoclonal antibodies (mAb); Erythropoietin; Biotech vaccines; Recombinant human (RH) insulin; Granulocyte colony-stimulating factor (G-CSF); Interferon; and Human growth hormones (HGH)63. A non-exhaustive list of drug types that can utilise F4 and F6 are shown in Table 4-1. 55 Introduction to biopharmaceuticals - https://iopscience.iop.org/book/mono/978-0-7503-3175- 3/chapter/bk978-0-7503-3175-3ch1 accessed July 2023. 56 What is a biopharmaceutical - https://www.bioprocessonline.com/doc/what-is-biopharmaceutical-0001 accessed July 2023. 57 A recombinant human insulin made from bacteria. 58 Rapid growth in biopharma: Challenges and opportunities - https://www.mckinsey.com/industries/life- sciences/our-insights/rapid-growth-in-biopharma accessed July 2023. 59 Biopharmaceutical market - https://www.nextmsc.com/report/biopharmaceutical-market accessed July 2023. 60 European biopharmaceutical market - https://www.marketdataforecast.com/market-reports/europe-bio- pharmaceuticals-market accessed July 2023. 61 Biopharmaceuticals market - https://www.biospace.com/article/biopharmaceuticals-market-size-to-hold- usd-856-1-bn-by- 2030/#:~:text=The%20global%20biopharmaceuticals%20market%20size,12.5%25%20from%202022%20to %202030. Accessed July 2023. 62 Plasma-derived medicines are unique - https://www.euneedsmoreplasma.com/plasma-derived-medicines accessed July 2023. 63 Europe biopharmaceuticals market - https://www.marketdataforecast.com/market-reports/europe-bio- pharmaceuticals-market accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 24 Prevot & Jolles (2020)64 discuss trends in demand for immunoglobulin (Ig). They note that overall global Ig demand had increased from 107 tonnes in 2010 to 211 tonnes in 2018. They note that factors influencing annual growth in consumption are complex and not only include increasing use in secondary immunodeficiency (SID) and neurological conditions but also improved diagnosis for primary immunodeficiency (PID) particularly in developed countries linked to increasing use of newborn and calculated globulin screening. However, the reality of massive worldwide underdiagnosis for around 70-90% of PID patients persists. They note there had been significant and year on year growth of around 6-8% in the requirement for immunoglobulin for predominantly immunology, Neurology and Haematology indications. Major drivers include increases in SID, better recognition and diagnosis of PID albeit on a background of massive underdiagnosis globally. Finally they note that novel therapies such as FcRn inhibitors may reduce demand in some of the current immunomodulatory indications for Ig. Monoclonal antibodies dominate the biopharmaceutical market in terms of product sales. Monoclonal antibodies can be used to treat diseases such as cancer, cardiovascular diseases, multiple sclerosis, and rheumatoid arthritis61. Monoclonal antibodies have been found to be successful in treating lung, breast, colorectal, and prostate cancer61. The biopharmaceutical product types in Figure 4-2 can be used for a variety of therapeutic treatments. The disease that has largely benefitted from these drugs is cancer, as seen in Figure 4-2. Oncology dominates the therapeutic applications followed by inflammatory and infectious diseases. Figure 4-2: Breakdown of biopharmaceuticals by therapeutic application Source: Global biopharmaceutical market outlook - https://www.expertmarketresearch.com/reports/biopharmaceutical-market accessed July 2023 The European biopharmaceutical market was valued at $48.2 billion in 2022 and is expected to reach $74 billion by 202763. Europe is a major player within the market being the second largest in the world 64 Prevot & Jolles, "Global immunoglobulin supply: steaming towards the iceberg?", Current Opinion in Allergy and Clinical Immunology, vol. 20(6), December 2020. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 25 behind North America and representing 21% of the global biopharmaceutical market65 with Western Europe housing more than 33% of manufacturing facilities worldwide63. Small molecule drugs have dominated the pharmaceutical market for a long time, for example in 2020 75% of all approved drugs were considered small molecule drug types46. However, recent reports have shown that biopharmaceutical sales are likely to overtake small molecule sales within the next five years by $120 billion66. The emergence of these ground-breaking drugs has allowed long time sufferers of diseases a form of treatment and as technology advances and knowledge increases it can be assumed that biopharmaceuticals will begin to dominate the industry. In 2016, eight of the top ten best-selling global drugs were biopharmaceuticals according to Pharmanews intelligence46. In 2022 seven of the top 10 selling products were biopharmaceuticals67. 65 Biopharmaceuticals forecast - https://www.industryarc.com/Report/9586/biopharmaceutical-market.html accessed July 2023. 66 Biologic sales forecast to pass innovative small molecule sales in next five years - https://www.pharmaceutical-technology.com/comment/biologic-sales-small-molecule-sales/#catfish accessed July 2023. 67 https://www.dcatvci.org/features/pharma-pulse-top-selling-small-molecules-biologics/ accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 26 4.3 Disease prevalence in Europe 4.3.1 Introduction F4 and F6 filter products produced by V3 are used in the manufacture of various biopharmaceuticals, used to target a number of diseases or conditions (see Table 4-1). The occurrence of diseases in the human population requires reliance on drugs to either cure or relieve the symptoms of diseases. Without drugs, mortality rates and infectious disease prevalence will increase. Disease prevalence refers to the proportion of individuals of the population at any given time with a disease or health condition68. This can help demonstrate the magnitude of a disease in the population. In this section, to help illustrate disease prevalence within Europe and the impacts reduced access to biopharmaceuticals could have, we will look at the burden of disease. 4.3.2 Burden of Disease The burden of disease is a concept to assess and quantify the impact of a health condition on a population69. For example, Public Health Scotland69 describes the burden of disease by measuring the disability adjusted life year (DALY). This takes into account years of life lost, and years of life lived with disability69. The burden of disease provides insights on the impacts of reduced access to medications in a society that restricts the use of F4 and F6 filters for biopharmaceutical manufacture. The burden of disease by cause within the European Region as defined by the World Health Organisation (WHO) for 2019 is shown in Figure 4-3. The graph includes non-communicable diseases70, communicable diseases71 and injuries. These are differentiated in the graph by colours (blue, red, and grey, respectively). 68 Department of Health - Prevalence Statistics - found here https://www.health- ni.gov.uk/articles/prevalence- statistics#:~:text=Prevalence%20is%20a%20measure%20of,within%20a%20particular%20time%20period). Accessed July 2023. 69 https://www.healthscotland.scot/health-inequalities/impact-of-ill-health/burden-of-disease- overview#:~:text=Burden%20of%20Disease%20is%20a,injury%2C%20disability%20and%20early%20death. Accessed July 2023. 70 Non-communicable diseases cannot be spread from person to person such as heart disease and cancer. 71 Communicable diseases are spread from one person to another via contact with bodily fluids, airborne or insect bites. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 30 Figure 4-3: Most prevalent disease burdens in Europe (2019). Non-communicable diseases are shown in blue; communicable, maternal, neonatal, and nutritional diseases are shown in red; injuries are shown in grey. Source: IHME, Global Burden of Disease (2019) accessed from Our World in Data (2023), Burden of Disease. https://ourworldindata.org/burden-of-disease accessed July 2023 As seen in Figure 4-3, cardiovascular disease and cancers have the most effect on the health of the European population (also see Figure 4-4). These categories of diseases are, however, made up of a number of a number of separate diseases that often vary significantly from one another. For example, cardiovascular diseases or diseases to the circulatory system can consist of high blood pressure, heart disease and diseases to the veins and arteries72. In Europe, the most common cause of death from cardiovascular diseases is ischemic heart disease (heart attack) and cerebrovascular diseases (stroke)72. The primary causes of death in Europe are seen below in Figure 4-4. As expected, and in relation to the burden of disease (Figure 4-3), the top two causes of death are cardiovascular diseases and cancers. 72 https://ec.europa.eu/eurostat/statistics- explained/index.php?title=Causes_of_death_statistics#Major_causes_of_death_in_the_EU_in_2020. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 31 Figure 4-4: Causes of Death in Europe (2019) Source: Our World in Data (2023), Cancer. https://ourworldindata.org/cancer accessed July 2023 The most common causes of death due to diseases of the circulatory system (per 100,000 residents) are73: 1. Ischaemic heart diseases (251 cases); 2. Other heart diseases (188 cases); 3. Other ischaemic heart diseases (164 cases); 4. Cerebrovascular diseases (162 cases); 5. Other diseases of the circulatory system (150 cases); and 6. Acute myocardial infarction (87 cases). In 2017, according to the European Heart Network, every year there are more than six million new cases and is estimated to cost the EU economy 210 billion a year74. However, the emergence of new biopharmaceutical drugs such as Apolipoprotein A-1, could likely help combat this issue. The second most common cause of death is cancer. There are more than 200 types of cancer that vary significantly from each other75. Despite Europe making up a tenth of the global population, it 73 https://ec.europa.eu/eurostat/statistics- explained/index.php?title=File:Standardised_death_rates_%E2%80%93_diseases_of_the_circulatory_syste m,_residents,_2019_(per_100_000_male_female_inhabitants)_Health2022.png. 74 European Cardiovascular Disease Statistics 2017 - found here https://ehnheart.org/cvd-statistics.html accessed July 2023. 75 https://www.cancerresearchuk.org/what-is-cancer/how-cancer-starts/types-of- cancer#:~:text=There%20are%20more%20than%20200,of%20cell%20they%20start%20in. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 32 accounts for 25% of annual cancer cases, according to the European Commission76. In Europe, the top five cancers causing death are77: 1. Tracheal, bronchus and lung cancer; 2. Colon and rectum cancer; 3. Breast cancer; 4. Pancreatic cancer; and 5. Stomach cancer. However, the top five cancers present in the population differs slightly. They are77: 1. Breast cancer (0.39%); 2. Prostate cancer (0.22%); 3. Colon and rectum cancer (0.2%); 4. Uterine cancer (0.09%); and 5. Bladder cancer (0.07%). Monoclonal antibodies are currently dominating the biopharmaceutical market, have been proven to treat lung, breast, prostate and colorectal cancers. These four cancers are some of the most prevalent types amongst the European population. Because the first biopharmaceutical was not marketed until 1982, the emergence and development of monoclonal antibodies to treat cancer has developed fairly quickly. As advances in this area continue, it is assumed that biopharmaceuticals and monoclonal antibodies in particular will play a huge role in the treatment of cancer. During the consultation phase of this study, V3 disclosed that a sizeable proportion of the drugs formulated using their specialist biofilters are used to target cancer, in particular monoclonal antibodies have had a large impact on treating different types of cancers (see Section 4.2 and Figure 4-1). The development of biopharmaceuticals used to treat cancer could play a key role in fulfilling the Pharmaceutical Strategy for Europe78 and Europe's Beating Cancer plan79. These plans focus on ensuring Europe has a robust supply chain to secure the supply of medicines across the EU and emphasizes innovative research and development for treating rare diseases. A flagship initiative within Europe's beating cancer plan is focused on linking cancer centres across EU Member States to allow patients access to the care needed. According to the plan, EU network of cancer centres "will facilitate the uptake of quality-assured diagnosis and treatment, including training, research and clinical trials across the EU" aiming for 90% of patients to have access to these centres79. The initiatives within this plan will be supported by a 1.25 billion budget. As discussed in Section 4.4, the average age of the European population is expected to increase over time. Typically, the prevalence of diseases, such as cardiovascular and cancers, is greater in adults over the age of 5077. Cancer, in particular, is typically a disease of old age. As the population ages, the need for medications, including biopharmaceuticals, to treat these diseases will increase. Without 76 Joint Research Centre of the European Commission - found here https://joint-research- centre.ec.europa.eu/jrc-news-and-updates/cancer-europe-5-things-data-tells-us-2022-01- 13_en#:~:text=According%20to%20the%20estimates%2C%20there,are%20disproportionately%20affected %20by%20cancer accessed July 2023. 77 Our World in Data (2023), Cancer. https://ourworldindata.org/cancer accessed July 2023. 78 Pharmaceutical Strategy for Europe - found here https://health.ec.europa.eu/system/files/2021- 02/pharma-strategy_report_en_0.pdf accessed August 2023. 79 Europe's Beating Cancer Plan - found here https://health.ec.europa.eu/system/files/2022-02/eu_cancer- plan_en_0.pdf accessed August 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 33 the proper equipment to efficiently and successfully manufacture the drugs needed to treat them, mortality rates will likely increase. 4.4 Demographic trends in Europe Cancer tends to be a disease of old age, and one of the main classes of biopharmaceutical products is used for cancer therapy. This section discusses trends in demographics that are likely to drive increases in cancer prevalence. This may be offset by ongoing improvements in prevention and treatment, such as the further development and use of biopharmaceuticals. As a result of advances in medicine, technology and overall quality of life, life expectancy in the EU has increased by 2.5 years since 2002.80 However, this increase in life expectancy has social impacts as well as the burden of contracting chronic diseases and disabilities associated with old age. For example, in 2017 the OECD reported81 about 37% of people aged 65 years or over have at least two chronic diseases on average across the EU. This number increases with age with 56% of women and 47% of men having multiple chronic diseases among people aged 80 and over81. It can be assumed that the increase in life expectancy and the increase in the prevalence of chronic diseases requires access to more medications and treatments to help the population. The emergence of biopharmaceuticals has led to significant breakthroughs in treating a variety of cancers, heart diseases and blood disorders. With a larger portion of the population reliant on drugs to treat these chronic diseases, any change to the availability of biopharmaceuticals could have significant impacts on the population. These impacts will be discussed further in Section 6.4. The EU and much of the industrialised world is currently going through a period of demographic and societal change. These rapid changes pose serious challenges for society such as social, food and housing security but also in relation to healthcare82. In 2018, the global elderly population, consisting of people aged 65 and older, surpassed the population aged under 1583. This is the first time in history this has happened. However, in some countries this has not happened yet (common in lower income countries with high fertility rates and a lower life expectancy83). With a population increase comes the need for increased access to medicines and treatments and as such the need for pharmaceutical companies to increase their capacity and continuous innovation to find more efficient treatments. The global age distribution has been changing over the last century. This is attributed to advances in medical technologies and treatments, and to decreased birth rates. Figure 4-5 shows the working age group (15 to 64 years) is estimated to decrease over the years 2022 to 2060. 80 Mortality and life expectancy statistics - found here https://ec.europa.eu/eurostat/statistics- explained/index.php?title=Mortality_and_life_expectancy_statistics#:~:text=Overall%2C%20between%202 002%20(the%20first,and%202.9%20years%20for%20men. 81 Chronic diseases and disabilities among older people - found here https://www.oecd- ilibrary.org/sites/f44c34f1-en/index.html?itemId=/content/component/f44c34f1- en#:~:text=Based%20on%20the%20latest%20wave,versus%2032%25%20on%20average accessed July 2023. 82 Population 2020 - found here https://www.imf.org/en/Publications/fandd/issues/2020/03/changing- demographics-and-economic-growth-bloom accessed July 2023. 83 Our World in Data, Age Structure - found here https://ourworldindata.org/age-structure#how-did-the-age- structure-of-populations-change accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 34 Figure 4-5: Population structure by major age groups, EU, 2007-2100 (2022 provisional/estimated). Source: https://ec.europa.eu/eurostat/statisticsexplained/SEPDF/cache/1271.pdf Accessed: 5th July 2023 Whilst it is expected the 15-to-64-year age group will remain dominant, 31% of the population will be aged 65 and over by 2100 (compared to 21% in 2022). This increase could result in an increase in prevalence of diseases associated with old age (such as cancer) and therefore an increase in demand for prescribed medications such as biopharmaceuticals. A study by Eurostat84 demonstrated the population aged 75 years and over reported the most use of a prescribed medication. The proportion of the population using prescribed medications ranged from 70% to 95% across EU member states. This reinforces the reliance of the elderly population on treatments and therapeutics to treat chronic diseases while also highlighting the vulnerability of an ageing EU population to any external forces that may play a role in restricting their ability to access and use certain medicines to target disease. 84 https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Medicine_use_statistics accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 35 5 Analysis of Alternatives 5.1 Introduction The Analysis of Alternatives (AoA) assesses the technical and economic feasibility, availability, and overall suitability of potential alternatives to the use of PVDF in F4 and F6 filters for purification and virus removal in the biopharmaceutical manufacturing process. Alternative substances to PVDF, and alternative technologies to virus filtration, have been assessed in this report. Whereas the socioeconomic analysis determines the potential impacts in the non-use scenario (see Section 7), the AoA can be considered as a determinant of the extent to which these impacts will be felt. If there are no suitable alternatives to PVDF for purification and virus removal, then the proposed restriction (see Section 1.2) is expected to put the manufacture of biopharmaceuticals in the EU at risk and the full socio-economic impacts as set out in Section 7 are expected to be experienced in the EU. The AoA feasibility criteria are based on the latest ECHA guidance documents for AoA and F56 .85,86 Elements included in the AoA are discussed below: Technical feasibility - identifying the technical feasibility/performance criteria relevant to the use of PVDF in purification and virus removal in the biopharmaceutical manufacturing process, and whether the potential alternatives provide the required functionality and deliver the necessary combination of performance requirements for the use. Economic feasibility - considering aspects such as material costs, costs associated with necessary modifications to manufacturing lines or the purchase of new equipment, waste streams and disposal costs, monitoring and process control costs, and any testing/approval/qualification costs. Impacts on competitiveness will also be considered with respect to non-EU competitors and the products/articles in which they are used. Safety - human health and environmental hazard classification of the potential alternatives and expected impact on risk, to identify regrettable substitution. This will comprise an overview of the hazard classifications of the alternatives with indications of the tonnages potentially required and will also consider existing and anticipated forthcoming regulatory activities that may impact potential alternatives. Availability - to identify whether the potential alternative, and any necessary machinery or equipment needed to use it, is expected to be accessible on the EU market in the required quantities and in the required timeframe for the relevant supply chains. It also considers whether the potential alternative needs to be certified or qualified (e.g. viral clearance studies and European Medicines Agency certifications), and the required timeframe and availability of testing facilities. Finally, considerations around intellectual property limitations (patents/licencing) that could impact the use of the potential alternative. Suitability - an overall summary of the potential alternative considering the aspects discussed above. 85 https://echa.europa.eu/documents/10162/13637/sea_format_with_instructions_v4_en.docx/0cbc5102- 6ba2-2170-480a-0061d2798f55. 86 https://echa.europa.eu/documents/10162/17235/authorisation_application_en.pdf/8f8fdb30-707b-4b2f- 946f-f4405c64cdc7?t=1610451346310. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 36 The AoA presented below discusses F4 and F6 87 separately. For each product it presents the functionality and performance requirements against which any potential alternatives need to be assessed, an assessment of potential alternatives to PVDF in filtration, and an assessment of potential alternatives filtration itself (i.e., other types of technology). In this highly specialist and regulated industry, the performance requirements are set by the downstream customer (the pharmaceutical manufacturer who operates under GMP, see Section 2.3.1), and the regulatory body (the European Medicines Agency). ICH Q5A viral safety guidelines88 for biopharmaceuticals must be observed. Any switch to an alternative will require a new viral clearance study and process requalification. V3 F45 5.2 F9 F4 for virus removal F4 is a type of nanofilter trademarked by V3 which uses size exclusion for virus removal, which is a key step in the biopharmaceutical drug manufacturing process related to safety and quality assurance of the produced medicines (see Figure 2-2 and Figure 2-3). The F4 filters comprise a PVDF membrane which is fully enclosed in a housing and includes modular connectors for easy installation and removal in the drug manufacturing line (see Figure 2-8). The PVDF has a combination of properties that make it highly suitable for virus removal. The PVDF has high compressive strength, high heat and chemical resistance, and low leachability. The PVDF has a uniform structure with few large pores so viruses cannot pass through. The uniform density reduces points of stress in the membrane so there is less chance of mechanical failure. F4 is suitable for use with higher protein concentrations (a trend discussed in Section 2.3.1). P2 89 (co-authored by V3 ) reported virus removal from human plasma-derived intravenous immunoglobulin (IVIG) using F4 , focussed on removing smaller, non-enveloped viruses which are resistant to usual inactivation treatments. IVIG solution was spiked with serum-containing and serum- free porcine parvovirus (used as a model of small non-enveloped viruses like B19V), and viral clearance and various other performance parameters measured to determine the optimum operating conditions (pressure, protein concentration, temperature, and pre-filtration condition) for the F4 filter. It was reported that best performance (virus removal) was achieved at the highest concentration, and nanofiltration under these conditions did not apparently alter the biological activity of IVIG. 87 F20 F46 88 "Viral Safety Evaluation Of Biotechnology Products Derived From Cell Lines Of Human Or Animal Origin", International Council For Harmonisation Of Technical Requirements For Pharmaceuticals For Human Use (ICH), Q5A, https://www.ema.europa.eu/en/ich-guideline-q5ar2-viral-safety-evaluation-biotechnology- products-derived-cell-lines-human-animal. 89 F9 F47 F4 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 37 There are two main approaches for ensuring there is no virus present in the biopharmaceutical product - virus removal, and virus inactivation: Virus removal technologies physically separate the virus from the biopharmaceutical product and include filtration methods by size exclusion - this includes both PVDF-based filtration ( F4 ) as well as non-PFAS based filtration using materials such as non-PFAS polymeric materials, or F48 (it should be noted that some non-PFAS membrane virus removal filters use PFAS in the filter housing). Other virus removal/separation methods are chromatography, and precipitation. Virus inactivation technologies reduce virus infectivity by chemical or physical modification and include heat treatment, use of solvents or detergents, acid/alkali treatment, and irradiation. All these virus removal and virus inactivation technologies are currently used in biopharmaceutical manufacturing processes. Each of these technologies have advantages and disadvantages and their relative effectiveness and performance depends on the type of virus, the type of cell, and other operating parameters. EMA guidance recommends the use of orthogonal technologies for virus removal; i.e. to use at least two independent virus removal technologies that use different modes of action (see Section 2.3.1). Any switch to an alternative to F4 must retain this orthogonality requirement. In consultation with V3 , it was explained that the main requirement is to achieve a certain total virus logarithmic reduction value (LRV) by counting the LRV of each orthogonal technology used for removing or inactivating certain types of viruses (enveloped viruses and non-enveloped viruses). In any downstream processing, there are already pH inactivation or solvent/detergent inactivation steps ("chemical mechanism") and chromatography step(s) (adsorption mechanism). Some technologies are more efficient for certain types of viruses. For example, pH inactivation works well on enveloped viruses but is much less efficient on non-enveloped viruses. In principle, filtration could be replaced by UV (mechanism different from Chromatography and pH inactivation or solvent/detergent). But UV is only efficient (sometimes depending on the operating parameters) on non-enveloped viruses, and much less on enveloped viruses. And it is the reverse for heat treatment, it can work (sometimes depending on the operating parameters) on enveloped viruses but much less on non-enveloped viruses. Both technologies may negatively impact on the drug product itself. Virus removal filtration is usable on any kind of viruses with a very high efficiency (= LRV > 4 log) without a negative impact on the drug product. In practice this may mean that F4 would need to be replaced by another virus filtration technology, rather than another virus removal or virus inactivation technology, in order to retain orthogonality. 5.2.1 Functionality and performance requirements Several metrics are used to assess the performance of virus removal and virus inactivation technologies. The most important metric is viral clearance, which is a measure of the extent to which a virus has been removed from the feed stream during the virus removal stage of biopharmaceutical manufacture. The typical unit of measurement is logarithmic reduction value (LRV). This is calculated by comparing the virus infectivity in the feed stream spiked with a viral stock prior to nanofiltration (or in a more scientifically correct manner, in an unprocessed sample stored during the entire duration of the experiment to detect any impact over time of the feed on virus infectivity), to that in the F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 38 filtrate90. A typical minimum requirement is to achieve an LRV of 4.0, which means the permeate has 1x104 i.e. 10,000 times less virus than the feed stream. Performance is measured in viral clearance studies which are designed to closely reproduce the conditions in the industrial process. Monitoring of the industrial process is then carried out to ensure ongoing viral clearance. Other parameters are also important, such as protein throughput. Performance metrics must be considered collectively, rather than in isolation, to assess the relative performance of virus removal technologies. Drug manufacturers need to demonstrate adequate virus removal performance (LRV 4) in their manufacturing process. The performance of virus removal filters is determined by the physico-chemical properties of the materials used in the filtration membrane, and the operating conditions (such as pressure) under which they are used. PVDF is used because it has several properties that make it an ideal material for use in virus filtration membranes, including chemical resistance, heat resistance, and mechanical strength (see Section 2.1.1). A summary of the relevant performance parameters for virus removal/inactivation, and underlying physico-chemical properties is shown in Table 5-1. Note some of these parameters generally apply to any type of virus removal technology, some apply specifically to virus filters, and some apply to the physico-chemical properties of membranes used in virus filters that are relevant to their performance. F49 5.2.2 Assessment of potential alternatives to PVDF Table 5-2 shows virus removal filters that are commercially available and used for biopharmaceutical manufacturing, using several different filtration membrane materials. Note that some of these products use PVDF as the filter membrane, and some use PFAS in the filter housing. 90 Inouye and Burnouf, "The Role of Nanofiltration in the Pathogen Safety of Biologicals: An Update", Current Nanoscience, 2020, Vol. 16, No. 3. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 39 F50 V3 F51 V3 F4 In the event of a PFAS ban, the ability of the supply chain to respond would not only be based on the need for updated viral clearance studies and recertification of the manufacturing process, but also on the ability of non-PFAS based virus filter suppliers to increase their production to cover the market occupied by PFAS-containing filters. This could result in additional disruption to the biopharmaceutical supply chain and availability of important biopharmaceutical products. F52 F4 F53 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 40 F54 F4 F55 Table 5-3 shows a summary of virus removal and virus inactivation technologies, a brief description of their operating principles, and the strengths and weaknesses of each option. For all technologies other than nanofiltration, there are limitations on their ability to remove/deactivate all types of viruses, or they present a risk to the integrity of the biopharmaceutical product of interest. As has been discussed in Section 2.3.1, some of these technologies are used in combination with each other, for example PVDF filters can withstand high temperatures and are therefore suitable for use with SIP (steam in place) sterilization. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 41 5.2.3 Assessment of potential alternatives to virus removal by filtration This is discussed in Section 5.2.2. Responses received from consultation Three responses were received from F4 customers during the consultation process (see consultation statistics in Section 1.3). This represents a very small proportion of the F4 market, and it is difficult to draw conclusions about the whole market from these responses (representative sampling cannot be assumed). In response to the question "If F9 F4 filters were not available, are you aware of any alternative technologies that could be used instead to achieve the required performance in your process?", companies that responded to the consultation commented on other filter types F104 In response to the question "If a restriction came into force banning the use of F9 F4 in the EU, what would be the likely consequences and reactions of your site, and the effect on your company's business?", companies that responded to the consultation selected "no impact" or "switch to alternative virus removal technologies". RPA were not able to engage in further discussions with these respondents to clarify their responses or obtain more detail (respondents did not provide permission for this). As such we present these responses at face value but it should be noted that they represent a very small proportion of V3 's customers, and we cannot assume their responses reflect that of the whole group. We also cannot be certain of the specific individual(s) who responded to the survey, or the detail/specificity of their subject matter knowledge. 5.2.4 Summary of suitability of alternatives to F4 Using the assessment criteria discussed in Section 5.1, Table 5-4 summarises the relative suitability of alternatives to F4 for virus removal in biopharmaceutical manufacturing. This table focusses on alternative filters - other types of alternatives are discussed in Table 5-3 (Section 5.2.2). Limited or no quantitative information on the economic feasibility of alternatives was obtained in the study (for example, purchasing cost of alternative filters, or net operating costs per kilogram of biopharmaceutical product produced). Therefore, semi-quantitative information has been provided in the table. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 45 F59 5.3 F6 for cell separation 5.3.1 Functionality and performance requirements F6 filters are used to separate the therapeutic protein of interest from cells and cell debris at the cell culture/bioreactor stage (not related to virus removal). They are particularly designed for the perfusion process to achieve more protein production and are currently being trialled by selected customers in the EU. V3 F60 Sales are expected to expand to other EU countries. Continuous manufacturing (the perfusion process) is a complicated operation used in bioprocessing. During consultation with V3 , they disclosed that F6 membranes are used in the upstream cell culture process where in the perfusion process media is constantly being exchanged over the course of many days. F6 membranes have been proven to be superior to other alternatives and will achieve higher overall process yield which in turn will increase the amount of drug substance produced (see Section 5.3.2, Figure 5-2). Protein sieving is critical for achieving high yield and F6 membrane based on PFAS has proven to be superior to other membrane materials. The PVDF membrane is resistant to many chemicals used in biologics manufacturing which allows for repeated use in manufacturing and can prevent extractables/leachables from entering the feed stream. This will prevent these from entering the final drug substance. A summary of the relevant performance parameters for separation of the therapeutic protein of interest from cells and cell debris is shown in Table 5-5. 92 https://echa.europa.eu/substance-information/-/substanceinfo/100.029.692. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 46 F61 5.3.2 Assessment of potential alternatives Other hollow fibre membranes that are commercially available and could be used in the perfusion filtration process F62 . These are manufactured from Polysulfone (PSU), Polyethersulfone (PES), or Polyethylene (PE). V3 F63 Figure 5-2 shows the product sieving/antibody transmission performance of PVDF versus PSU membrane filters. PVDF has higher antibody penetration performance, this could translate into higher productivity/less product loss, and therefore PVDF offers the potential to improve productivity of the perfusion process. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 47 F64 Responses received from consultation No responses were received from F6 customers during the consultation process (see consultation statistics in Section 1.3). 5.3.3 Summary of suitability of alternatives to F6 Using the assessment criteria discussed in Section 5.1, Table 5-6 summarises the relative suitability of alternatives to F4 for virus removal in biopharmaceutical manufacturing. Limited or no quantitative information on the economic feasibility of alternatives was obtained in the study (for example, purchasing cost of alternative filters). However, data on protein sieving and higher protein throughput suggested that productivity improvements could be achieved with F6 , which could have economic benefits on net operating costs per kilogram of biopharmaceutical product produced. This semi-quantitative information has been provided in the table. F56 F66 5.4 Qualification requirements for drug manufacturing process See Section 2.3.1 for a further description of regulatory and qualification requirements. These apply to the whole drug manufacturing process and therefore to both F4 and F6 and their potential alternatives. V3 F67 In addition, it is necessary for clients to perform product validation (three to five years) in the manufacturing process from development to switching to a new product, F68 5.5 Conclusion Switching to alternatives for F4 and F6 will take time and be costly to implement. F4 is already in use in the EU market, F103 are currently in the market development phase in the EU where selected customers are engaged with ongoing production trials. Both F4 and F6 are being used for the manufacture of investigational pharmaceutical products (i.e., products that are in clinical trials). Data from such manufacturing trials are used in the dossier to apply for a Marketing Authorisation for the drug (i.e., a drug licence). For customers engaged in this process, a need to switch to alternative filtration technologies will mean the data collected up to that point would no longer be able to be used for the Marketing Authorization application, and the trial process would need to be re-started, taking additional time and cost. Limited data from V3 's F4 customers (i.e. biopharmaceutical manufacturers using F4 for virus filtration) was obtained in the consultation, and these data consequently represent only a small fraction of the F4 market (no responses were received from F6 customers). It has therefore not been possible to prepare a robust estimate of the potential impacts on V3 's customers of a ban on the use of F4 or F6 . Data from the AoA and the consultation process suggests that many customers would be able to make the switch from F4 to other virus removal filtration technologies ( F69 , however the switching process will require revalidation and the completion of new viral reduction studies to assure acceptable virus removal. F71 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 49 F4 F70 Data from the AoA suggests that if customers are unable to use F6 , potential benefits related to higher protein throughput, and hence higher yield, may not be realised. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 50 6 Continued Use Scenario 6.1 Introduction This section sets out the continued use scenario for V3 and its downstream users in relation to the importation and sale of F4 and F6 products containing PVDF in the EU27/EEA. The scenario assumes that V3 will be able to continue the importation and sale of these products in the EU27/EEA allowing downstream users (biopharmaceutical manufacturers) to continue to use F4 and F6 products for manufacturing biopharmaceuticals. In this section, the study team has estimated the economic contribution that V3 's F4 and F6 products bring to the European economy through their turnover and profits, as well as the employment they provide. Wider impacts such as European policy objectives and wider societal impacts are also explored. Benefits to V3 , their customers (biopharmaceutical manufacturers), and patients are considered in separate sub-sections. 6.2 V3 This section presents various economic indicators for V3 , including the import volume of F4 and F6 products in terms of revenue and profits generated from the sale of these products. The RPA study team has used revenue and profit data reported by V3 for 2022 and calculated expected future revenues and profits by using annual growth estimates provided by V3 . A period from 2022 to 2030 has been selected to demonstrate how each product will develop between now and the possible start of a restriction. The assessment period used will be discussed in more detail in the non-use scenario (Section 7). 6.2.1 Production and imports V3 F4 F6 F4 F6 F4 F4 F4 V3 F4 V3 also provided revenue and profit growth rates throughout the study period. The revenue growth rate for 2023 was used to estimate the total number of filters sold in 2022. For the years 2026 to 2029 the number of filters were estimated based on a growth factor93 derived by the RPA study team. 93 This growth factor was derived by taking the known number of filters in 2023 and 2030 determining the growth over this 7-year period and distributing it evenly over the years 2026 - 2029. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 51 To disguise the true values disclosed to RPA, the figures in Table 6-1 and Table 6-2 are reported as an upper and lower bound. The true values fall within these ranges. Similarly, only the figures for 2022, 2030, and the total for the assessment period are presented. F4 F73 V3 F4 F74 Table 6-2 presents the estimated amount of PVDF imported into the EU27/EEA. The quantity of PVDF within F4 filters was disclosed to the RPA study team. F75 F76 F4 F77 F4 V3 F6 F6 F6 6.2.2 Turnover and profits F4 F6 F78 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 52 F4 F6 F4 F80 V3 F4 F6 V3 F4 F6 F6 F4 F6 F4 F6 6.2.3 Health and environmental impacts F4 F6 F481 F6 V3 As determined in the hazard assessment, Section 2.2, PVDF is not a concern to human or environmental health. The polymer is inert and based on its characteristics it is unlikely to have any intrinsic toxicological hazards (not related to particle size). The available information indicates that the only property of concern is persistency, however, due to its large molecular weight uptake by organisms is not expected. SIP (Sterilisation In Place) using steam at 121C is used for sterilization in the drug manufacturing process. This is significantly lower than the 375C thermal decomposition temperature of PVDF. Therefore, decomposition is unlikely and subsequently a low risk of emissions released into the surrounding environment during the use of these filters. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 54 At the end-of-life, the F4 and F6 filters contain viruses. This requires incineration of the filters as hazardous materials in accordance with Annex III of the Waste Framework Directive95. This type of incineration has been considered to destroy PFAS, although the RPA team were unable to obtain more detailed data on the incineration processes and conditions from the waste facilities drug manufacturers use at the end of life. Incineration must be done at proper facilities and using adequate temperatures. If high enough temperatures are not used, then short-chain PFAS could be generated. Short-chain PFAS typically possess more hazardous properties and due to their lower molecular weight could have the potential to bioaccumulate. Typically, temperatures more than 1,000C are needed, to ensure no hazardous by-products remain, however, there is varying data on the effectiveness of destruction 96 . Residence times in the incinerator will also contribute to the effectiveness of destruction97. 6.2.4 Employment V3 F82 F4 F6 V3 [1] V3 [2] 95 Directive 2008/98/EC of the European Parliament and of the Council - https://www.legislation.gov.uk/eudr/2008/98/annex/III accessed July 2023. 96 Smith Beuthe M Dunk S Demeure JMM Carmona A Medve MJ Spence, J. B. (2016). Environmental fate and effects of poly-and perfluoroalkyl substances (PFAS) Prepared for the Concawe Soil and Groundwater Taskforce (STF/33). 97 Tsang, W., Burgess, D. R., & Babushok, V. (1998). On the incinerability of highly fluorinated organic compounds. Combustion Science and Technology, 139(1), 385-402. https://doi.org/10.1080/00102209808952095. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 55 Table 6-6: Economic contribution of employment from V3 's European operations Tax income Household Disposable Member Number of Average per person saving income per State(s) Employees[1] Salary ()[1] ()[2] Net pay () ratio[3] person () [3] Source https://www.ceicdata.com/en/indicator/european-union/gross-savings-rate accessed July 2023 F83 V3 V3 V3 V3 F84 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 56 F85 F86 V3 F56 6.2.5 Innovations and investment V3 F87 V3 V3 V3 F6 V3 V3 F9 F6 6.3 Drug manufacturers 6.3.1 Production and imports Drug manufacturers or pharmaceutical companies are responsible for the manufacture and distribution of basic pharmaceutical products and preparations. This could include R&D for drugs that are currently undergoing clinical trials, identifying potential drug candidates and performing safety tests. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 57 Drug manufacturers must meet stringent safety regulations and requirements (see Section 2.3.1). As previously discussed, an important metric for safety standards is the removal of viruses that might be present during the biopharmaceutical manufacturing process. These virus removal filters undergo studies to determine if they can effectively remove viruses before being introduced into the drug manufacturing process. Thus, drug manufacturers must use filter products that have been qualified for use. F88 F4 F4 V3 F6 F4 F4 F4 F4 V3 6.3.2 Turnover and profits F89 F4 V3 F4 V3 F4 60 F4 F4 F4 6.3.3 Health and environmental impacts The health and environmental impacts can be assumed to be the same as discussed in Section 6.2.3. As discussed in Section 2.2, PVDF is a stable inert polymer and is unlikely to degrade under the operating conditions, therefore the likelihood of emissions taking place are negligible. Similarly, due to the inherent chemical resistance of PVDF, the likelihood of leaching into the manufactured products that could be ingested by humans is unlikely. 6.3.4 Employment Due to a lack of data received from V3 downstream users, the exact number of employees whose jobs are directly or indirectly impacted by the use of F4 filters could not be determined. However, 98 Based on the exchange rate on 23 August 2023 $1 = 0.93 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 58 desk-based research can be used to make an estimate of the number of employees whose jobs are related to the use of F4 filers. Based on a report by the European Commission in 201999, there were 2.4 million employees in Europe's biopharmaceuticals industry with an average salary of 50,800. F90 F4 F4 F91 F4 Based on the 2019 report, Germany has 204,700 employees whose jobs are related to biopharmaceuticals. Germany is the leading pharmaceutical market in Europe and also accounts for over 670 biotechnology companies. Other regions with high numbers of employment in biopharmaceuticals are Belgium and Ireland. It's possible that under a non-use scenario, Germany would likely have the largest impacts on employment due its share in the market. 6.3.5 Innovations and investment Drug manufacturers do not conduct any R&D with regard to developing virus removal filters but conduct testing to ensure the filters are performing to the required standard (e.g., virus removal efficiency). Research and development efforts for virus removal filters are typically conducted by the suppliers themselves, for example V3 . The R&D conducted by drug manufacturers is related to drug development. This R&D could include the use of F4 or F6 filters. Downstream users disclosed to RPA that F4 virus removal filters and UMP filters are being used in clinical trials for the development of new biopharmaceutical drugs. The data gathered during these trials will be used to get approval for the drug to be placed on the market. In line with good manufacturing practice, the approved drug must continue to be manufactured in the same way as done in the trial. Specific information regarding timelines and costs for clinical trials were not disclosed. In the event of a non-use scenario, the development and approval of these new biopharmaceuticals could be in jeopardy., as costs will be incurred to develop new equipment and re-design clinical trials. 6.4 Impact to patients Biopharmaceuticals have proven their effectiveness since the emergence of the first biopharmaceutical product in 1982. Since then, the industry has grown exponentially and developed ground-breaking drugs for the treatment of rare diseases (e.g., plasma protein deficiencies) and some types of cancers (see Section 4.2). The development of these drugs has no doubt had a positive impact on individuals burdened with these diseases. F92 F4 some of these drugs include cancer treatments. Biopharmaceuticals represent a significant part of the pharmaceutical market and include important therapeutic proteins such as immunoglobulin/monoclonal antibodies, which are used to treat a number of prevalent, serious diseases for example primary immunodeficiency (PID) syndromes and haemophilia. Immunoglobulin therapies for PID and Kawasaki diseases are on the WHO List of 99 Priority Sector Report: Biopharmaceuticals. (2019). https://doi.org/10.2826/68966 accessed July 2023. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 59 Essential Medicines. 100 , 101 Monoclonal antibodies are used in targeted cancer therapies. Biopharmaceuticals are expected to increase in importance as trends in demographics imply that for example cancer, predominantly a disease of old age, will increase in prevalence. Additionally, with ongoing research and development it is expected that a proportion of the biopharmaceutical products currently at the clinical trials stage will achieve marketing authorisation (licencing/approval), and new types of biopharmaceuticals will be developed. It is expected that biopharmaceuticals contribute to meeting the intentions of Europe's Beating Cancer Plan.102 100 WHO 22nd model list of essential medicines (2021), https://www.who.int/publications/i/item/WHO-MHP- HPS-EML-2021.02. 101 WHO 8th model list of essential medicines for children (2021), https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.03. 102 https://commission.europa.eu/strategy-and-policy/priorities-2019-2024/promoting-our-european-way- life/european-health-union/cancer-plan-europe_en ; https://www.ipaac.eu/news-detail/en/53-europe-s- beating-cancer-plan-a-new-eu-approach-to-prevention-treatment-and-care/. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 60 7 Non-use Scenario 7.1 Introduction This section sets out the non-use scenario (NUS) for V3 and its downstream users in relation to the importation and sale of F4 and F6 products containing PVDF in the EU27/EEA. In the non- use scenario, it is assumed that the restriction of PFAS is implemented in 2025 with no derogations for the specified uses in this study. Therefore, for the purposes of this report from the start of the year 2025, V3 will have six months to phase out and stop the sale of F4 and F6 products containing PVDF in the EU27/EEA and a further six months to sell all remaining stocks. This timeline will also apply to downstream customers of V3 . The first year of no PFAS-related activities is assumed to be 2026 and this is the year for which first year losses are modelled and outlined in further sections. The non-use scenario discussed in this section is informed by the continued-use scenario outlined in Section 6. There will also be higher level generalisations and extrapolations to the wider context of this market alongside a discussion of the impacts on other related markets or entities. It should be noted that the NUS is impacted by the outcomes of the AoA (Section 5). For example, if it is concluded there are no viable alternatives for the specified use, the impacts will be greater. Alternatively, if alternatives are deemed to be technically and economically feasible and commercially available then the NUS will have fewer impacts. This will be highlighted in more detail in the following sections. 7.2 V3 In this section the NUS data for V3 are outlined and discussed. These data follow the same structure as in Section 6.2; however, in this case the imports, turnover and profit data are representative of the future situation should the use of PFAS be restricted in the EU. These data therefore relate to the quantified impacts that may be felt by V3 in response to the proposed PFAS restriction and can be observed in the following figures, which outline both the continued use up to 2025 and non-use estimates from 2026 onwards, known as the assessment period. The non-use scenario also describes not only the economic impacts but the social impacts of a restriction as well. 7.2.1 F93 F4 F6 V3 F4 F6 F4 F6 F4 F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 61 7.3.4 Unemployment As explained in Section 6.3.4, estimates on the number of jobs directly or indirectly related to the use of F4 filters could not be determined. Similarly, estimates on the number of jobs lost via a non- use scenario also could not be determined. It is possible that under a non-use scenario, Germany would likely see the largest negative impacts on employment due its share in the market (see section 6.3.4). Other EU member states with high numbers of employment in the pharmaceutical industry are Belgium and Ireland, given this they would also stand to incur some of the highest job losses in the EU alongside Germany. F96 F4 7.3.5 Innovations and investment Under a non-use scenario the investments companies made into R&D and clinical trials of new biopharmaceutical drugs utilising F4 and F6 filters would be lost. However, during consultation downstream users indicated they would switch to an alternative virus removal filter product; therefore any testing or clinical trials using F4 or F6 filters would need to be carried out again using the alternative in order to gain approval (see Section 6.3.5). This would be a sunk cost for these companies but no impact on EU27/EEA economy would result. If alternatives could not fulfil the performance requirements of F4 or F6 in these clinical trials and R&D could not continue, this would result in a loss to European economy. The exact monetary value of this spending cannot be quantified due to the lack of data provided during the consultation phase of this study. 7.4 Impact to patients One of the most prevalent diseases in Europe is cancer as discussed in Section 4.3. The emergence of monoclonal antibodies to treat certain types of cancers has had a positive impact on patients' lives. Monoclonal antibodies dominate the biopharmaceutical market; however, data is lacking on whether these drugs utilise F4 . V3 has disclosed that F4 is used to manufacture some types of cancer drugs (see Table 4-1). The cessation of these drugs could potentially have a significant impact on patients being treated with them. It Is assumed that 16.5% of the European pharmaceuticals market is biopharmaceuticals. F97 V3 F4 . Patients could potentially go without an effective treatment option for three to five years whilst implementation and recertification is done to switch manufacturing processes to an alternative. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 64 8 Conclusions Summary of the socio-economic impact assessment Table 8-1 sets out a summary of the societal costs associated with the non-use scenario during the assessment period 2026-2030. Figures are provided as annualised values. F98 Drug manufacturers Turnover Profit The European biopharmaceuticals market was estimated to be worth $48.2 (44.6) billion in 2022 and it was disclosed to RPA that up to F99 of the European biopharmaceuticals market uses F4 for virus removal. Based on these estimations, it can be assumed that these drug manufacturers have a revenue of C1 ( C2 ) billion associated with the use of F4 filters. This could be at risk under the NUS. It is also expected that this level of business lost could also negatively impact the profitability of these downstream users and therefore may also come with other impacts arising from the loss of business. F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 65 Patients Health/environmental impacts Employment Innovation/investment F4 F6 F100 there are no risks or impacts from the PVDF associated with these products under the NUS. Based on a report by the European Commission in 2019, there were 2.4 million employees in Europe's biopharmaceuticals industry. Assuming F101 of the biopharmaceuticals market in Europe uses F4 filters, it can be assumed that F102 employees in Europe have jobs associated with the use of F4 filters. These jobs could be at risk under a NUS. Costs will arise in the event clinical trials need to be repeated, however no data on specific costs of these clinical trials was received from drug manufacturers. Impact to Patients Patients could potentially go without an effective treatment option for three to five years whilst implementation and recertification is done to switch manufacturing processes to an alternative. Source: RPA study team F56 for PVDF in Biopharmaceutical Manufacture 20230823 RPA | 66 110RPA Risk & Policy Analysts Risk & Policy Analysts Limited Suite C, 2nd floor, The Atrium, St Georges Street Norwich, Norfolk, NR3 1AB, United Kingdom Tel: E-mail: IIIM@rpaltd.co.uk Website: www.rpaltd.co.uk If printed by RPA, this report is published on 100% recycled paper