Document zQKryoDDMBx0Ne7m2wBd3KgOm

== AKT 8358484 == [ VB: Possible meeting in Stockholm - PFAS V1 ] == Dokument 2 == [ V2 Reach Restriction Advocacy Slide Deck v2. - SWEDEN ] == CONFIDENTIAL FOR THE SWEDISH REACH COMPETENT AUTHORITY PFAS Restriction under REACH: Why PVDF for use in Biotherapeutic Filters Must Be Derogated P1 , Managing Partner, EU Focus Group P2 , Partner, EU Focus Group 13 September 2023 Agenda 1. Introduction: V1 & place of PVDF in product portfolio 2. Annex XV: Our Concerns 3. Annex XV: What Impact on PVDF? 4. Way Forward 11 -- IInnttrroodduccttiioon EEUU'rEFOOCCUU5.Sj GGRROOUUPP About V1 Medical V1 Medical is part of the V1 Group, a global company with its headquarters located in Japan Provides innovative, science-based solutions to a diverse range of markets. V1 Medical is one of the world's F1 leading manufacturers of filters employed in the production of biopharmaceuticals, i.e. complex medicines derived from characterized cell lines of human or animal origin (e.g. mammalian, avian, insect). F2 Substances and Articles of Concern PVDF F3 (hydrophilized polyvinylidene fluoride ("PVDF") hollow fibers) F4 (polyvinylidene fluoride ("PVDF") hollow fibers a new generation of virus filter made with, designed to achieve robust retention of parvoviruses and other small viruses under a broad range of operating conditions. a new generation of cell clarification filter for purification of protein solution. About Biopharmaceuticals Biopharmaceuticals are produced in living cells or extracted from human plasma, unlike synthetic drugs which are the result of chemical processes. Since its introduction in 1982, biopharmaceutical drugs have revolutionized the treatment of a broad spectrum of diseases and are increasingly used in nearly all branches of medicine. In recent years, the biopharmaceuticals market has developed much faster than the market for all drugs They are crucial for treating various pathologies such as cancer, and patients rely on their availability. Advantages over synthetic drugs they target only specific molecules, rarely causing the side effects associated with conventional small-molecule drugs. Thus, they are vital for patients in volatile conditions. Biopharmaceuticals are vital for medicine and have advantages over synthetic drugs, including targeting specific molecules and causing fewer side effects. They exhibit high specificity and activity. some patients react poorly to synthetic drugs, thus they are dependent on the broad availability of biopharmaceuticals Manufacturing of Biopharmaceuticals F4 F3 F5 Both F3 and F4 (" V1 Medical products") are made with PVDF and are used in the manufacturing of biopharmaceutical drugs, ensuring that biopharmaceuticals are safe, ultimately protecting human health and patient safety. Required step by various Directives and Guidelines Nanofiltration & Microfiltration Nanofiltration a well-established method allowing the removal of viruses based on size-exclusion that entails filtering of protein solutions through membranes with pores of nanometric sizes that have the capability to effectively retain a wide range of viruses. The use of this filter during nanofiltration is a necessary step in the production of biopharmaceuticals to effectively remove viruses from the end-products, i.e. human medicines. Microfiltration designed to have a higher filterability of antibodies. a well-established method that allows the separation of the antibodies (proteins) from the animal cells. The use of this filter during microfiltration occurs upstream in the filtration of impurities, before the virus removal stage. Necessary step in the production of biopharmaceuticals aimed to separate the animal cells from the antibodies. Why nanofiltration in the first place? 1. Inherent risks Biological products, made from human or mammalian cells possess an inherent risk of being contaminated by viruses that can be pathogenic to humans. 2. Societal Implications in case of a viral contamination significant burden from financial, regulatory and time aspects implies that production at the facility where it occurred is stopped until the causes are eliminated. may lead to product shortages for patient treatments 3. Product Requirement In addition, the safety and efficacy of biopharmaceuticals in humans require drugs of highest purity, right concentration allowing the API to work effectively Examples of removed viruses (HIV, HAV, and B19V), and model viruses covering a wide range of physicochemical proper ties and sizes . parvoviruses (B19V, BPV, CPV, MVM, PPV;), picornaviruses (HAV, BEV, EMCV, PEV, HPV-1, TMEV; caliciviruses (FCV;), papovaviruses (SV40;), flaviviruses (BVDV, WNV), togaviruses (SINV, SFV), reovirus 3 (Reo3;), retroviruses (HIV;), rhabdoviruses (VSV), and herpesviruses (PRV, HSV, IBRV) Coronaviruses (SARS-CoV-1, SARS-CoV-2) Nanofiltration is an integral part of the manufacturing process of biopharmaceuticals 120,0% 100,0% 80,0% 60,0% 40,0% 20,0% 0,0% % of products licensed with nanofiltration step Conventional 1997 2000 2002 Source: Innouye, M., & Burnouf, T. (2020). The Role of Nanofiltration in the Pathogen Safety of Biologicals: An Update. Bentham Science Publishers. doi:10.2174/1573413715666190328223130 In recent years nanofiltration has increasingly become dominant in the field of human plasma derived products. 1997 two out of seven products licensed contained a nanofiltration step, this rate increased to 6 out of 7 in 2000 and 100% in 2002 and 2003 Note for microfiltration: These filters are in the market entry/market development stage and are being trialled by some EU drug manufacturers as they can increase productivity significantly. 2. Annex XV: Our Concerns EUr OCU5_, GROUP PFAS Restriction Timeline (2023-2026) TODAY Restriction Dossier Submission Public Consultation Publication (7 February) RAC adopts opinion and draft SEAC opinion ECHA Opinion Consultation on draft SEAC opinion Council/EP Scrutiny (tbc) Entry into force Draft Annex XVII Restriction adopted (tbc) Quality Check 13 Jan 2023 Conformity check 22 March 2023-Sep 2023 PREPARATORY PHASE STAGE 1: Annex XV Preparation STAGE 2: Public Consultation Nov 2023 Nov 2023-Jan 2024 ECHA PHASE STAGE 3: Opinion Development Feb-Mar 2024 Q1-Q3 2025 (tbc) Q3 2025 (tbc) Q4 2025 Early 2026 (tbc) COMMISSION PHASE SCRUTINY/ENTRY INTO FORCE PHASE STAGE 4: STAGE 5: Commission Stage Entry into Force & Enforcement "REACH Committee" First bans expected as from July 2027 onwards Approach of the Five Countries: "BAN, BAN, BAN" "Universal Ban" Time-limited derogations = "delayed ban" Annex XVII restriction to apply to all PFAS (fulfilling OECD definition), 18 months of `transition period' after Entry into Force (EiF). applied either 6.5 or 13.5 years later from EiF Derogations tentative derogations proposed in square brackets [...] where data is not enough pesticidal active substances biocidal active substance human and veterinary medicinal products Time-limited derogations = "delayed ban" Dominating "anti-PFAS" narrative is based on old technologies based PFOS, PFOA PFOS, PFOA are banned since more than 10 years in Europe! REACH PFAS Annex XV - Our Concerns THE PROPOSAL BY 5 COUNTRIES IS FLAWED No derogations, only bans (+18 months after EiF) or "delayed bans" (+6.5 or +13.5 years after EiF) Persistency - main criterion for ban ("P-sufficient approach"): No hazard assessment No information on use resulting in emissions Nor risk assessment Insufficient analysis of alternatives No causal link between alleged presence of PFAS and actual fluoropolymers usage Wrong premises (e.g. non-fluorinated polymerization aids are `better' for the environment) Alternative RMOs not considered OVERALL: no demonstration of unacceptable risk & no recognition that fluoropolymers can be produced responsibly DIRECT IMPACT ON PVDF 1. All PFAS as per definition, unless explicitly derogated, will be banned as from July 2027 2. Most substances will be completely banned after a transition period (if at all) 3. While the report includes consideration of the use of PFAS in medical device and some limited pharmaceutical applications, the biopharma sector is a missing use category and needs to be appropriately considered 4. PVDF in medical biotherapeutic filters are in scope of restriction proposal. 5. Fluorinated Polymerization aids are banned for the production of PVDF 6. Transported isolated intermediates used under strictly controlled conditions are banned (contrary to REACH). OVERALL: indirect ban on high-tech economic sectors, including green technologies, relying on fluoropolymers. Main Concern of the Five Countries: PERSISTENCY Hazards/Risks (Problem identification L.C.D.: carbon-fluorine bond particularly strong and highly persistent "All PFASs are considered to be very persistent, either on the basis of their own very persistent properties or the very persistent properties of their terminal degradation product (arrowhead)" (p.22) "P-Sufficient approach" Very Persistent Definition Grouping "Additional hazardous properties depend on the specific structure of a PFAS": Long-range transport potential ("LRTP") Mobility Accumulation in plants Bioaccumulation Ecotoxicity Endocrine Activity/Endocrine Disruption Effects on Human Health Referenced "additional hazardous properties" are not applicable to fluoropolymers 3. Annex XV: What Impact on PVDF? EUr OCU5_, GROUP Fluoropolymers > very persistent (vP) > Not toxic (T) > No bioaccumulation (B/vB) Not mobile (M or vM) > Stable in environment Biologically inert Fluoropolymers are: > Distinct subclass of PFAS > Thermal decomposition in waste to energy plants v Example of Fluoropolymers: PVDF PTFE PFA Proposal: The durability of Fluoropolymers provides applications the essential longevity and needed performance and should be exempted from any potential restrictions *According to the OECD criteria Preliminary assessment ~ May be subject to change EUFOCUS GROUP Risk Assessment: Biotherapeutic filters NO Hazards very persistent (vP) Not toxic (T) No bioaccumulation (B/vB) Not mobile (M or vM) Stable in environment Biologically inert Polymer of Low Concern (OECD*) NO Exposure Manufacturing Not manufactured in the EU Concerns regarding manufacturing can be addressed at site (at Source) Use operated by trained professionals, with no exposure to workers or patients as the PVDF membrane is encapsulated in the filter. No adverse events related to nanofiltration have been recorded so far, and regulators recognize and mandate it as a safe virus removal method. End of life Filter are considered as hazardous waste under the Waste Framework Directive. filters need to be incinerated due to their contamination with pathogens at special facilities as hazardous waste at high temperatures Under these extreme conditions, the C-F bond breaks down, thus completely destroying any PFAS (confirmed by several studies) next slide NO Risks Fluoropolymers, such as PVDF, do not pose any risks to the environment and human health and should be generally exempted from the PFAS Restriction End of Life - Mandated Incineration Under EU and national legislations, filters need to be incinerated due to their contamination with pathogens at special facilities as hazardous waste at high temperatures. For hazardous waste, the minimum temperature of the combustion gases must be 1100 C Polytetrafluoroethylene (PTFE or Teflon) is the most stable fluorine containing polymer and it can be concluded that complete thermal decomposition is achieved at a temperature of about 800 C. Other fluorine-containing polymers thermally decompose completely at a temperature of 850 C. thermal resistance chart to the right A perfect, complete combustion of PFASs results, in theory, in the emission of water, CO2, HF and, depending on the functional groups in the PFAS, sulphur dioxide, phosphorus oxide and nitrogen dioxide Additional cleaning steps for the flue gas are required/mandated to remove potential remaining pollutants Source: Dutch National Institute for Public Health and the Environment, RIVM report 2021-0143 Order of thermal resistance (high to low): PTFE PFA MFA FEP ETFE PVDF PE ECTFE PCTFE Impacts of the non-use scenario in the assessment period 2026-2030. Supply chain sector Criteria Overview (quantified where possible) 28,000 to 43,000 1m2 F6 will not be imported because of this 1,900 kg to 2,900 kg of PVDF will not enter the EU. V1 V2 , Ltd. Production/imports F7 filters are in their infancy. However, 5,000 - 10,000 of these filters are projected to enter the EU by the end of 2030. This would not happen under a non-use scenario. Health/environmental Due to no F8 or F7 filters being imported into the EU, there are no risks or impacts from the PVDF associated with these products under impacts the NUS. 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 10% of the Turnover European biopharmaceuticals market uses F8 for virus removal. Based on these estimations, it can be assumed that these drug manufacturers have a revenue of $4.82 (4.46) billion associated with the use of F6 . This could be at risk under the NUS. Profit 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. Drug Health/environmental Due to no F8 or F7 filters being imported into the EU, there are no risks or impacts from the PVDF associated with these products under manufacturers impacts the NUS. Based on a report by the European Commission in 2019, there were 2.4 million employees in Europe's biopharmaceuticals industry. Assuming 10% of Employment the biopharmaceuticals market in Europe uses F6 , it can be assumed that 240,000 employees in Europe have jobs associated with the use of F6 . These jobs could be at risk under a NUS. Innovation/ 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 investment manufacturers. Patients 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 Alternatives F9 There are three primary types of nanofiltration, each designed for their unique use case and environment, as such they cannot be interchanged 1:1. 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 type of virus removal must retain this orthogonality requirement. PVDF enables nanofiltration, which is the only process in the nanofiltration targeting effectively smaller viruses. There are practically no alternatives that can replace the high performance provided by PVDF in in the biopharmaceutical sector and Protein concentration plays a crucial role in determining the right filter. (See Image) - However, taking significant trade-offs into account a switch to alternatives may be possible in the long term (Note: Alternatives may use PVDF in their housing) E.g. Both types of filters are widely used in pharmaceutical products which 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. alternatives have a lower transmission of the targeted protein of interest while only PVDF can meet the various performances required for drug product applications PES and polysulfone require an asymmetric pore structure, causing the clogging of the membrane interior progresses during filtration 10-15 years of development and regulatory timeframe required for the development of alternative filters and the availability of certain biopharmaceuticals may be negatively affected Biotherapeutic Filters are well regulated and mandated Biotechnology-based drugs(ICH Q 5 A): ICH Q5AR1: VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN Step 4 version , dated 23 September 1999 ICH Q5A(R2): VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN Draft version, Endorsed on 29 September 2022, Currently under public consultation. Plasma derived drugs EU guideline: EMA/CHMP/BWP/706271/2010 prepared by the Committee for medicinal products for human use (CHMP) Guideline on plasma-derived medicinal products (EMA/CHMP/BWP/706271/2010 ) 1.EMA/CHMP Guideline: Guideline on Plasmaderived Medicinal Products. EMA/CHMP/BWP/706271/2010. Amsterdam: European Medicines Agency (EMA); 2011 Jul 21. European Medicines Agency. Guideline on the clinical investigation of human normal immunoglobulin for intravenous administration (IVIg). EMA/CHMP/BPWP/94033/2007 rev. 3. Committee for Medicinal Products for Human Use (CHMP), 28 June 2018. European Medicines Agency. Guideline on the clinical investigation of human normal immunoglobulin for subcutaneous and/or intramuscular administration (SCIg/IMIg). EMA/CHMP/BPWP/410415/2011 rev 1. 23 July, 2015. European Medicines Agency. Guideline on plasma-derived medicinal products. EMA/CHMP/BWP/706271/2010. London. 21 July, 2011. European Medicines Agency. Guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIg). 28 June 2018. 8 Legal Areas of Concern 1. There are inaccuracies in the conditions on the proposed restriction - no exemption or derogations for the biopharmaceutical sector and V1 Medical products; 2. PVDF is generally included among more than 10,000 substances that possess different properties; 3. PVDF would fall under the scope of the restriction by solely meeting a non-legally binding accepted definition; 4. The assessment of hazard and risks of PVDF does not appear legally sound; 5. The grouping approach is incorrect; 6. There is insufficient information on the uses, resulting emissions or exposure of PFAS in the biopharmaceutical manufacture sector; 7. The information on alternatives is not properly assessed as regards the production of PVDF; 8. The Proposal does not properly assess the interplay with other EU legislation such as the EU Pharmaceutical legislation. As such, the proposal opposes the principles of 'Better Regulation' and creates significant uncertainties on the market 44. WWaayy FFoorrwwaarrdd EEUU'rEFOOCCUU5.Sj GGRROOUUPP Way Forward Preferred RMO The restriction of PFASs must be substance-related and risk-based (Article 68 para. 1 of the REACH Regulation). It is clear that not all PFAS pose an unacceptable risk that would justify a restriction. Especially, the restriction must differentiate between the different groups of PFAS and the risks, and the risks posed by their uses. Fluoropolymers, such as PVDF, do not pose any risks to the environment and human health and should be generally exempted from the PFAS Restriction or benefit from a time-unlimited derogation. Alternative RMOs Option 1: V1 Medical products (biotherapeutic filters) should be exempted a priori from the Proposal as they should not be covered by the REACH Regulation; or, Option 2: V1 Medical products should be exempted a priori from the Proposal as they are used in a closed system; in alternative, Option 3: V1 Medical products should benefit from a time- unlimited derogation in relation to the Proposal as the same rationale of plant protections products, biocides and human and veterinary medicines should apply. QQuueessttiioonnss?? EEUUE'FFOOCCUUSSJ GGRROOUUPP TThhaannkk yyoouu!! EEUUE'EFOOCCUUSJ GROUP