Document jy2DOVM719OxkKzgmBXJ25ayR

Human Health Medicinal Products Sector Survey Impact of Proposed PFAS Restric=on on Pa=ent Access to Medicines & EU Strategic Autonomy Disclaimer: This document was prepared in good faith by represented associa6ons for the purposes of preparing the public consulta6on response to the PFAS Restric6on proposed under Title VIII of the REACH Regula6on. The 6meframe of the survey undertaken to gather the evidence was very short and companies therefore priori6sed the compounds for which they would provide informa6on with the intent to provide as much substan6ated informa6on as possible during the ECHA consulta6on period. The informa6on received does not cover the full EU porFolio of the human pharmacu6cal industry. Table of Contents 1. Execu6ve Summary ........................................................................................................................3 2. Glossary of Terms ...........................................................................................................................4 3. Introduc6on....................................................................................................................................6 4. Survey Methodology ......................................................................................................................6 5. Survey Findings...............................................................................................................................8 5.1 ATC Code Analysis & Types of Therapeu6c Areas Impacted ......................................................... 8 5.2 Medicinal Product Regulatory Approvals - Global & European Impact .....................................11 5.3 PFAS Use Scenarios.....................................................................................................................14 5.3.1 Research & Development - PPORD Jus6fica6on .................................................................14 5.3.2 Fluoropolymers used in the plant, equipment & single use systems within Manufacturing Facili6es ........................................................................................................................................ 16 5.3.3 PFAS Process Chemicals used in the Manufacture of Fluorinated & non-fluorinated APIs .18 5.3.4 APIs with PFAS moiety .........................................................................................................20 5.3.5 Excipients with PFAS moiety ................................................................................................ 21 5.3.6 Packaging containing PFAS cons6tuents or components ....................................................23 5.3.7 PFAS cons6tuents or components present in drug delivery devices ...................................24 5.4 Pa6ent Impact ............................................................................................................................ 27 5.4.1 Prevalence of Disease State & Pa6ent Number Es6mates ..................................................27 5.4.2 WHO Essen6al Medicines List ............................................................................................. 29 5.4.3 Cri6cal Medicines List - EU Member States ........................................................................30 5.4.4 Netherlands Case Study ......................................................................................................32 6. Summary Conclusions ..................................................................................................................35 Appendix 1 ...........................................................................................................................................37 Appendix 2 ...........................................................................................................................................40 Appendix 3 ...........................................................................................................................................42 Infographic 1.........................................................................................................................................51 Infographic 2.........................................................................................................................................53 Engaging Associa6ons .......................................................................................................................... 55 2 1. Execu3ve Summary The European Federa.on of Pharmaceu.cal Industries and Associa.ons (EFPIA), the European Fine Chemicals Group (EFCG), the Associa.on of the European Self-Care Industry (AESGP), Medicines for Europe (MfE) and Vaccines Europe represent the major associa.ons of the European human pharmaceu.cal supply chain. The restric.on proposal plans to restrict the manufacture, marke.ng and use of per- and polyfluoroalkylated substances and will be the widest ever put in place, as it could concern up to 10,000 substances and would have an irredeemable impact on many industrial sectors, including the essen.al health products and technologies sector. The procedure currently underway could lead to a ban on all PFASs by 2027, with very limited deroga.ons. It is our interpreta.on that the most important socio-economic impact to evaluate, is nonavailability of medicinal products on pa.ents. The associa.ons therefore gathered evidence across their membership to jus.fy deroga.ons, to prevent medicine shortages, and to inform ECHA and the Commission of the poten.al impact of the PFAS Restric.on on medicinal product supply chain. Such a restric.on will have an in-depth impact on the EU's Strategic Autonomy targets and compe..veness, as well as on the accessibility and availability of medicinal products for European ci.zens. The expected consequences of the ban will jeopardise all produc.on of pharmaceu.cal substances in Europe and will work against the efforts of most European Member States to relocate cri.cal pharmaceu.cal produc.on chains on EU territory. Furthermore, it will definitely curb the ini.a.ve of European Member States to promote a "Cri.cal Medicines Act" to reduce Europe's health dependence on non-European countries. To allow for the con.nued research, development and manufacturing of medicines including biopharmaceu.cals and vaccines, the products in scope of specific regula.ons should generally be derogated from a universal PFAS restric.on, including all steps which are necessary for their manufacturing, packaging and delivery devices, in the EEA. Highlights on evidence gathered: - The 40 companies par.cipa.ng in the survey iden.fied 1922 ac.ve substances, which will be impacted by the proposed Restric.on. At least 93% of APIs and or medicinal products are produced in a manufacturing facility which depends upon fluoropolymer use in piping, equipment (process/u.li.es), & consumables for process safety and regulatory reasons; - Only 7% (139 out of 1922) of APIs contain the PFAS moiety, and therefore fall under the proposed deroga.on for APIs - 9.5 % (169 out of 1794) APIs were reported to be undergoing R&D, at an EU manufacturing facility, and would have to be produced at a non-EU facility - Only 86 APIs out of 1,922 (4.4%) are manufactured completely outside of the EU showing the importance of pharmaceu.cal manufacturing in the EU; - The number of cri.cal medicines impacted if EU manufacturing opera.ons ceased, results in 61% - 78% when comparing with EU member state cri.cal medicines lists. - 674 references are on the WHO essen.al medicines list. 3 2. Glossary of Terms Raw Material Star,ng Material Pharmaceu,cal Intermediate Ac,ve pharmaceu,cal ingredient Medicinal Product Excipient Bulk product Finished medicinal product Drug Delivery Device "A raw material is a substance or mixture of substances that is used in the produc7on process of a drug substance, but which is not incorporated as a significant structural fragment into the structure of the drug substance (e.g. process solvent, catalyst, reagent)". => Pharmaceu7cal manufacturers are typically the downstream user of raw materials API starting material is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or produced in-house. API Starting Materials normally have defined chemical properties and structure. ICH Guideline Q7A => Meets the definition of Intermediate as defined in REACH Article 3(15) A material produced during steps of the processing of an API that undergoes further molecular change or purifica7on before it becomes an API. Intermediates may or may not be isolated. [ICH Guideline Q7A] => Meets the defini7on of Intermediate as defined in REACH Ar7cle 3(15) An ac7ve substance or API (Ac7ve pharmaceu7cal ingredient) is intended to be used in the manufacture of a drug (medicinal) product and that, when used in the produc7on of a drug, becomes an ac7ve ingredient of the drug product. Such substances are intended to furnish pharmacological ac7vity or other direct effect in the diagnosis, cure, mi7ga7on, treatment, or preven7on of disease or to affect the structure and func7on of the body. [ICH Guideline Q7A "Good Manufacturing Prac7ce Guide for Ac7ve Pharmaceu7cal ingredients"] => As per Ar7cle 2(5)(a) of REACH - Ac7ve substances used in the manufacture medicinal products are exempt from Authorisa7on and Registra7on Medicinal product as defined in Direc7ve 2001/83/EC - Any substance or combina7on of substances presented as having proper7es for trea7ng or preven7ng disease in human beings; or Any substance or combina7on of substances which may be used in or administered to human beings either with a view to restoring, correc7ng, or modifying physiological func7ons by exer7ng a pharmacological, immunological or metabolic ac7on, or to making a medical diagnosis. A cons7tuent of a medicine other than the ac7ve substance (h]ps://www.ema.europa.eu/en/glossary/excipient) => As per Ar7cle 2(5)(a) of REACH - excipients used in the manufacture medicinal products are exempt from Authorisa7on and Registra7on Any product which has completed all processing stages up to, but not including, final packaging [EudraLex - Volume 4 - Good Manufacturing Prac7ce (GMP) guidelines] A medicinal product which has undergone all stages of produc7on, including packaging in its final container [EudraLex - Volume 4 - Good Manufacturing Prac7ce (GMP) guidelines] Drug delivery device (non-integral): any device intended to administer medicinal products, 7ssues or cells of human or animal origin, or their deriva7ves, or biological substances. A non-integral drug delivery device is governed by Regula7on 2017/745 and is CE marked. (Regula7on 2017/745 (EU MDR - defini7on 9)) Drug delivery device as part of single integral product: if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combina7on and which is not reusable, that single integral product shall be governed by Direc7ve 2001/83/EC. A single integral drug delivery device is not CE marked and is subject to a No7fied Body Opinion on the conformity to Annex I General Safety and Performance Requirements. (EMA guideline on quality documenta7on for medicinal products when used with a medical device) 4 On-site or transported intermediate As per Ar7cle 3(15), an intermediate is a substance that is manufactured for and consumed in or used for chemical processing in order to be transformed into another substance (hereinaier referred to as "synthesis"). If the manufacture and subsequent synthesis of an intermediate into another substance takes place on the same site, this is an on-site intermediate. If an intermediate is transported between or supplied to other sites, for synthesis into another substance, this is a transported intermediate. => Ar7cle 2(8)(b) of REACH - intermediates, as defined in Ar7cle 3(15), are exempt from Authorisa7on. Ar7cle 68(1) of REACH - restric7ons in general do not apply to on-site intermediates 5 3. Introduc3on The Associa.ons acknowledge the bona fide human health and environmental risk associated with some of the fluorine-containing compounds that fall within scope of the proposed PFAS Restric.on. The proposed PFAS restric.on is a deliverable of the chemical strategy for sustainability1, the objec.ves of which are strongly supported by our sector. However, the PFAS Restric.on as proposed has the poten.al to conflict with the pharmaceu.cal strategy for Europe2, which aims to support compe..veness, innova.on, and sustainability of the EU's pharmaceu.cal industry. It is our interpreta.on that the proposed universal ban on PFAS will accelerate the erosion of innova.on in EU, discourage medicine manufacturing, jeopardize jobs and growth as well as nega.vely impac.ng pa.ents' access to medicines. More than 10,000 PFAS chemicals could fall within the scope of the PFAS Restric.on, which makes it the most complex ever proposed in the EU. For example SEAC guidance (SEAC-52 of 15 September 20213) on the prepara.on of the poten.al impact of a proposed restric.on on consumers, notes an excep.on for medicinal products, where pa.ents stand to lose the corresponding health benefit. It is our interpreta.on that the most important socio-economic impact to evaluate, is non-availability of medicinal products on pa.ents. As part of the prepara.on of a submission to the ECHA consulta.on on the proposal for an EEA ban on all PFAS, the European based human pharmaceu.cal trade associa.ons carried out a survey across their memberships to outline how the proposed PFAS Restric.on could impact pa.ent access to medicines and hinder the u.lisa.on of pharmaceu.cal manufacturing capacity in the EU. The objec.ve of this work was to gather evidence to jus.fy deroga.ons, to prevent medicine shortages, and to inform ECHA and the Commission of the poten.al impact of the PFAS Restric.on on medicinal product supply chains. 4. Survey Methodology This report presents the findings of a comprehensive industry-wide inter-associa.on survey of pharmaceu.cal manufacturers in Europe. A survey ques.onnaire was open to members of the aforemen.oned trade associa.ons over a 6-week period in July and August 2023. To aim of this survey was to iden.fy: Which pharmaceu.cal substances are currently relying on the use of PFAS chemicals in their manufacturing processes, composi.on, and packaging? What would the impact of the restric.on be on these products and the pa.ents who rely on them? Given the short .meframe of the ECHA consulta.on, a full assessment of companies' porjolios was not feasible for all respondents. Member companies with larger product 1 h]ps://environment.ec.europa.eu/strategy/chemicals-strategy_en 2 h]ps://health.ec.europa.eu/medicinal-products/pharmaceu7cal-strategy-europe_en 3 h]ps://echa.europa.eu/documents/10162/0/afa_seac_surplus-loss_seac-52_en.pdf/5e24c796-d6fa-d8cc882c-df887c6cf6be?t=1633422139138 6 porjolios were instructed to priori.se the ac.ve substances included in the survey. Therefore, the received findings represent an "at minimum" es.ma.on of PFAS use in pharmaceu.cals and should be seen as a star.ng point in the further explora.on of the overall impact of the ban on the industry and pa.ents. The scope of the survey covered: APIs in manufacturing and packaging opera.ons at a facility in the EEA and / or Medicinal products with PFAS cons.tuents present in the intermediate packaging or drug delivery device of a medicinal product placed on the market in the EEA. Respondents were asked to provide ATC code4 data and number of global marke.ng authorisa.ons for each ac.ve substance in company product porjolios. By obtaining the number of impacted ac.ve substances associated with each ATC code, it was possible to iden.fy the disease states that are affected most and summarise epidemiology informa.on from publicly available sources. Using ATC data, it is possible to conduct a search of cri.cal medicines lists e.g. WHO Essen.al Medicines List, EU Member State's cri.cal medicines lists. In addi.on, respondents were asked to indicate if an ac.ve substance is on the WHO Essen.al Medicines list. In addi.on to EU medicinal products legisla.on, raw materials and other chemicals used in pharmaceu.cal produc.on facili.es are regulated by REACH. Therefore, respondents were asked to indicate if an ac.ve substance: Is produced in a manufacturing facility which depends upon fluoropolymer use in piping, equipment (process/u.li.es), and consumables and / or Containing a CF2 / CF3 func.onal group which is specified in the marke.ng authorisa.on of medicinal product. In this survey, a specified substance refers to a raw material, solvent, catalyst, reagent, star.ng material5, intermediate, ac.ve pharmaceu.cal ingredient, excipient listed in the CTD (common technical document). The CTD is submioed as part of a marke.ng authorisa.on applica.on and includes a descrip.on of the manufacturing process, in which specified substances are iden.fied. As already indicated the proposed restric.on (RO2) as wrioen only proposes a deroga.on for ac.ve pharmaceu.cal ingredients with EU marke.ng authorisa.on containing a CF2 / CF3 func.onal group. The PFAS restric.on, as phrased in the proposal, will generate a significant number of changes to the marke.ng authorisa.ons of medicinal products. This survey does not evaluate the .me and capacity constraints for EMA, na.onal or global health authori.es. It is foreseen that these regulatory agencies would be faced with a significant volume of submissions for varia.ons to marke.ng authorisa.ons. 4 The ATC (Anatomical Therapeu3c Chemical) code is an interna3onally accepted classifica3on system for medicines which is maintained by WHO. An ATC code is a unique iden3fier assigned to a medicine according to the organ or system it works and how it works. 5 API star7ng material is defined in ICH Guideline Q7A - a raw material, intermediate, or an API that is used in the produc7on of an API and that is incorporated as a significant structural fragment into the structure of the API. Star7ng material meets the defini7on of an Intermediate as defined in REACH. 7 5. Survey Findings Data was received across 40 companies represen.ng a range of prescrip.on-only medicines (POMs) and over-the-counter (OTC) products, 80 % and 20 % respec.vely. This accounted for 47 677 global marke.ng authorisa.ons across 12 product categories Small Molecule 1383 Peptide 180 Monoclonal antibody 113 Vitamin 48 Vaccine 30 Carbohyd rate 25 Herbal & homeopa thic product 21 Blood product 10 Oligonucl eotide 9 Cell therapy 5 Gene therapy biological 2 Evidence received for this report covers the types of therapeu.c areas which will be impacted, including the impact across exis.ng market authorisa.ons in the EU and globally. The report further focuses on PFAS use scenarios across research & development; use in the plant, equipment & single use systems within manufacturing facili.es; raw, star.ng materials and intermediates of both fluorinated and non-fluorinated APIs; APIs and excipients with PFAS moiety; and packaging and drug delivery devices. We provide further informa.on on the expected pa.ent Impact considering medicines impacted from the WHO essen.al medicines list and cri.cal medicines list of various EEA member states. 5.1 ATC Code Analysis & Types of Therapeu7c Areas Impacted This survey represents a wide range of the pharmaceu.cal industry. This is evident as all 14 main anatomical/pharmacological groups (1st level ATC codes) are represented in this survey. The chart below shows the distribu.on of these groups. 8 Figure 1: Distribu.on of the 14 main anatomical/pharmacological groups (1st level ATC codes) are represented in this survey 400 350 Number of ATC Codes (Level 1) 300 250 200 150 100 50 0 olism rgans stem gicals ones s and...c Use gents stem stem llents stem rgans rious etab ing O ular Sy atolo Horm mone stemi ting A etal Sy ous Sy repe ory Sy sory o - Va V t and md Formiovasc - Derm nd Sex ex hor For Sy odula o-Skel - Nerv es and spirat - Sen rac Bloo Card D A em xcl. S tives unom uscul N cticid R - Re S - tec e tary t nd C en od A o ry Sys tions, ntiinfe Imm d - M M rina ara - A An s, ins duct lim - Bl U p J tic ro A - A B enito al pre oplas itic p G - Ghormon Antine L - tiparas - An ic stem P - Sy H Out of these, 674 references are on the WHO essen.al medicines list6 of which 499 prescrip.on-only medicines (POM) and 171 over-the-counter (OTC) medicines. The companies par.cipa.ng in this survey have provided informa.on on how the proposed restric.on on PFAS will affect the supply and availability of medicines. The level of detail provided allows us to differen.ate between the impacts on different pharmacological/ therapeu.c groups (3rd level ATC code). In this survey, 192 pharmacological/therapeu.c groups (3rd level ATC code) are represented. The 15 most commonly reported are presented in the table below. It is evident that these represent both important and diverse pharmacological/therapeu.c areas. 6 2023 WHO model list of essen7al medicines (23rd list): h]ps://www.who.int/publica7ons/i/item/WHO-MHPHPS-EML-2023.02 9 Figure 2: The 15 most reported ATC codes (level 3) J05A (Direct acting antivirals) J01C (Beta-lactam antibacterials, penicillins) N06A (Antidepressants) R06A (Antihistamines for systemic use) D01A (Antifungals for topical use) B01A (Antithrombotic agents) R03A (Adrenergics, inhalants) L01X (Other antineoplastic agents) M01A (Antiinflammatory and antirheumatic products,... B02B (Vitamin k and other hemostatics) L04A (Immunosuppressants) A10B (Blood glucose lowering drugs, excl. Insulins) A02A (Antacids) N02B (Other analgesics and antipyretics) A10A (Insulins and analogues) 0 10 20 30 40 50 60 70 80 An overview of the distribu.on of pharmacological/therapeu.c areas (3rd level ATC codes) is provided in Appendix 1. 10 5.2 Medicinal Product Regulatory Approvals - Global & European Impact In restric.on proposal op.on 2 (RO2)7, APIs with EU marke.ng authorisa.on are proposed a .me-unlimited deroga.on from the full ban. It is important to note, that not all API produc.on in EU have marke.ng authorisa.on. As can be seen from Figure 3, 13 % of APIs manufactured in EU will not be derogated by proposed RO2 4c, as they are s.ll under development or are only manufactured for export. Further, the regulatory status of 1% of the APIs in the survey was not provided. Figure 3 EU Regulatory Approval Status of Ac.ve Substance EU Regulatory Approval Status of Active Substance APIs with EU market approval APIs without EU market approval (active substance is in development) APIs without EU market approval (manufacture active substance for export) No info on regulatary status In total 1696 ATC codes were reported for the 1662 APIs with EU market approval8. 7Restric7on proposal op7on 2 of the Annex XV restric7on proposal (h]ps://echa.europa.eu/documents/10162/1c480180-ece9-1bdd-1eb8-0f3f8e7c0c49) for PFAS proposes a ban with use-specific deroga7ons and indicates a 7me unlimited deroga7on for ac7ve substances 8 More than one ATC code can be reported for each API 11 Figure 4 lists the top 10 most reported pharmacological/therapeu.c areas (3rd level ATC codes) with EU market approval in this survey. The full list of Level 3 ATC codes for APIs with EU market approval in this survey with number of .mes the ATC code is reported can be found in Appendix 1. Figure 4 - Top 10 Therapeu.c Areas Associated with Ac.ve Substances Approved in the EU L01X (Other antineoplastic agents) B01A (Antithrombotic agents) D01A (Antifungals for topical use) L04A (Immunosuppressants) M01A (Antiinflammatory and antirheumatic products, non-steroids) B02B (Vitamin k and other hemostatics) A10B (Blood glucose lowering drugs, excl. Insulins) A02A (Antacids) A10A (Insulins and analogues) N02B (Other analgesics and antipyretics) 0 10 20 30 40 50 60 70 80 Of the 1922 APIs reported in this survey, 71 (3.7%) were reported to be manufactured in EU only for export. Figure 5 shows the 10 most reported ATC codes without EU market approval in this survey. Table ZYX: The full list of 3rd level ATC codes for APIs for export with number of .mes the ATC code is reported can be found in Appendix 1. 12 Figure 5 Top 15 Therapeu.c Areas Associated with Ac.ve Substances not Approved in the EU (export) A03F (Propulsives) N07X (Other nervous system drugs) N02C (Antimigraine preparations) N01B (Anesthetics, local) J07B (Viral vaccines) J01C (Beta-lactam antibacterials, penicillins) A02B (Drugs for peptic ulcer and gastro-oesophageal... R03A (Adrenergics, inhalants) L04A (Immunosuppressants) G04C (Drugs used in benign prostatic hypertrophy) B05A (Blood and related products) A16A (Other alimentary tract and metabolism products) C09B (Ace inhibitors, combinations) A10B (Blood glucose lowering drugs, excl. Insulins) N02A (Opioids) 0 1 2 3 4 5 6 In the survey, 169 APIs were reported to be under late-stage development. Out of these, 15 (8.8%) reported the relevant ATC code. Hence, details on therapeu.c area in this sec.on is regarded insufficient to report. Informa.on on the 3 rd. level ATC codes for APIs in development can be located in Appendix 1. 13 5.3 PFAS Use Scenarios 5.3.1 Research & Development - PPORD Jus;fica;on New APIs under development in the EU are not included in the proposed .me-unlimited deroga.on. The generic exemp.on for scien.fic research and development is capped at 1000kg. When a new medicinal product is in late-stage clinical trials9, the size of manufacturing campaigns (and its intermediate steps in produc.on) can exceed 1000kg per year. The produced material may be used to supply clinical trials, or the product launch campaign post a successful regulatory approval. The PFAS Restric.on must include a deroga.on for PPORD (Product, process-oriented research, and development) to facilitate both development of API manufacturing processes and clinical trial supply campaigns. If not, the development of medicinal products in the EU would be severely impacted by the restric.on proposal. In the survey, 169 APIs were reported to be under development, at an EU manufacturing facility. These facili.es depend on fluoropolymer materials in plant, equipment, and single use systems. Figure 6 provides an indica.on of how the development of these APIs could be impacted, i.e. manufacturing opera.ons only or manufacturing opera.ons and use of a specified substance containing a PFAS moiety occurs. Figure 6 - Impact of PFAS Restric.on on R&D Manufacturing Opera.ons (169 Ac.ve Substances) R&D manufacturing operations + API with PFAS moiety in structure R&D manufacturing operations + intermediate with PFAS moiety in structure R&D manufacturing operations + PFAS processing chemicals R&D manufacturing operations + PFAS excipient in medicinal product R&D manufacturing operations only 9 Late-stage clinical trials refers to the third and last stage in the clinical development of a new medicinal product. 14 Of these APIs under development 49 (29%) indicated that at least one specified substance containing a -CF2- or -CF3 group was used in the manufacture of the API. This final development of these APIs will not be possible in EU if the restric.on proposal is accepted in its current wording. Only 15 (8.8%) of the APIs under late-stage development had ATC code reported. Hence, details on therapeu.c area in this sec.on is regarded insufficient to report. 16 APIs are under development (9%) with at least one -CF2 or -CF3 group. These will not be covered by the proposed deroga.on as an EU marke.ng authorisa.on has not yet been obtained. Hence, the final development of these APIs will not be possible in the EU. 17 APIs under development (10%) reported using staring material and/or intermediates with at least one -CF2 or -CF3 group. These will not be covered by the proposed deroga.on as an EU marke.ng authorisa.on has not yet been obtained. Hence, the final development of APIs will not be possible in EU with these star.ng materials with the consequence that either the final development will take place outside of the EU or a substan.al delay will occur in the development and placing on the market of the medicinal product if another star.ng material has to be iden.fied, tested and approved. 21 APIs under development (12%) reported using process chemicals with at least one CF2 or CF3 group. These will not be covered by the proposed deroga.on as currently there are no deroga.on for process chemicals used for pharmaceu.cal manufacture. Hence, the final development of APIs will not be possible in EU with this manufacture process. It should be noted that changes to the manufacture process in late-stage development could result in new clinical trials and registra.ons with authori.es. Eight APIs under development (5%) reported using non-ac.ve ingredients (excipients) which contained at least one CF2 or CF3 group in the final pharmaceu.cal product. These will not be covered by the proposed deroga.on as currently there are no deroga.on for non-ac.ve ingredients (excipients) in medicinal products. Hence, the final development of the medicinal product will not be possible in EU. It should be noted that changes to the non-ac.ve ingredients in late-stage development would likely require addi.onal clinical trials. In short, the proposed PFAS Restric6on has the poten6al to severely hinder or stop research and development of new medicinal products containing both fluorinated and non-fluorinated APIs. 15 5.3.2 Fluoropolymers used in the plant, equipment & single use systems within Manufacturing Facili;es Medicinal product manufacturing facili.es are governed by a GMP (good manufacturing prac.ce) cer.ficate, issued by global health authori.es. Opera.on of these facili.es are heavily dependent upon fluoropolymer use in u.li.es, piping, equipment (process/u.li.es), and single use systems. Fluoropolymer materials are widely used in the pharmaceu.cal manufacturing industry because of their corrosion resistance and are deemed to be inert by most regulatory agencies and are considered desirable to produce medicinal products, e.g. they are EMA cer.fied. Commission working document10 describes the complexity and geographical diversifica.on of medicinal product supply chains. Ac.ve substances may or may not be manufactured at a facility in the EU. In some supply chains formula.on of the medicinal product may take place in a non-EU facility but final packaging opera.ons occur at an EU facility. Supply chains of 1794 out of 1922 (93%)11 ac.ve substances included in the survey involve manufacturing opera.ons at an EU facility. Respondents were asked to indicate what type of manufacturing opera.ons take place at an EU facility as this will influence fluoropolymer usage. Figure 7 provides a breakdown of EU manufacturing opera.ons. Figure 7 EU manufacturing operaBons - acBve substance and / or medicinal product 1088 321 385 EU manufacturing operations - active substance only EU manufacturing operations - active substance & medicinal product EU manufacturing operations - medicinal product only The type of manufacturing opera.on will influence the fluoropolymer used. Chemical synthesis of an ac.ve substance will depend on the use PFA, PTFE, PVDF and ETFE lined 10 mp_vulnerabili7es_global-supply_swd_en.pdf (europa.eu) 11 Supply chains of 86 APIs do not involve EU manufacturing opera6on but fall within scope of the survey because a PFAS component is present in the packaging or drug delivery device. For 42 survey records informa6on on loca6on of manufacturing opera6ons was not provided 16 components, to provide corrosion protec.on against aggressive process solu.ons. In parenteral12 manufacturing facili.es, product filling lines depend on single use sterilisa.on filters containing PVDF components and PTFE tubing, to ensure sterility of the medicine. Respondents were asked to indicate mi.ga.on op.ons, if a ban of PFAS containing manufacturing equipment and consumables were to be introduced. Only for 23 APIs (1.2%), available alterna.ve, non-PFAS op.ons were selected as a mi.ga.on measure. In the majority of cases (66.3%) the field about mi.ga.on was leu blank or `don't know' was selected as response. This indicates that there are currently no non-PFAS alterna.ves readily available or yet been iden.fied that would not cons.tute a regreoable subs.tu.on both from a regulatory and from a performance viewpoint. Also, this concurs with a more in-depth analysis of the types of fluoropolymer materials used in pharmaceu.cal manufacturing facili.es conducted by ISPE (Interna.onal society of pharmaceu.cal engineers)13. A further consequence of the proposed restric.on could be a severe decrease of the produc.on of APIs in the EU. For about 183 (9.2%) APIs it was stated that the produc.on would be moved outside of EEA if suitable manufacturing capacity is available and for about 318 (16.5%) APIs EEA manufacturing opera.ons will eventually cease. The survey indicates that supply chains of 93% ac.ve substances involve EU manufacturing opera.ons, which depend on fluoropolymers, within plant, equipment and single use systems. Compared to the wider chemicals industry, the pharmaceu.cal sector could be regarded as a niche user of fluoropolymer materials. If the proposed PFAS restric.on prohibits the supply of these cri.cal raw materials, manufacturing opera.ons at EU facili.es will cease when con.ngency stock levels are depleted. Therefore, a deroga.on for fluoropolymers in the plant, equipment and single use systems within manufacturing facili.es is needed to keep manufacturing of medicinal products in EEA. 12 Parenteral drug administra7on refers to medicinal products administered by routes other than the diges7ve tract, par7cularly by injec7on or infusion. For pa7ent safety, sterile manufacturing opera7ons are required to produce parenteral medicines. 13 See Annex 3 - Industrial Use of Fluoropolymers in Pharma Manufacturing 17 5.3.3 PFAS Process Chemicals used in the Manufacture of Fluorinated & non-fluorinated APIs The chemical iden.ty of raw materials, star.ng materials and intermediates are specified in the marke.ng authorisa.on of the medicinal product. An in-depth analysis of the findings of the survey indicates that PFAS are used addi.onally as raw materials in 119 records (6.2% of total records). Respondents were asked to provide a CAS number of any raw material or star.ng materials that fulfil the PFAS criteria. A list of the CAS numbers provided by survey respondents is provided in Appendix 1. This list is regarded as a non-exhaus.ve list and should not be used as the basis for any substance specific deroga.on for processing chemicals used in the manufacture of pharmaceu.cals. 20 different PFAS compounds were reported to be used in the manufacture of small molecules, peptides and oligonucleotides. Trifluoroacetic acid (TFA) is the most commonly used chemical accounting for 50.4% (60 instances of use), followed by Trifluoracetic anhydride 16.8% (20 instances of use) and Trifluoromethanesulfonic Anhydride (TfMSA) 3.4% (4 instance of use). The most commonly used PFAS raw material, TFA, is employed in the manufacture of peptides 41.2% (49 instance of use), small molecules 7.6% (9 instances of use), and oligonucleotides 1.2% (2 instance of use). Figure 8 - Usage of PFAS Process Chemicals by Product Type 3,3% 0,8% 39,8% 56,1% Small Molecule Peptide Oligonucleotide Other It is not unexpected that the only product type iden.fied are small molecules, pep.des and oligonucleo.des, as these are produced by chemical synthesis manufacturing methods. 18 Figure 9 - Most Frequently Iden.fied PFAS Processing Chemicals 31,7% 2,4% 3,3% 16,3% 48,8% TFA TFA Anhydride TfMSA Potassium TFA CAS No. not provided As men.oned above, this lis.ng of PFAS used as raw materials in Appendix 2 should not be used as the basis for any substance specific deroga.on, as it is not considered to be complete. Some survey respondents were not able to cover en.re product porjolios in the short .meframe available to conduct the survey. Even with this limited data it is apparent what damage could be caused to the European API manufacturing industry if there will be a lack of, or par.al deroga.on. 19 5.3.4 APIs with PFAS moiety The restric.on dossier men.ons APIs, but only those corresponding to the defini.on of PFAS: "ac.ve substances in medicinal products ouen only contain one or more CF3-group(s) in an otherwise complex non-fluorinated molecular structure. In many cases the CF3-groups are aoached to aroma.c rings". Based on the survey 139 APIs with PFAS moity have been reported by the companies (7.2% of total records), 133 of which are small molecules and 5 are pep.des-modality APIs. A total of 44 different ATC (Anatomical Therapeu.c Chemical) codes associated with these types of APIs. The top 6 ATC codes are related with blood glucose lowering drugs, excluding insulins (A10B), an.viral medicine including HIV treatment (J05A), hormone antagonist therapies (L02B), an.depressant (N06A), an.neoplas.c therapies (L01X) and immunosuppressants (L04A). Figure 10 - Top 6 Recorded ATC codes (level 3) for APIs with PFAS moiety immunosuppressants (L04A) antineoplastic therapies (L01X) antidepressant (N06A) hormone antagonist therapies (L02B) antiviral medicine including HIV treatment (J05A) blood glucose lowering drugs (A10B) 0 2 4 6 8 10 12 Star.ng materials and intermediates are required to build a final fluorinated API structure. For the 139 APIs with PFAS moity iden.fied in the survey, respondents indicated that 63 PFAS star.ng materials and/or intermediates would also be impacted. It is common business prac.ce for star.ng materials and pharmaceu.cal intermediates to be imported into an EU based manufacturing facili.es for the synthesis of small molecule APIs. Any deroga.on for APIs must also include the fluorinated star.ng materials and intermediates that are required to efficiently build a final API structure. These materials would be regarded as transported intermediates from a REACH perspec.ve and should also be included in the deroga.on for APIs. The iden.fied loca.ons from the survey of these API manufacturing facili.es are Italy, Spain, Ireland, Germany, Slovenia and Switzerland. It is important to note that not all survey respondents indicated loca.ons of manufacturing facili.es. A lack of deroga.on or restricted 20 deroga.on for PFAS raw materials, star.ng materials and intermediates which are part of the process manufacturing of APIswith PFAS moity will start an "exodus" or par.al movement of manufacturing API facili.es to non-EU loca.ons. Figure 11 - Member State Loca.ons of Chemical Synthesis Facili.es that Produce PFAS APIs 5 5 24 7 9 23 Italy Spain Ireland Germany Slovenia Switzerland 5.3.5 Excipients with PFAS moiety PFAS are used as excipients in 23 (1.2% of total records) provided records in the survey. 1,1,1,2-Tetrafluoroethane was the most commonly used PFAS chemical based on the informa.on provided and is employed as an excipient accoun.ng for 43.5% (10 instances of use), and other PFAS substances (with no CAS supplied) was used in 56.5% of cases (13 instances of use). 21 Figure 12- CAS Number informa.on Provided on Excipients with PFAS moiety 56,5% 43,5% TFE CAS No. not provided Figure 13- Recorded ATC codes (level 3) for Excipients with PFAS moiety R03B - Other drugs for obstructive airway diseases, inhalants R03A - Adrenergics, inhalants R01A - Decongestants and other nasal preparations for topical use N06D - Anti-dementia drugs N04B - Dopaminergic Agents N01B - Anthesthetics, local 0 2 4 6 8 10 12 All cases of PFAS use for excipients are related with the manufacture of small molecule based medicinal products and will affect at least 38 medicinal product manufacturing facili.es which reported use of PFAS excipients during produc.on of drug product. 86% iden.fied are located in EU (Italy, France, Germany, Poland and Spain). Assuming poten.al lack of deroga.on or par.al deroga.on in the near future, transi.on to new non-PFAS excipient will most likely not be completed across products and geographies. The consequence will be a shortage or a withdrawal of medicinal products from markets. 22 5.3.6 Packaging containing PFAS cons;tuents or components Primary packaging is an integral part of a drug product. Depending on the product it can have a role in protec.ng the product from adverse environmental condi.ons, ensuring sterility, enhancing stability, allowing compliance with child safety regula.ons (child resistant packaging) and enabling usability (for example with the geriatric popula.on). All primary packaging materials and drug delivery devices form part of the valid marke.ng authorisa.on and so any restric.on will impact the supply of medicines in Europe and beyond. Fluoropolymers are used in the packaging of medicinal products include Laminated films for blister packs and PFAS coated elastomers in vials, cartridges and syringes. Looking at the data contained within the survey there are several conclusions that can be made: There are 276 products u.lising polymeric PFAS in their packaging and listed as having a Marke.ng Authorisa.on in Europe. The impacted products are distributed between all 14 of the main ATC (1st level ATC codes) groups as listed in the graph in Figure 1. In other geographies there are 16 314 products with Marke.ng Authorisa.ons that would be impacted in the same 14 ATC code groups but with different rankings (see graphs in Figure 14, Figure 15). There are also 9 products (5,3%) undergoing clinical studies or regulatory approval in the EU. There is currently no technically viable alterna.ve for packaging. Packaging is part of registered medicines, therefore the regulatory environment requires toxicological evalua.ons, extrac.ve and leachable studies and product stability to ensure the con.nued quality of the product. In addi.on, child resistance and pa.ent usability studies may be required. All this takes over 10 years. This data will form part of a regulatory assessment and approval processes taking between 6 months to 2 years. There is a need to evaluate these poten.al subs.tu.ons to avoid immediate drug shortages and an appropriate deroga.on .ming must be allowed to allow the full program of ac.vi.es to be completed and regulatory approval to be gained if a technical solu.on can be developed. 23 Figure 14: Total Number of EU Marke.ng Authoriza.ons for each ATC (1st level ATC codes) group ANTIPARASITICS, INSECTICIDES AND REPELLENTS SENSORY ORGANS DERMATOLOGICALS SYSTEMIC HORMONES, EXCL. SEX HORMONES AND... VARIOUS MUSCULO-SKELETAL SYSTEM CARDIOVASCULAR SYSTEM GENITO URINARY SYSTEM AND SEX HORMONES BLOOD AND BLOOD FORMING ORGANS ALIMENTARY TRACT AND METABOLISM ANTIINFECTIVES FOR SYSTEMIC USE NERVOUS SYSTEM RESPIRATORY SYSTEM ANTINEOPLASTIC / IMMUNOMODULATORS 0 10 20 30 40 50 60 70 80 90 Figure 15: Total Number of non-EU Marke.ng Authoriza.ons for each ATC (1st level ATC codes) group ANTIPARASITICS, INSECTICIDES AND REPELLENTS SENSORY ORGANS DERMATOLOGICALS SYSTEMIC HORMONES, EXCL. SEX HORMONES AND... VARIOUS MUSCULO-SKELETAL SYSTEM CARDIOVASCULAR SYSTEM GENITO URINARY SYSTEM AND SEX HORMONES BLOOD AND BLOOD FORMING ORGANS ALIMENTARY TRACT AND METABOLISM ANTIINFECTIVES FOR SYSTEMIC USE NERVOUS SYSTEM RESPIRATORY SYSTEM ANTINEOPLASTIC / IMMUNOMODULATORS 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5.3.7 PFAS cons;tuents or components present in drug delivery devices All drug delivery devices form part of the valid marke.ng authorisa.on and so any restric.on will impact the supply of medicines in Europe and beyond. There are many examples of drug delivery device using PFAS which include prefilled syringes, prefilled pens, autoinjectors and transdermal patches. Looking at the data contained within the survey to which an ATC code has been allocated there are several observa.ons that can be made: For the 98 products listed as having a Marke.ng Authorisa.on in Europe there are products in 12 of the main 14 WHO ATC (Anatomical Therapeu.c Chemical) code groups: 24 o Alimentary Tract and Metabolism o An.neoplas.c / Immunomodulators o Respiratory System o Nervous System o Blood and blood forming organs o Various o Musculo Skeletal System o An.-infec.ve for systemic use o Systemic hormones excluding sex hormones and insulins o Cardiovascular system o Dermatologicals o Sensory organs In other geographies there are 5192 Marke.ng Authorisa.ons that would be impacted in the same 12 ATC code groups but with different rankings (see graphs in Figure 16 and 17). There are also 6 products undergoing clinical studies or regulatory approval in 3 ATC groups in the EU: o Respiratory system o Sensory organs o Nervous system For respiratory medicinal products (e.g. metered dose inhalers, MDI) these also use PFAS. Currently the REACH proposal specifically calls out that `Given the sufficiently strong evidence poin.ng to the existence of technically and economically feasible alterna.ves ..., no deroga.on is proposed'. If this is not revised, it will be very difficult to con.nue to manufacture MDIs in Europe. If a technically feasible alterna.ve is iden.fied, then, as these products are registered medicines, the regulatory environment will, depending on the product, demand; toxicological evalua.ons, extrac.ve and leachable studies and product stability (including end of shelf-life func.onality). To ensure the con.nued quality of the product. In addi.on, child resistance and pa.ent usability studies may be required. Once this data is obtained, and if it is acceptable, then there are regulatory assessment and approval processes that need to be undertaken. Depending on the market these processes can be between 6m months to 2 years before the marke.ng authorisa.ons are modified for the changed packaging material and the product can legally be supplied. In general, it is an.cipated that it may take at least 10 - 20 years to find, test and implement replacements avoiding regreoable subs.tu.ons. There is a need to evaluate these poten.al subs.tu.ons and, to avoid immediate drug shortages, a .me unlimited deroga.on must be allowed to allow the full program of ac.vi.es to be completed and regulatory approval to be gained if a technical solu.on can be developed. 25 Figure 16: Total Number of EU Approved Devices for each ATC (1st level ATC codes) group ALIMENTARY TRACT AND METABOLISM ANTINEOPLASTIC : IMMUNOMODULATORS RESPIRATORY SYSTEM NERVOUS SYSTEM BLOOD AND BLOOD FORMING ORGANS VARIOUS MUSCULO_SKELETAL SYSTEM ANITIFECTIVES FOR SYSTEMIC USE SYSTEMIC HORMONES, EXCL. SEX HORMONES AND... CARDIOVASCULAR SYSTEM SENSORY ORGANS DERMATOLOGICALS 0 5 10 15 20 25 30 Figure 17: Total Number of non-EU Approved Devices for each ATC (1st level ATC codes) group Total number of Non-EU approved devices for ATC code groups impacted ALIMENTARY TRACT AND METABOLISM ANTINEOPLASTIC : IMMUNOMODULATORS RESPIRATORY SYSTEM NERVOUS SYSTEM BLOOD AND BLOOD FORMING ORGANS VARIOUS MUSCULO_SKELETAL SYSTEM ANITIFECTIVES FOR SYSTEMIC USE SYSTEMIC HORMONES, EXCL. SEX HORMONES AND... CARDIOVASCULAR SYSTEM SENSORY ORGANS DERMATOLOGICALS 0 500 1000 1500 2000 2500 26 5.4 Pa7ent Impact 5.4.1 Prevalence of Disease State & Pa;ent Number Es;mates EU based manufacturing facili.es are global suppliers of medicines. As indicated in Figure 1 the impacted medicinal products are from important and diverse pharmacological/ therapeu.c areas. From this list, the following five non-communicable diseases, were selected for further analysis: Cardiovascular disease C03A (Low ceiling diure6cs, Thiazides); C08C (Selec6ve Calcium Channel Blockers); C09A (ACE Inhibitors); C07A (Beta Blocking Agents); C10A (Lipid modifying agents) Chronic respiratory disease R03A (Adrenergic Inhalants); R03B (other drugs for obstruc6ve airway diseases, inhalants); R06A (An6histamines for systemic use) Cancer L01A (Alkyla6ng agents); L01B (An6-metabolites); L01C (Plant Alkaloids and other natural products); L01E (Protein Kinase Inhibitors); L01F (Monoclonal an6bodies and an6body drug conjugates) Diabetes A10A (Insulins and Analogues): A10B (Blood glucose lowering drugs, excluding Insulins) Mental health disorders N06A (An6depressants) Total Count (No of ac.ve substances) 85 87 58 144 34 Pa.ent numbers associated with these disease states are increasing. To give an indica.on of the global pa.ent numbers, a literature search was conducted, par.cularly looking at WHO data. There are several observa.ons that can be made: Asthma & COPD: Chronic obstruc.ve pulmonary disease (COPD) is the third leading cause of death worldwide, causing 3.23 million deaths in 2019. Asthma affected an es.mated 262 million people in 2019 and caused 455,000 deaths.14 Asthma affected an es.mated 262 million people in 2019 and caused 455 000 deaths15. Mental health: In 2019 1 in every 8 people, or 970 million people around the world were living with a mental disorder.16 Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an es.mated 17.9 million lives each year.17 Currently there are more than 6 million new cases 14 h]ps://www.who.int/news-room/fact-sheets/detail/chronic-obstruc7ve-pulmonary-disease-(copd) 15 Asthma (who.int) 16 Mental disorders (who.int) 17 Cardiovascular diseases (who.int) 27 of CVD in the EU and more than 11 million in Europe as a whole, every year. With almost 49 million people living with the disease in the EU in 201918. In a recent World Health Sta.s.cs report, the number of adults aged 30-79 years with raised blood pressure (hypertension) is es.mated to have almost doubled to 1.28 billion between 1990 and 2019, mainly due to popula.on growth and ageing. There was liole change in the overall rate of hypertension globally, although the burden has shiued from high-income to lowand middle-income countries.19 Cancer: Cancer is a leading cause of death worldwide, accoun.ng for nearly 10 million deaths in 2020. There are an es.mate 18.1 million cancer deaths around the world in 202020. Results of an epidemiology study on the incidence of early onset cancers in adults under 50 years was published in the BMJ. It indicates that cancers historically perceived to be more common in older age groups are now being diagnosed in younger adults, including colorectal breast, oesophageal, gastric, and pancrea.c cancers, amongst others21. Diabetes: The IDF Diabetes Atlas (2021)22 reports that 10.5% of the adult popula.on (2079 years) has diabetes, this is around 23 . Diabetes is a chronic (long-las.ng) health condi.on which has a significant impact on the health and well-being of individuals, families and socie.es. 18 Fact sheets for Press (escardio.org) 19 h]ps://iris.who.int/bitstream/handle/10665/356584/9789240051140-eng.pdf?sequence=1 20 https://www.wcrf.org/cancer-trends/worldwide-cancer-data/ 21 Hamilton AC, Coleman HG. Shiiing 7des: the rising 7de of early onset cancers demands a]en7on. BMJ Oncology (2023) 22 h]ps://idf.org/about-diabetes/diabetes-facts-figures/ 23 h]ps://www.who.int/health-topics/diabetes#tab=tab_1 28 5.4.2 WHO Essen;al Medicines List A WHO Expert Commioee on the Selec.on and Use of Essen.al Medicines is responsible for the development and the revision of Essen.al Medicines List (EML) every 2 years. This list is ouen used as a reference point for countries to define products which are essen.al to the func.oning of healthcare systems. Respondents indicated if the ac.ve substance appears on the current WHO Essen.al Medicines List. 35% or 674 of the 1922 ac.ve substances were found on the WHO list. A strong indica.on that the proposed PFAS restric.on will have a significant impact on the availability of these products to pa.ents all around the world. Figure 18 shows the distribu.on of pharmacological/therapeu.c groups that could be impacted. This is the breakdown by ATC code family, the total is > 691 because some medicines had mul.ple ATC codes, both in the same family or in different families. Figure 18 - Impacted Medicines on the WHO Essen.al Medicines List in each ATC (1st level ATC codes) group 160 148 140 120 106 100 80 77 75 66 65 60 40 36 35 32 20 4 21 9 11 6 0 olism rgans ystem gicals ones ations ic use gents ystem ystem llents ystem rgans arious metab ming o cular s atolo m x horm prepar system lating a letal s vous s & repe atory s ry o nso V - V ct and od for diovas - Der m & se onal es for modu ulo-ske - Ner icides Respir S - se tra nd blo - Car D syste horm c fectiv uno m usc M N insect R - mentary ood a C rinary stemi nti-in & im M - ucts, A - Ali B - Bl nito u H - Sy J - A plastic ic prod G - Ge ntineo arasit - A ntip A L P- 29 5.4.3 Cri;cal Medicines List - EU Member States Cri.cal medicines are a subgroup of essen.al medicines which certain EU member States have set up to ensure there should never be supply problems in the health system24. They are, for example, those that are considered by the EU (EEA) Member State to be most cri.cal, due to their importance for the resilience of health care systems, public health and pa.ent care at all .mes or due to the vulnerability of the supply chain. They are ouen selected with due regard to the therapeu.c indica.on of the medicine and / or the availability of adequate alterna.ves. For the 1794 ac.ve substances, with associated manufacturing opera.ons at an EU facility, ATC data was cross checked against na.onal cri.cal medicines lists in Finland, France, Germany, Norway, Slovenia, Spain, and Sweden. Figure 19 illustrates the poten.al impact on cri.cal medicines lists if these facili.es are unable to manufacture ac.ve substance and / or the medicinal product. Figure 19: Impact on European Cri.cal Medicines Lists if Deroga.on is not Granted for -Use of Fluoropolymers Manufacturing Opera.ons* *Cri0cal medicines lists accurate as of August 202325 24 In May 2023, 21 Member States endorsed a Non-Paper on `Improving the security of medicines supply in Europe' that provides for three points of ac7on to address severe medicines shortages: (i) Installing a voluntary solidarity mechanism within the Execu7ve Steering Group on Shortages of Medicines caused by Major Events (MSSG) to, as a last resort, temporarily alleviate acute shortages in Member States; (ii) Establishing a European list of cri7cal medicines whose supply, produc7on and value chains must be monitored; (iii) Exploring a Cri7cal Medicines Act to reduce dependencies for cri7cal medicines and ingredients, par7cularly for products where there are only a few supplying manufacturers or countries 25 Slovenia (Essen7al) list is characteris7c of an essen7al medicines list; however, it is intrinsically linked to a second list, Slovenia's (Indispensable) list, which is more typical of a cri7cal medicines list and therefore both are included in this analysis. France MITM - Medicines of Major Therapeu7c Interest 30 The number of cri.cal medicines impacted if EU manufacturing opera.ons ceased, results in overlaps with 61% (Slovenia) - 78% (Norway) of the ATC codes iden.fied in the survey with the European member state cri.cal medicines lists. When considering how to strengthen supply chains, both the environmental impact as well as the poten.al impact of environmental legisla.on on supply should also be considered. 31 5.4.4 Netherlands Case Study When es.ma.ng the impact of the proposed ban on pa.ents, it is important to look at the implica.ons in rela.on to the availability of products on the market in case no deroga.on for PFAS used in the manufacturing process or as the substance in all medicinal products is secured. In this case study we aoempt to do so using the example of the Netherlands. The data from the Dutch Healthcare Ins.tute over the last three years provides insights into the poten.al impact of this ban on specific medicine categories. Extrapola.ng these findings to the EU level, we can an.cipate similar consequences for pa.ents across the European Union. Our analysis indicates a large therapeu.c dependence on the products which, under the proposed ban, could face unavailability. ATC data from the industry survey was cross checked against the Dutch Healthcare Ins.tute prescrip.on informa.on. 691 products that hold marke.ng authorisa.on in the country would be impacted. This accounts for 64% of all medicines contained in the Dutch Healthcare Ins.tute public database on the use of medicines in the country. Many of the medicines manufactured using PFAS are used in trea.ng life-threatening condi.ons, including cancer and cardiovascular diseases. In the absence of deroga.ons to the ban, pa.ents would face delays or be forced to switch to less effec.ve treatments, compromising pa.ent outcomes and safety. In many cases, they would completely lose access to treatments. In par.cular pa.ents with rare diseases or unique condi.ons may be dispropor.onally affected by the ban, as alterna.ve treatments may not be available or affordable. In total for all associated ATC codes, there are more than 40 million users per year in the Netherlands. 26 In terms of product characteris.cs, substances which will be affected by the ban are found across various ATC groups. Table 1 and Table 2 present an overview of the top 20 and booom 20 affected substances in terms of the number of users per year in the country. As indicated in the table, the ban will affect both widely used products (e.g., proton pump inhibitors, laxa.ves, beta blockers and wide-spectrum an.bio.cs), as well as less frequently used medicines including medica.ons for rare diseases. For 205 of the iden.fied substances, only up to 5 products are authorised, making them par.cularly vulnerable to supply disrup.on caused by changes in the composi.on of the market. For 76 of the iden.fied substances, the product impacted by the PFAS ban is the only available medicine on the market in the country. For these products, the impact would be cri.cal to pa.ent access. A full overview of all affected products and the respec.ve pa.ent popula.on in 2022 is available in the Appendix 3 to this report. 26 Note: here individual users for every product are counted. One pa7ent can receive numerous products; therefore the number is higher than the total country popula7on. 32 Table 1 Top 20 substances impacted by the PFAS ban by the number of patients in the Netherlands in 2022 Substance name Proton pump inhibitors HMG CoA reductase inhibitors Osmotically acting laxatives Contact laxatives Beta blocking agents, selective Platelet aggregation inhibitors excl. heparin Propionic acid derivatives ACE inhibitors, plain Penicillins with extended spectrum Other emollients and protectives ATC code A02BC C10AA A06AD A06AB C07AB B01AC M01AE C09AA J01CA D02AX Number of patients 2.219.000 1.991.000 1.421.000 1.421.000 1.331.000 1.195.000 1.116.000 1.081.000 1.032.000 1.021.000 Substance name Dihydropyridine derivatives Vitamin D and analogues Selective beta-2-adrenoreceptor agonists Other antihistamines for systemic use Acetic acid derivatives and related substances Other ophthalmologicals Angiotensin II receptor blockers (ARBs), plain Imidazole and triazole derivatives Biguanides Combinations of penicillins, incl. betalactamase inhibitors ATC code C08CA A11CC R03AC R06AX M01AB S01XA C09CA D01AC A10BA J01CR Number of patients 1.010.000 1.003.000 902.850 858.660 858.520 767.650 743.690 689.160 672.420 648.350 Table 2 Bottom 20 substances impacted by the PFAS ban by the number of patients in the Netherlands in 2022 Substance name Enzymes Antidotes Phosphonic acid derivatives Enzymes Estrogens, combinations with other drugs Folic acid analogues Anti-gonadotropin-releasing hormones Other plain vitamin preparations Blood substitutes and plasma protein fractions Biguanides and amidines ATC code A16AB V03AB J05AD B01AD G03CC L01BA H01CC A11HA B05AA D08AC Number of patients 1 1 2 4 5 8 9 11 12 14 Substance name Calcitonin preparations Ascorbic acid (vitamin C), plain Methanolquinolines Ergot alkaloids Estren derivatives Antibiotics Pyrazolones Other muscle relaxants, peripherally acting agents Drugs for treatment of hypoglycemia Drugs used in hereditary angioedema ATC code H05BA A11GA P01BC G02AB A14AB J02AA N02BB M03AX Number of patients 34 39 68 70 74 77 156 170 V03AH 189 B06AC 217 Case study methodology and limita.ons For this case study two data sources were consulted, namely the data provided by the pharmaceu.cal manufacturers as a part of the inter-associa.on survey on the PFAS use in the pharmaceu.cal value chain, and the publicly available data27 on na.onal medicine use by the Dutch Healthcare Ins.tute. The respondents of the inter-associa.on industry survey were asked to iden.fy ATC codes for products where PFAS (fluoropolymer) are used either in the industrial manufacturing process (in Europe) or as substances (API and other materials) in the products, product packaging and/or delivery devices. The underlying goal was to iden.fy how many products would be affected by the PFAS ban, or more specifically by the manufacturing and regulatory restric.ons that accompany the ban. The product ATC codes were extracted from the inter-associa.on industry survey responses and linked to the medicines use data available in the Dutch database for the same ATC codes (at the same level), thus connec.ng the ATC code with the number of users in the country. 27 h]ps://www.gipdatabank.nl/ 33 Connec.ng the two datasets allows us to es.mate which pa.ent categories may be impacted by the restric.on and support evidence-based policymaking. For both datasets, 4th-level ATC codes were analysed. Whilst the 4th level ATC code does not allow iden.fying the actual product, it provides a granular classifica.on of medicines compared to higher levels, allowing us to gain insights into specific medicine classes and subcategories. The here-presented analysis also has several methodological limita.ons which need to be acknowledged: - The responses received through the inter-associa.on industry survey do not present a complete overview of all products which may be affected by the PFAS ban but should be seen as the "minimum list of affected products". - Not all the ATC codes received through the inter-associa.on industry survey were available in the Dutch database. This may be due to certain products not being in use in the country. The results of the analysis provide a glimpse into the poten.al impact of the ban on the availability of medicines in the Netherlands. Whilst this case study can serve as an indica.on of the impact in other European countries, the findings should be carefully extrapolated taking into account the specifics of each Member State in rela.on to medicines use, prescrip.on prac.ces and other health system-related considera.ons. 34 6. Summary Conclusions The 40 companies par.cipa.ng in the survey iden.fied 1922 ac.ve substances, which could be impacted by the proposed Restric.on because: APIs in manufacturing and packaging opera.ons at a facility in the EEA and / or Medicinal products with PFAS cons.tuents present in the intermediate packaging or drug delivery device of a medicinal product placed on the market in the EEA. Key Survey findings: In the survey, 169 APIs were reported to be undergoing process development, at an EU manufacturing facility. A PPORD deroga.on is necessary to support the research and development of new medicinal products containing both fluorinated and nonfluorinated APIs. In this way material manufactured in EU facili.es can be used to supply clinical trials been conducted to meet unmet medical needs. Supply chains of 93% of ac.ve substances involve EU manufacturing opera.ons, which depend on fluoropolymers, within plant, equipment and single use systems. If the proposed PFAS restric.on prohibits the supply of these cri.cal raw materials, manufacturing opera.ons at EU facili.es will cease when con.ngency stock levels are depleted. There is a specified substance with a PFAS moiety in the medicinal product marke.ng authorisa.on filed for 18% of the ac.ve substances with EU manufacturing opera.ons. These include raw materials, star.ng materials, intermediates, APIs and excipients. Only 139 APIs with PFAS moiety have been reported by the companies and would therefore fall under the proposed deroga.on for APIs. There is currently no technically viable alterna.ve for packaging. Packaging and drug delivery devices are part of registered medicines, therefore the regulatory environment requires toxicological evalua.ons, extrac.ve and leachable studies and product stability to ensure the con.nued quality of the product. In addi.on, child resistance and pa.ent usability studies may be required. All this takes over 10 years. This data will form part of a regulatory assessment and approval processes taking between 6 months to 2 years. The survey iden.fies at least 47,677 global marke.ng authorisa.ons that could be impacted If the proposed restric.on is implemented, a significant number of cri.cal medicines will no longer be available impac.ng pa.ents access to medicines. The WHO Essen.al Medicines List (EML) is a reference point for countries to define products which are essen.al to the func.oning of healthcare systems. 674 medicines from the WHO list, distributed across a variety of pharmacological/therapeu.c groups that could be impacted. Furthermore, a heavy impact was iden.fied across the European Member State's "Cri.cal Medicines lists" developed to counter shortages and to reduce Europe's health dependence on non-European countries. For example, 78% of the cri.cal medicines list in Norway could be impacted by the proposed Restric.on. 35 Evidence suggests that for the con.nued research, development and marke.ng of medicines (biopharmaceu.cals and vaccines), including all steps which are necessary for their manufacturing, packaging and delivery devices of medicines in the EEA, they should generally be derogated from a universal PFAS restric.on. Furthermore, currently for all PFAS use scenarios associated with the development, manufacture, and supply of medicinal products there are no suitable alterna.ves. This further strengthens the need for a deroga.on that encompasses all parts of the supply chain as this is a necessary medicine shortage mi.ga.on measure. 36 Appendix 1 37 Overview of distribu7on of ATC codes (level 3) A: Alimentary tract and metabolism A01A 5 A02A 71 A02B 23 A03A 9 A03F 5 A04A 3 A05A 1 A05B 1 A06A 14 A07A 1 A07D 3 A07E 3 A08A 3 A09A 3 A10A 76 A10B 68 A11A 7 A11C 1 A11D 3 A11E 17 A11G 13 A11H 5 A11J 2 A12A 1 A12B 1 A14A 3 A16A 13 SUM 355 B: Blood And Blood Forming Organs B01A 39 B02A 3 B02B 46 B03A 4 B03X 4 B05A 5 B05B 1 B05X 4 B06A 2 SUM 108 C: Cardiovascular System C01B 3 C01C 2 C01D 3 C01E 4 C02A 2 C02B 1 C02C 1 C02K 7 C02L 1 C03A 13 C03B 3 C03C 5 C03D 2 C07F 5 C08C 11 C08D 3 C08E 1 C08G 2 C09A 18 C09B 8 C09C 8 C09D 7 C03E 2 C04A 1 C05A 7 C05B 1 C05C 6 C07A 20 C07B 2 C10A 23 C10B 1 SUM 173 D: Dermatologicals D01A 38 D01B 2 D02A 1 D03A 10 D04A 3 D05A 5 D06A 5 D06B 2 D07A 3 D07B 1 D07C 7 D08A 9 D09A 1 D10A 2 D10B 1 D11A 7 SUM 97 G: Genito Urinary System And Sex Hormones G01A 20 G02A 3 G02B 1 G02C 2 G03A 12 G03B 11 G03C 18 G03D 11 G03E 4 G03F 14 G03G 9 G03H 3 G03X 1 G04B 9 G04C 9 SUM 127 H: Systemic hormonal preparaAons, excl. sex hormones and insulins H01A 15 H01B 2 H01C 10 H03A 2 H03B 2 H04A 1 H05A 1 H05B 3 SUM 36 AnAinfecAves For Systemic Use J01A 1 J01C 34 J01D 21 J01E 1 J01F 2 J01G 3 J01M 1 J01R 1 J01X 3 J02A 8 J04A 2 J04B 3 J05A 30 J06B 5 J07A 2 J07B 18 J07C 4 SUM 139 AnAneoplasAc And ImmunomodulaAng Agents L01A 2 L01B 10 L01C 6 L01D 12 L01E 23 L01F 17 L01X 40 L02A 5 L02B 24 L03A 9 L04A 50 SUM 198 M: Musculo-Skeletal System M01A 42 M01B 1 M02A 8 M03A 2 M03B 3 M04A 4 M05B 5 M09A 1 SUM 66 N: Nervous Syste N01A 3 N01B 7 N02A 21 N02B 73 N02C 17 N03A 18 N04B 14 N05A 20 N05B 5 N05C 6 N06A 34 N06B 14 N06C 6 N06D 13 N07B 8 N07C 3 N07X 4 SUM 266 P: AnAparasiAc products, insecAcides and repellents P01B 6 P01C 2 P02B 2 P02C 1 P02D 1 SUM 12 R: Respiratory System R01A 13 R01B 20 R02A 6 R03A 40 R03B 12 R03C 1 R03D 11 R05C 6 R05D 2 R05X 0 R06A 35 R07A 3 RO3B 9 SUM 158 S: Sensory organs S01A 9 S01B 7 S01C 5 S01E 13 S01G 5 S01L 4 S01X 6 S02A 2 S02C 2 S03A 2 SUM 55 V: Various V03A 18 V04C 2 V08A 2 V08C 3 V09A 2 V09I 2 V10X 2 SUM 31 Blanks 125 TOTAL 1944 38 Table Level 3 ATC codes for all APIs with EU market approval in this survey (number of 6mes the ATC code is reported) N02B (73) A10A (72) A02A (71) A10B (59) B02B (43) M01A (41) L04A (42) D01A (38) B01A (38) L01X (35) R06A (35) N06A (34) J01C (29) J05A (28) R03A (27) C09B (27) J01D (21) C07A (20) R01B (20) G01A (20) A02B (20) L02B (19) C09A (18) N05A (18) C10A (17) V03A (18) G03C (17) L01E (17) A11E (17) N03A (16) J07B (16) N02C (15) N02A (15) G03F (15) H01A (14) N06B (14) A06A (14) R01A (13) N04B (13) S01E (13) C03A (13) G03A (13) A11G (13) R03B (12) L01F (12) L01D (12) C08C (11) R03D (11) G03D (11) N06D (10) A16A (10) G03B (10) D03A (10) H01C (9) G03G (9) L03A (9) S01A (9) L01B (9) D08A (9) A03A (9) M02A (8) G04B (8) N07B (8) C09D (7) C09C (7) S01B (7) D06A (7) C02K (7) C05A (7) A11A (7) C05C (6) S01X (6) D11A (6) G04C (6) D07C (6) R05C (6) R02A (6) L02A (5) L01C (5) S01C (5) S01G (5) J06B (5) D05A (5) N05B (5) N05C (5) A11H (5) N01B (5) A01A (5) C03C (5) M04A (4) B03X (4) M05B (4) P01B (4) J02A (4) B03A (4) C07F (4) G03E (4) A03F (4) B05X (4) C01E (4) M03B (3) J01G (3) D07A (3) J04B (3) G02A (3) H05B (3) C01D (3) J07C (3) C01B (3) D10A (3) C08D (3) B02A (3) G03H (3) V08C (3) A14A (3) A11D (3) A03 (3) D04A (3) A07E (3) C03B (3) A07D (3) J01X (3) A08A (3) J01F (2) C01C (2) S01L (2) B06A (2) V09I (2) V10X (2) S02C (2) P02B (2) S03A (2) A04A (2) J07A (2) N07X (2) N07C (2) A09A (2) B05A (2) RO3B (2) V08A (2) G02C (2) S02A (2) C03D (2) D01B (2) A11J (2) R05D (2) M03A (2) N01A (4) C03E (2) D06B (2) H03B (2) H03A (2) C02A (2) R07A (2) H01B (2) V04C (2) C08G (2) J04A (2) M09A (1) D10B (1) C02B (1) D09A (1) H04A (1) D07B (1) P02C (1) A12B (1) G02B (1) P02D (1) P01C (1) D02A (1) A12A (1) M01B (1) A13 (1) R05X (1) NOTA (1) V09A (1) H05A (1) C02C (1) C05B (1) C04A (1) J01A (1) A07A (1) C07B (1) A05A (1) B05B (1) A11C (1) J01E (1) C08E (1) R03C (1) J01R (1) C02L (1) Table Level 3 ATC codes for APIs for export (number of 6mes the ATC code is reported) N02A (6) A10B (5) C09B (5) A16A (3) B05A (3) G04C (3) L04A (3) R03A (3) A02B (2) J01C (2) J07B (2) N01B (2) N02C (2) N07X (2) A03F (1) A04A (1) A09A (1) A10A (1) B01A (1) C07B (1) C09C (1) C10B (1) C10A (1) G03B (1) G03X (1) G04B (1) H01C (1) J05A (1) J07C (1) L01X (1) L01A (1) M01A (1) N03A (1) N05C (1) N06C (1) N07C (1) P01B (1) P01C (1) V09A (1) Table Level 3 ATC codes for APIs for development (number of 6mes the ATC code is reported) A10B (3) L01E (1) B02B (2) R03A (1) A10A (2) L04A (2) H01A (1) A05B (1) N06D (1) D11A (1) 39 Appendix 2 40 PFAS Process Chemicals Iden7fied by the Survey* CAS No. Chemical Name MPS-EDATFA, trifluoroacetic acid salt of N-(2-aminoethyl)-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- 11550-02-00 yl)propanamide 121788-73-6 (R,R)-N,N'-Bis(trifluoromethanesulfonyl)-1,2-diphenylethylenediamine 14533-84-7 Pentafluorophenyl trifluoroacetate 1493-13-6 Trifluoromethanesulfonic acid 27607-77-8 Trimethylsilyl Trifluoromethanesulfonate 2923-16-2 Potassium Trifluoroacetate 2923-18-4 Sodium Trifluoroacetate 2923-28-6 Silver trifluoromethanesulfonate 32247-96-4 3,5-Bis(trifluoromethyl)benzyl Bromide 33454-82-9 Lithium Trifluoromethanesulfonate 351-35-9 3-(Trifluoromethyl)phenylacetic Acid 358-23-6 Trifluoromethanesulfonic Anhydride 375-72-4 Perfluoro-1-butanesulfonyl Fluoride 407-25-0 Trifluoroacetic Anhydride 6226-25-1 2,2,2-Trifluoroethyl Trifluoromethanesulfonate 75-89-8 2,2,2-Trifluoroethanol 753-90-2 2,2,2-Trifluoroethylamine 75706-12-6 Leflunomide 76-05-1 Trifluoroacetic Acid 79271-56-0 Triethylsilyl Trifluoromethanesulfonate 811-97-2 1,1,1,2-Tetrafluoroethane 886536-37-4 4-(2,2,2-Trifluoroethoxy)benzeneboronic acid 98-08-0 ,,-Trifluorotoluene 98-17-9 3-Trifluoromethylphenol *This list is not an exhaus6ve list and should not be used as the basis for any substance specific deroga6on for processing chemicals used in the manufacture of medicinal products 41 Appendix 3 42 ATC code (level 4) A02BC C10AA A06AD A06AB C07AB B01AC M01AE C09AA J01CA D02AX C08CA A11CC R03AC R06AX M01AB S01XA C09CA D01AC A10BA J01CR D06AX R03AK R05DA N06AB D07AC C03AA H03AA N02AA B01AF N02AX R06AE J01AA C03CA J01CF G04CA Substance name 2018 Proton pump inhibitors HMG CoA reductase inhibitors Osmo6cally ac6ng laxa6ves Contact laxa6ves Beta blocking agents, selec6ve Platelet aggrega6on inhibitors excl. heparin Propionic acid deriva6ves ACE inhibitors, plain Penicillins with extended spectrum Other emollients and protec6ves Dihydropyridine deriva6ves Vitamin D and analogues Selec6ve beta-2-adrenoreceptor agonists Other an6histamines for systemic use Ace6c acid deriva6ves and related substances Other ophthalmologicals Angiotensin II receptor blockers (ARBs), plain Imidazole and triazole deriva6ves Biguanides Combina6ons of penicillins, incl. betalactamase inhibitors Other an6bio6cs for topical use Adrenergics in combina6on with cor6costeroids or other drugs, excl. an6cholinergics Opium alkaloids and deriva6ves Selec6ve serotonin reuptake inhibitors Cor6costeroids, potent (group III) Thiazides, plain Thyroid hormones Natural opium alkaloids Direct factor Xa inhibitors Other opioids Piperazine deriva6ves Tetracyclines Sulfonamides, plain Beta-lactamase resistant penicillins Alpha-adrenoreceptor antagonists 2.139.000 1.966.000 1.307.000 1.307.000 1.355.000 1.206.000 1.110.000 1.037.000 1.121.000 916.670 856.950 1.110.000 939.420 823.600 1.154.000 679.660 699.720 773.010 651.630 658.870 652.870 588.440 653.090 548.670 573.380 656.450 501.000 509.470 211.710 428.300 446.420 593.730 371.480 323.480 301.360 2019 2.214.000 1.971.000 1.319.000 1.319.000 1.351.000 1.206.000 1.188.000 1.066.000 1.070.000 930.160 904.410 961.800 949.510 839.480 993.470 716.820 742.640 744.910 658.230 653.340 639.360 585.540 621.670 556.670 588.720 671.190 511.820 481.740 277.440 425.650 437.330 539.920 366.440 318.180 308.890 2020 2021 2022 2.233.000 1.929.000 1.290.000 1.290.000 1.335.000 1.191.000 1.074.000 1.059.000 805.110 914.150 926.280 930.860 874.420 840.630 860.060 698.030 707.770 681.780 659.650 560.540 556.710 577.590 2.218.000 1.947.000 1.374.000 1.374.000 1.325.000 1.189.000 1.089.000 1.072.000 805.020 972.430 972.890 983.040 841.490 869.610 842.520 735.840 721.990 639.740 666.830 556.960 550.600 566.830 2.219.000 1.991.000 1.421.000 1.421.000 1.331.000 1.195.000 1.116.000 1.081.000 1.032.000 1.021.000 1.010.000 1.003.000 902.850 858.660 858.520 767.650 743.690 689.160 672.420 648.350 623.570 602.680 393.220 558.540 541.450 608.730 516.850 459.670 330.380 419.330 433.640 378.600 358.080 309.770 309.390 388.350 565.850 570.280 606.600 520.080 489.610 391.890 430.830 441.940 310.730 355.890 308.690 319.910 590.620 584.780 576.540 574.620 531.040 520.840 454.500 448.960 425.800 406.100 353.770 344.030 332.610 43 ATC code (level 4) R03BA B03AA A10BB N06AA J01MA A03FA N06AX N05BA N03AX G03AA N06BA C01DA N05AH C10AX M04AA N02CC C03DA N01BB A10AE B01AA C07AA M01AH J01XX A10AB C09DA B01AB J02AC R03AL G01AF G03CA N02AJ L04AX A04AA Substance name 2018 Glucocor6coids Iron bivalent, oral prepara6ons Sulfonylureas Non-selec6ve monoamine reuptake inhibitors Fluoroquinolones Propulsives Other an6depressants Benzodiazepine deriva6ves Other an6epilep6cs Progestogens and estrogens, fixed combina6ons Centrally ac6ng sympathomime6cs Organic nitrates Diazepines, oxazepines, thiazepines and oxepines Other lipid modifying agents Prepara6ons inhibi6ng uric acid produc6on Selec6ve serotonin (5HT1) agonists Aldosterone antagonists Amides Insulins and analogues for injec6on, long-ac6ng Vitamin K antagonists Beta blocking agents, non-selec6ve Coxibs Other an6bacterials Insulins and analogues for injec6on, fastac6ng Angiotensin II receptor blockers (ARBs) and diure6cs Heparin group Triazole and tetrazole deriva6ves Adrenergics in combina6on with an6cholinergics incl. triple combina6ons with cor6costeroids Imidazole deriva6ves Natural and semisynthe6c estrogens, plain Opioids in combina6on with non-opioid analgesics Other immunosuppressants Serotonin (5HT3) antagonists 374.300 280.110 304.010 285.160 337.230 307.960 291.300 302.100 256.650 345.200 225.960 263.240 182.840 139.240 201.730 202.390 161.200 180.570 192.270 315.830 204.400 183.170 186.710 169.810 250.750 177.120 173.070 97.497 216.970 119.500 157.600 124.410 75.994 2019 366.170 285.860 308.320 292.510 311.400 296.520 291.500 300.110 266.550 349.310 227.480 249.190 194.350 161.240 205.800 205.470 167.460 188.380 193.900 278.860 204.160 178.190 167.460 169.370 215.160 171.110 165.230 114.000 210.870 123.070 151.490 128.370 83.088 2020 2021 2022 342.400 276.030 311.110 287.920 282.640 281.930 285.740 297.360 267.620 326.850 231.360 247.910 205.570 177.270 206.400 201.120 171.630 174.860 194.060 244.760 185.630 162.660 193.180 169.310 190.170 147.590 146.070 116.010 320.330 300.580 320.220 293.870 276.410 290.190 285.070 291.090 273.150 290.340 239.200 250.310 213.290 195.460 208.210 203.810 190.370 189.700 195.140 212.520 182.910 166.550 179.190 170.990 179.030 156.190 140.940 127.970 327.930 326.670 325.010 305.260 294.530 291.880 288.530 287.640 286.150 285.590 264.910 252.620 217.990 216.800 213.330 209.910 205.380 197.540 194.930 185.210 184.160 178.510 177.930 169.650 168.790 161.240 158.330 143.580 197.050 120.580 141.000 128.030 76.093 187.200 129.440 136.290 129.740 102.910 143.140 142.180 134.400 132.300 126.550 44 ATC code (level 4) A10BK D10AF N02AB J01CE J01FF J01EE J05AB C09BA D01BA A10BJ L01BC D11AH D05AX N05AX C08DA N05CF D01AE G03DC C01CA R06AA A07AA C03BA N05AD B01AE N07CA G04CB S02AA C09DX M01AC N04BC A10BH R03DC C08DB P01BA G03DA C01BC Substance name Sodium-glucose co-transporter 2 (SGLT2) inhibitors An6infec6ves for treatment of acne Phenylpiperidine deriva6ves Beta-lactamase sensi6ve penicillins Lincosamides Combina6ons of sulfonamides and trimethoprim, incl. deriva6ves Nucleosides and nucleo6des excl. reverse transcriptase inhibitors ACE inhibitors and diure6cs An6fungals for systemic use Glucagon-like pep6de-1 (GLP-1) analogues Pyrimidine analogues Agents for derma66s, excluding cor6costeroids Other an6psoria6cs for topical use Other an6psycho6cs Phenylalkylamine deriva6ves Benzodiazepine related drugs Other an6fungals for topical use Estren deriva6ves Adrenergic and dopaminergic agents Aminoalkyl ethers An6bio6cs Sulfonamides, plain Butyrophenone deriva6ves Direct thrombin inhibitors An6ver6go prepara6ons Testosterone-5-alpha reductase inhibitors An6infec6ves Angiotensin II receptor blockers (ARBs), other combina6ons Oxicams Dopamine agonists Dipep6dyl pep6dase 4 (DPP-4) inhibitors Leukotriene receptor antagonists Benzothiazepine deriva6ves Aminoquinolines Pregnen (4) deriva6ves An6arrhythmics, class Ic 2018 15.443 132.590 104.760 47.138 81.890 85.614 88.392 123.700 83.702 15.895 55.332 62.456 73.148 75.118 66.060 62.228 62.544 72.390 52.519 85.324 72.567 71.385 71.896 60.460 78.154 56.416 54.612 17.243 76.269 50.164 38.148 48.485 44.030 47.050 33.244 43.768 2019 16.887 128.160 102.620 82.872 85.407 94.446 90.127 116.500 81.263 26.253 64.350 64.804 77.343 77.192 67.812 61.717 63.086 67.273 53.416 80.426 68.657 74.466 66.958 63.342 72.551 56.990 55.260 21.851 71.097 50.314 44.219 48.742 44.151 46.826 31.890 43.224 2020 2021 2022 19.946 116.450 104.630 56.059 83.251 84.354 86.115 103.090 69.607 39.515 69.385 67.216 75.386 77.493 67.866 62.392 61.806 44.061 52.645 70.128 63.934 69.471 68.091 61.656 66.533 57.224 57.031 27.364 54.154 49.644 46.885 47.414 44.613 46.593 31.914 41.820 39.715 119.180 106.300 55.052 84.639 84.019 86.970 95.601 76.321 54.928 76.981 74.767 77.216 77.564 69.692 62.267 66.702 51.448 50.766 69.753 62.347 66.956 64.763 60.964 62.043 57.628 50.183 39.375 53.459 50.247 48.884 46.260 44.243 43.774 37.143 41.721 113.180 112.790 105.920 95.960 94.358 93.450 91.513 88.528 85.268 82.581 82.169 82.134 80.503 78.803 71.505 69.206 68.196 66.395 65.926 65.105 64.906 63.375 61.553 60.175 58.638 58.240 54.373 52.900 52.362 50.360 47.838 46.076 44.475 43.789 42.517 42.156 45 ATC code (level 4) N04BA D06BB L02AE L02BG N03AF N02AE M05BX A02BX L04AA C07AG L02BA A10AC C01BD A12BA G03AC A07EA N03AE G03BA J05AR G03FA D11AX A07DA H03BB A09AA N02CX D06BA L04AD N06DA C07BB G03FB A05AA N07BC N01BX A01AD S01EA Substance name 2018 Dopa and dopa deriva6ves An6virals Gonadotropin releasing hormone analogues Aromatase inhibitors Carboxamide deriva6ves Oripavine deriva6ves Other drugs affec6ng bone structure and mineraliza6on Other drugs for pep6c ulcer and gastrooesophageal reflux disease (GORD) Selec6ve immunosuppressants Alpha and beta blocking agents An6-estrogens Insulins and analogues for injec6on, intermediate-ac6ng An6arrhythmics, class III Potassium Progestogens Cor6costeroids ac6ng locally Benzodiazepine deriva6ves 3-oxoandrosten (4) deriva6ves An6virals for treatment of HIV infec6ons, combina6ons Progestogens and estrogens, fixed combina6ons Other dermatologicals An6propulsives Sulfur-containing imidazole deriva6ves Enzyme prepara6ons Other an6migraine prepara6ons Sulfonamides Calcineurin inhibitors An6cholinesterases Beta blocking agents, selec6ve, and thiazides Progestogens and estrogens, sequen6al prepara6ons Bile acids and deriva6ves Drugs used in opioid dependence Other local anesthe6cs Other agents for local oral treatment Sympathomime6cs in glaucoma therapy 38.205 41.948 30.494 31.442 41.034 38.391 30.466 33.549 25.713 33.081 32.144 27.156 27.578 29.757 23.269 22.011 28.880 19.157 21.762 17.649 12.190 29.687 21.370 16.375 25.291 32.490 18.012 20.281 28.200 13.566 15.493 14.992 13.135 16.254 20.342 2019 39.436 42.957 32.395 32.705 39.610 36.325 31.534 34.901 27.132 32.397 31.440 27.828 27.396 27.331 20.984 23.440 27.844 20.010 23.037 19.424 14.075 25.296 21.100 17.766 23.895 27.026 18.645 19.355 25.774 15.311 16.121 15.888 13.939 17.723 13.171 2020 40.000 41.398 34.373 33.530 38.064 34.833 31.618 36.917 27.726 29.537 30.483 28.191 26.595 27.950 20.320 23.924 26.563 20.951 22.868 19.998 17.469 23.226 21.089 18.739 21.914 22.915 18.764 18.628 22.963 15.457 15.769 16.053 13.385 15.130 12.851 2021 40.398 40.720 36.448 35.153 36.768 35.122 32.633 37.641 29.081 29.586 29.806 29.082 27.227 27.446 25.007 24.568 25.294 22.166 22.928 20.499 19.642 22.922 21.540 19.726 21.618 20.920 19.272 18.267 20.202 16.715 15.979 16.487 15.358 16.267 14.426 2022 41.798 41.197 38.600 37.546 35.863 34.787 34.531 33.166 30.951 29.683 29.509 28.738 27.673 26.872 26.061 25.597 25.428 24.155 23.649 23.098 23.086 22.325 22.246 20.882 20.011 20.008 19.909 18.321 18.219 17.663 17.279 16.657 15.916 15.079 14.964 46 ATC code (level 4) N07BB G02BA A04AD C03EA B02BA C01EB H01BA C09DB J01DD A02BB A10BD C09BB L02BB N05AF G03DB A01AC C02AC M03AC G03CX H01BB N03AA H01CB G03HA N02CD A06AX A06AC A06AG N03AB G01AA N05AL N02BA N04BB B01AX R06AB C01DX L03AB Substance name Drugs used in alcohol dependence Intrauterine contracep6ves Other an6eme6cs Low-ceiling diure6cs and potassiumsparing agents Vitamin K Other cardiac prepara6ons Vasopressin and analogues Angiotensin II receptor blockers (ARBs) and calcium channel blockers Third-genera6on cephalosporins Prostaglandins Combina6ons of oral blood glucose lowering drugs ACE inhibitors and calcium channel blockers An6-androgens Thioxanthene deriva6ves Pregnadien deriva6ves Cor6costeroids for local oral treatment Imidazoline receptor agonists Other quaternary ammonium compounds Other estrogens Oxytocin and analogues Barbiturates and deriva6ves Somatosta6n and analogues An6androgens, plain Calcitonin gene-related pep6de (CGRP) antagonists Other drugs for cons6pa6on Bulk-forming laxa6ves Enemas Hydantoin deriva6ves An6bio6cs Benzamides Salicylic acid and deriva6ves Adamantane deriva6ves Other an6thrombo6c agents Subs6tuted alkylamines Other vasodilators used in cardiac diseases Interferons 2018 16.421 11.443 16.018 41.064 22.399 10.934 16.654 12.195 7.927 9.463 10.951 9.291 11.947 11.525 4.854 5.207 3.663 4.436 9.286 5.893 5.601 3.793 5.001 . 1.740 1.740 1.740 5.839 3.339 2.371 5.474 4.324 4.596 6.624 955 3.320 2019 15.631 12.252 14.218 36.370 17.720 11.288 16.278 12.046 10.072 10.268 11.060 9.705 11.697 11.010 5.947 6.090 4.202 4.637 8.484 5.888 5.255 3.930 5.026 . 2.253 2.253 2.253 5.327 3.659 2.550 4.932 4.141 3.705 4.722 1.230 3.092 2020 14.496 13.328 11.605 32.214 15.448 11.914 13.398 12.008 10.519 10.776 10.710 9.691 10.977 10.534 5.718 6.530 4.256 5.274 7.712 5.101 5.052 3.946 4.723 . 2.624 2.624 2.624 4.759 3.634 2.703 4.416 3.810 2.829 3.775 1.708 2.947 2021 14.183 15.100 12.420 24.273 15.500 12.618 12.828 12.031 10.131 11.459 10.505 9.772 10.425 10.052 6.787 7.407 4.395 5.605 6.746 5.571 4.723 3.964 4.270 1.587 3.154 3.154 3.154 3.903 3.474 3.200 4.043 3.612 3.043 3.664 2.359 2.946 2022 14.384 13.978 13.599 13.229 12.927 12.851 12.836 12.248 11.757 11.423 10.225 10.123 10.052 9.641 8.616 7.998 7.987 6.263 5.977 5.306 4.527 3.980 3.964 3.938 3.826 3.826 3.826 3.665 3.650 3.634 3.617 3.611 3.389 3.389 3.083 2.986 47 ATC code (level 4) J01DC B05XA B05BA H05AA J06BD C09BX N04BX N05BE J04AM G04BE G03AB C02KX L01EX A11DA B02BX J01GB R07AX C01BA J05AE J04BA C04AD N01AH R05CB J01DB A10BF N06DX N06BX M01AX N06AG L02BX C08GA A10BX N01AX A16AX A08AA J01XA Substance name Second-genera6on cephalosporins Electrolyte solu6ons Solu6ons for parenteral nutri6on Parathyroid hormones and analogues An6viral monoclonal an6bodies ACE inhibitors, other combina6ons Other dopaminergic agents Azaspirodecanedione deriva6ves Combina6ons of drugs for treatment of tuberculosis Drugs used in erec6le dysfunc6on Progestogens and estrogens, sequen6al prepara6ons An6hypertensives for pulmonary arterial hypertension Other protein kinase inhibitors Vitamin B1, plain Other systemic hemosta6cs Other aminoglycosides Other respiratory system products An6arrhythmics, class Ia Protease inhibitors Drugs for treatment of lepra Purine deriva6ves Opioid anesthe6cs Mucoly6cs First-genera6on cephalosporins Alpha glucosidase inhibitors Other an6-demen6a drugs Other psychos6mulants and nootropics Other an6inflammatory and an6rheuma6c agents, non-steroids Monoamine oxidase A inhibitors Other hormone antagonists and related agents Calcium channel blockers and diure6cs Other blood glucose lowering drugs, excl. insulins Other general anesthe6cs Various alimentary tract and metabolism products Centrally ac6ng an6obesity products Glycopep6de an6bacterials 2018 4.744 1.573 1.573 1.855 2.747 969 1.828 2.333 2.440 1.481 3.731 1.398 564 1.536 699 1.145 659 1.299 2.687 1.222 1.443 1.449 962 782 1.400 1.645 1.171 1.536 1.022 779 513 697 425 406 298 2019 4.396 2.169 2.169 2.260 2.764 1.298 1.748 2.142 2.238 1.563 3.400 1.454 662 1.363 849 1.238 776 1.217 2.027 1.192 1.383 1.412 962 776 1.235 1.306 1.028 1.353 951 710 628 700 602 444 302 2020 2.912 2.218 2.218 2.403 2.663 1.464 1.831 2.012 1.880 1.647 2.966 1.505 752 1.586 1.005 1.199 761 1.173 1.603 1.114 1.263 1.061 947 790 900 1.070 902 1.139 852 664 590 703 557 469 319 2021 2.654 2.082 2.082 2.513 2.541 1.737 1.823 2.021 1.952 1.658 2.234 1.599 1.171 1.400 1.203 1.289 854 1.135 1.359 1.075 1.176 1.025 921 691 780 916 792 968 759 680 619 660 516 496 409 2022 2.888 2.515 2.515 2.454 2.442 1.967 1.950 1.873 1.867 1.785 1.744 1.634 1.483 1.427 1.404 1.332 1.308 1.171 1.143 1.076 1.050 1.045 810 787 782 774 753 742 728 699 638 612 528 520 462 421 48 ATC code (level 4) J05AP B05AX N05AB J05AX B06AC V03AH M03AX N02BB J02AA A14AB G02AB P01BC A11GA H05BA D08AC B05AA A11HA H01CC L01BA G03CC B01AD J05AD A16AB V03AB Substance name 2018 An6virals for treatment of HCV infec6ons Other blood products Phenothiazines with piperazine structure Other an6virals Drugs used in hereditary angioedema Drugs for treatment of hypoglycemia Other muscle relaxants, peripherally ac6ng agents Pyrazolones An6bio6cs Estren deriva6ves Ergot alkaloids Methanolquinolines Ascorbic acid (vitamin C), plain Calcitonin prepara6ons Biguanides and amidines Blood subs6tutes and plasma protein frac6ons Other plain vitamin prepara6ons An6-gonadotropin-releasing hormones Folic acid analogues Estrogens, combina6ons with other drugs Enzymes Phosphonic acid deriva6ves Enzymes An6dotes 1.063 1.185 1.502 110 165 137 153 6 79 120 36 91 24 40 34 12 7 34 96 2 6 67 3 2019 895 1.153 822 113 173 156 134 15 102 118 56 117 36 42 25 12 16 6 128 . 4 66 1 2020 571 1.140 451 151 185 145 142 23 90 93 67 65 39 42 37 16 1 15 112 3 1 68 1 2021 477 434 398 181 201 147 136 54 84 85 63 67 26 42 19 15 11 8 2 2 2 2 1 2022 403 386 357 311 217 189 170 156 77 74 70 68 39 34 14 12 11 9 8 5 4 2 1 1 49 50 Infographic 1 THE VALUE OF ACTIVE PHARMACEUTICAL INGREDIENTS efcg What are APIs? MN* (Arliwe Plurrnaen Weal Ingroilinnet)an.retpnnelhl the therapoutk effect of forelulated pharmaceutical ixoducts fmedicinesX TMyx nmdiund was highly twhnninetralIM.ahbipenman. both cluing the R&D And commercial production ruses. How is a pharmaceutical specialty developed? 5 PHASES -10 YEARS The dembpreent of 3 new pharmaceutical spnialy b lens and costly and cal last ye to ten years. A DISCOVERY PHASE Several hundred or sometimes thousand mimics are niajected a preliminary lalaniuty Lola. PRECLINICAL PHASE During this pretrnical phase. pharmacciogiol screening indwing taticologkal. in vitro. in vino aid:. liar aluudea 3 PHASES OF CLINICAL TRIALS an Increasingly large numter of subjects These phases evaluate the efficacy and safehrof medicines en large nunber uf volution wad.L. At the end Ot thli tleCtiOn procts` Only one in ter molecules remain that can evened to Clinical Phases 1. i and 3 subject to prior authodsatbn by the competent MAGMA bodies and very few of then make It to the end of the ful selection proCess iscmnIngand clinical trials). An Active Ingredient must in e Demonstrate Its therapeutic actlyty Have a good drevery WSW, Be *sorted once delivered or be effective viten 'squired Reach its tartstIsl Perim, its action and be iubsequendy eliminated _mil 51 How is an e Pharmace ' al Ingredient produced? APIs are produced according to Good Manufacturing Practices (GMP) defined by regulatory authorities. The entire system is controlled by very strict regulatory procedures. O 0 9 A license to manufacture, certifying that the company works in accordance with the requirements of the EU legislation on GMP. A plant that has the adequately trained personnel, premises and equipment for the production and the conservation of each and every product. Quality systems and processes that guarantee the proper functioning of the equipment and the consistency and quality of the APIs produced. It is crucial for the API manufacturer to have a cutting-edge Research & Development (R&D) facility, enabling the transition from laboratory scale to pilot plant and then to full industrial scale. To achieve this an excellent level of technology is needed. 4 4 GMP standards require from manufacturers, inter alia, the validation of their equipment, processes, analytical methods and cleaning methods. Strict environmental, health and safety (EHS) standards are required to operate manufacturing plants. "Gold standards" are applied to meet excellence in industrial safety, environmental protection and health & safety at work. Am At the expiry of its patent the active ingredient can be used for the production of generic and biosimilar drugs, allowing access to affordable healthcare to a wider patient population, including in lower-income countries, NATIONAL e4r HEALTH SERVICES and reducing the cost for health services and insurers thus freeing up resources for innovative therapies. https://efcg.cenc.org 52 Infographic 2 Delivering treatments to patients: The medicines manufacturing journey efpia Manufacturing includes all the operations and the quality controls that are required to produce and distribute an Active Pharmaceutical Ingredient (API) and medicinal product. It is a highly regulated process: at each step, quality assurance confirmation ensures that the product has been manufactured and tested in accordance with marketing authorisation applications, regulations and commitments. Once all requirements are met, a final certification can be given to release the product for wholesale distribution. Manufacturing facilities must operate to strict standards and are regularly inspected by competent authorities. Besides the unproductive time during cleaning, each facility is often shut down for 2-8 weeks each year to ensure maintenance, equipment qualifications and the implementation of innovations, e.g. for sustainability. Local regulatory requirements are part of the global manufacturing process. This means that the same manufacturing process delivers the same product to patients living in different parts of the World. European ziecturing by the r -based pharm .ndustry in figur Today, the EU-27 is a leading location for the manufacturing of innovative medicines and related active ingredients, contributing to a trade surplus of 175 million euros in 2022' and continued supply to patients. The changing policy environment may put this contribution at risk. 324 hittior (EFPIA total): The value of pharmaceutical production in Europe in 20212 175 millior : Trade surplus of medicinal and pharmaceutical products in 20223 64% of APIs are manufactured in Europe (EU-27, Switzerland, UK)4 54% EU27 15% North America 8% Switzerland r 6% India 5% China 3% Japan 2% Singapore 2% UK 1% South Korea 4% Other Innovative manufacturing is key to continue to meet patients' needs Manufacturing enables access to medicines The research-based pharmaceutical industry is constantly making investments in innovative manufacturing technologies such as continuous processing, automation, modular/mobile manufacturing for all medicines including vaccines, biologics, and advanced therapy medicines. These innovations help improve supply reliability, meet regulatory requirements, as well as facilitating the green and digital transitions. 1,2,3 EFPIA, The Pharmaceutical Industry in Figures, 2023, https //www.efpia.eu/media/rm4kzdlx/the-pharmaceutical-industry-in-figures-2023.pdf 4 EFPIA survey conducted in April 2021. Number of APIs (biological and chemical) sourced or manufactured per region of origin (irrespective of value/volume). A total of 16 EFPIA member companies submitted their input to the survey referring to in-patent and off-patent medicines 5 Deoxyribonucleic Acid 6 Physical separation of a chemical substance of interest from foreign or contaminating substances 7 Bulk materials include any materials that are dry, granular, powdery, or lumpy in nature 53 The Manufacturing process: Continuously optimised by implementing innovations Our Commitment efpara Developing and manufacturing high quality and greener medicines. Ensuring a stronger European voice while being at the forefront of developing and implementing innovative products and processes. Defining a strategic vision to proactively prevent medicines shortages caused by disruptions to global manufacturing and supply chains. Raw materials: These are usually commercially available and sourced from plants, organic and inorganic compounds, oil, or DNA5. Many are sourced from the bulk chemical industry from suppliers all over the world, with the pharmaceutical industry representing a minor customer. Pharmaceutical products: (1-10 weeks) These are manufactured from the API with excipients towards 'bulk' material and further processed into containers or devices. Conditions to ensure sterility are applied when required (e.g., for injectable products). Starting material: (12-28 weeks) Some API starting materials may be commercially available; others may be manufactured/ modified for the specific use and require complex chemical transformations. For biotech products, a working cell bank is created from the master cell bank. Excipients, containers, and packaging materials added: Usually commercially available from the chemical or food industry. They can also be designed and manufactured specifically for pharmaceuticals. Quality is controlled by adherence to pharmacopoeia or internal standards. Major changes in demand may take between 1-12 months to implement. API manufacturing: (1-10 weeks) Manufacturing of the Active Pharmaceutical ingredient (API) from API starting materials is conducted in a carefully controlled manner which is critical to the production of high quality, safe, and efficacious medicinal product. API manufacturing may require many chemical and purification' steps. Each of these steps may be performed in a dedicated facility, and in a continuous or batch manufacturing mode. For many products, especially biological, manufacture may be in a sterile environment. Cleaning is necessary after each manufacturing cycle and may take additional 1-3 weeks. Devices used: (as applicable) Devices (e.g., inhalers, pre-filled syringes, on-body injectors) may be used for better patient experience. Where medical devices are required, they are manufactured and controlled to predefined specifications. Medicinal product: (1-2 weeks) The packaging step prepares the final drug product to be delivered to patients. This step is applied to comply to country specific rules, including labels, packaging, and specific content for each country, including leaflets. Repackaging might occur, e.g., if the product is needed in another country or there is a change in the leaflet. Distribution to patients: (1-4 weeks) The finished product gets delivered to different owners (e.g., distributors, wholesalers, pharmacies or directly to local health authorities), ensuring all Good Distribution Practices are respected. The distribution chain of medicinal products needs careful maintenance to ensure their quality, potency, and purity. Call to action Ft_cl Promote a policy environment that fosters R&D in Europe -- the first step to locating advanced manufacturing in the bloc. Streamline and harmonize regulatory requirements to support innovation. Build a collaborative, best-practice led approach to sustainable manufacturing to address environmental challenges. 54 Engaging Associa3ons www.aesgp.eu hJps://efcg.cefic.org/ www.efpia.eu www.medicinesforeurope.com www.vaccineseurope.eu 55