Document 5D3xdBvYbwX6KD5qrRjbdyjy0

24 September 2023 Global Initiative for Asthma (GINA) submission to ECHA REACH on proposal to restrict PFAS GINA response to consultaon on proposed restricon on the manufacture, placing on the market and use of per- and polyfluoroalkyl substances (PFAS) Use sector: Medical devices. Sub-use: Propellants in metered dose inhalers (MDIs) About GINA The Global Iniave for Asthma (GINA) is an internaonal non-profit organisaon that works with healthcare professionals, health officials and the general public to raise awareness of asthma and improve its management asthma worldwide. GINA is an independent organisaon with no financial links to industry, funded solely through sale and licensing of its educaonal publicaons. Members of the GINA Board of Directors are drawn globally from leaders with an outstanding demonstrated commitment to asthma research, asthma clinical management, public health and paent advocacy. GINA Science Commitee members are highly experienced asthma experts from around the world, who connually review and synthesise scienfic evidence to provide guidance on asthma prevenon, diagnosis and management. GINA shares concerns about global environmental health and supports efforts to reduce exposure to per- and polyfluoroalkyl substances (PFAS), but we warn about serious unintended medical consequences of the proposed banning of propellants that are essenal for survival and safety of paents with respiratory condions. Comments on Annex XV restricon report Our comments focus on PFAS applicaons in metered-dose inhalers used to deliver respiratory medicines. Coangs of Metered Dose Inhalers (MDIs): We welcome the proposed 12-year derogaon for coangs of metered-dose inhalers. Propellants in Metered Dose Inhalers (MDIs): We request a change in the status of three PFAS propellants in pressurised metered-dose inhalers (pMDIs). These propellants (HFC-134a, HFC-227ea and HFO-1234ze(E)) are essenal for the delivery to the paent of the medicaons contained in the pMDI. However, all three are currently classified as Restricon Opon 1 (RO1) status, i.e. they would be subject to a full ban with no derogaons and a transion period of only 18 months. For the current propellants HFC-134a and HFC-227ea, we request a change from RO1 to RO2 status, providing a 12-year derogaon, with the same consideraons as for coangs of metered dose inhalers; that is: Technically and economically feasible alternaves are NOT generally available. Substuon potenal at entry into force is VERY LIMITED. The lack of technically feasible alternaves and the high societal value of the medicinal product indicates that a full ban would be associated with high socio-economic costs in the EU and also especially in persons with lung diseases in poorly resourced countries. A 12-year derogaon is warranted because idenficaon, development and cerficaon of alternaves would take more than five years to complete. 1 For the future propellant HFO-1234ze(E), we request exempon from the ban, or a me-unlimited derogaon because: Technically and economically feasible alternaves are NOT available. There is NO substuon potenal at entry into force. The lack of technically feasible alternaves and the high societal value of the medicinal product indicates that a full ban or even 12-year derogaon would be associated with high socio-economic costs in the EU, and also especially in persons with lung diseases in poorly resourced countries. Exempon or me-unlimited derogaon is warranted for this propellant because idenficaon, development and cerficaon of alternaves would take more than 12 years to complete. Key points Pressurised metered-dose inhalers (pMDIs) are used to deliver essenal medicines for paents with asthma and COPD. In these inhalers, a propellant is essenal to deliver the medicine to the paent's lungs. For many paents, parcularly children and the elderly, pMDIs cannot be substuted with any other devices, and some regions of the world do not have access to alternave types of inhalers. Three propellants for use in pMDIs would be affected by the proposed RO1 ban. Two of them (HFC-134a and HFC-227ea) are currently in widespread use in pMDIs around the world and the other (HFO-1234ze(E)), which has very low global warming potenal (GWP), is being developed to replace the current propellants. A ban on these three propellants would have serious unintended medical consequences, pung paents' health and lives at significant risk. A different propellant cannot simply be substuted in medical devices. Many years are required to develop devices containing new propellants because they must pass stringent clinical tests and regulatory processes. Delayed implementaon of PFAS restricons should apply to pMDI propellants, to allow me for new devices with new propellants to be tested for efficacy and safety, approved for use, and manufactured in sufficient quanty to meet needs of paents, both in Europe and in global export markets. Impossibility of substuon with alternaves for medical needs within the proposed meframe The propellants in currently available pMDIs are hydrofluoroalkanes HFC-134a and HFC-227ea. These will be phased out under proposed fluorinated gas restricons1 in the transion to alternaves with low GWP. Both of these propellants are also classified as PFAS. However, pMDIs using alternave propellant will not become available for several years. As Internaonal Pharmaceucal Aerosol Consorum (IPAC), and Internaonal Pharmaceucal Aerosol Consorum on Regulaon and Sciences (IPAC-RS) have explained:2 It is not possible to simply "drop in" an alternative medical propellant to MDIs. Propellants for medical uses must be non-toxic and must have specific physico-chemical characteristics to enable appropriate 1 European Commission. Proposal for a regulaon of the European Parliament and of the Council on fluorinated greenhouse gases, amending Direcve (EU) 2019/1937 and repealing Regulaon (EU) No 517/2014. COM(2022) 150 final. European Commission, 2022. htps://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52022PC0150 European Parliament. P9_TA(2023)0092. Fluorinated gases regulaon. Fluorinated gases regulaon Amendments adopted by the European Parliament on 30 March 2023 on the proposal for a regulaon of the European Parliament and of the Council on fluorinated greenhouse gases, amending Direcve (EU) 2019/1937 and repealing Regulaon (EU) No 517/2014 (COM(2022)0150 - C9-0142/2022 - 2022/0099(COD)). (Ordinary legislave procedure: first reading): European Parliament; 2023. Available at: htps://www.europarl.europa.eu/doceo/document/TA-9-2023- 0092_EN.pdf 2 Internaonal Pharmaceucal Aerosol Consorum (IPAC), Internaonal Pharmaceucal Aerosol Consorum on Regulaon and Sciences (IPAC-RS). Preliminary joint comments to ECHA REACH on proposal to restrict PFAS. May 2023. 2 performance, meeting high standards of safety and efficacy; they cannot be replaced easily. Ensuring that a new propellant is safe for patients, compatible with the device components and formulation, and supports required particle size distributions and delivered dose uniformity, is an extensive, resource-intensive process. The change in propellants also impacts many elements of the supply chain, including elastomers, valves, and any other device components in the drug delivery pathway. Many of these must be tested and/or redesigned with the new propellant for compatibility and final product tested for leachables. New manufacturing equipment must be developed and built to adapt to the characteristics of any new medical propellants (e.g., flammability). It is also important to understand that these changes involve regulatory assessment, and depend on regulatory approval, by the European Medicines Agency (EMA) and national regulatory authorities. EMA has advised the pharmaceucal industry that: propellant replacement constitutes a major change to the finished product formulation with potential impact also on the construction of the inhaler; therefore, data confirming maintenance of adequate finished product performance need to be provided for each modified product. In addition, data addressing possible toxicity and local tolerance of novel propellants need to be provided.3 The EMA guide sets out rigorous data requirements. Substuon of current propellants within 18 months of finalising the proposed restricons is therefore not technically or economically feasible - this would risk the health of paents in Europe and elsewhere. IPAC/IPAC-RS have explained that:4 [p]rematurely banning these essential products could lead to drug shortages of essential, life-saving medicines. A significant proportion of medicines manufactured in Europe are exported around the world. Adequate time must be provided to allow replacement products to be developed, tested, and approved by medicines regulators and for patients to be safely and seamlessly transitioned. pMDIs using new, lower-GWP propellants are under development5 to replace the current high-GWP propellants (HFC-134a and HFC-227ea). Although the new propellants are already available for other industrial applicaons, pMDIs containing them will not be available for several years. Moreover, one of the only two future pMDIs announced to date contains a propellant (HFC-152A) that is subject to phase-down under EU F-gas legislaon.6 3 European Medicines Agency Commitee for Medicinal Products for Human Use. Quesons and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers. EMA/CHMP/83033/2023. European Medicines Agency, 2023. htps://www.ema.europa.eu/en/documents/scienficguideline/quesons-answers-data-requirements-when-replacing-hydrofluorocarbons-propellants-oralpressurised_en.pdf 4 Internaonal Pharmaceucal Aerosol Consorum (IPAC), Internaonal Pharmaceucal Aerosol Consorum on Regulaon and Sciences (IPAC-RS). Preliminary joint comments to ECHA REACH on proposal to restrict PFAS. May 2023. 5 Honeywell. Honeywell teams with AstraZeneca to develop next-generaon respiratory inhalers that use near-zero global warming potenal propellant. Honeywell, 2022. htps://www.honeywell.com/us/en/press/2022/02/honeywellteams-with-astrazeneca-to-develop-next-generaon-respiratory-inhalers-that-use-near-zero-global-warming-potenalpropellant ; Chiesi. Chiesi outlines 350 million investment and announces the development of the first carbon minimal pressurised Metered Dose Inhaler (pMDI) for Asthma and COPD: Chiesi, 2019. htps://www.chiesi.uk.com/img/news/613_final-021219_chiesi-investment-in-carbon-minimal-pmdis-december2019.pdf 6 European Commission. ANNEXES to the Proposal for a Regulaon of the European Parliament and of the Council on fluorinated greenhouse gases, amending Direcve (EU) 2019/1937 and repealing Regulaon (EU) No 517/2014. Annex to: European Commission. Proposal for a regulaon of the European Parliament and of the Council on fluorinated greenhouse gases, amending Direcve (EU) 2019/1937 and repealing Regulaon (EU) No 517/2014. COM(2022) 150 final. European Commission, 2022. htps://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52022PC0150 3 The other new propellant, HFO-1234ze(E) (trans- 1,3,3,3-tetrafluoroprop-1- ene; tetrafluoropropene, Honeywell),7 is reported to have extremely low GWP, but it is currently classified as a PFAS. An immediate ban on this propellant would set back by many years efforts to reduce global warming associated with respiratory treatments, and leave no potenal replacement for delivery of essenal medicines. GINA is concerned by inconsistency in the ECHA regulaons proposed for inhalers, compared with that for other medicaons; derogaon is provided for acve medicaons and for the lining of the pMDI canister, but not for the ingredient that is essenal for the delivery of the acve medicaon (the propellant) and without which paents will be denied essenal and life-saving medicaons. The medicinal product has a high societal value Inhalaon remains the opmal mode of medicaon delivery for paents with asthma and chronic obstrucve pulmonary disease (COPD). pMDIs with spacers are essenal for young children and for many older paents, as they are unable to use the alternave inhaled drug delivery devices such as dry-powder inhalers (DPIs).8 For all age groups, selecng the right inhaler for the individual paent is crucial to reduce paents' symptom burden and risk of severe atacks requiring emergency treatment and hospitalizaon, and even death. Furthermore, not all treatments required for the management of asthma and COPD are available in DPI formulaons, nor are they likely to be in the next five years. In addion, DPIs are not widely available or used in low-income countries, owing to their greater cost.9 Therefore, global access to pMDIs remains crucial for people with asthma and COPD. The potenal harm to persons with asthma and COPD, if access to pMDIs is even temporally restricted, may be gauged from the following facts: In 2019, 3.20 million persons died from COPD and 455,000 from asthma.10 Ninety-five per cent of deaths from asthma and 84% of deaths from COPD were in low- and middle-income countries (LMICs),11 and the heterogeneity of mortality rates is strongly associated with socio-economic factors.10 The widening gap between morbidity and mortality from asthma in high- versus lower-income countries is atributable to the lack of access to medicaons in inhaler form, as treatments in oral forms have litle efficacy.12 7 Honeywell. Honeywell teams with AstraZeneca to develop next-generaon respiratory inhalers that use near-zero global warming potenal propellant. Honeywell, 2022. htps://www.honeywell.com/us/en/press/2022/02/honeywellteams-with-astrazeneca-to-develop-next-generaon-respiratory-inhalers-that-use-near-zero-global-warming-potenalpropellant 8 Levy ML, Bateman ED, Allan K, et al. Global access and paent safety in the transion to environmentally friendly respiratory inhalers: the Global Iniave for Asthma perspecve. Lancet. 2023;402(10406):1012-1016. htps://www.thelancet.com/journals/lancet/arcle/PIIS0140-6736(23)01358-2/fulltext 9 Kponee-Shovein K, Marvel J, Ishikawa R, et al. Impact of choice of inhalers for asthma care on global carbon footprint and societal costs: a long-term economic evaluaon. J Med Econ. 2022;25(1):940-953. doi:10.1080/13696998.2022.2088196 htps://www.tandfonline.com/doi/full/10.1080/13696998.2022.2088196 10 Li X, Cao X, Guo M, Xie M, Liu X. Trends and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systemac analysis for the Global Burden of Disease Study 2017 [published correcon appears in BMJ. 2020 Aug 6;370:m3150]. BMJ. 2020;368:m234. htps://www.ncbi.nlm.nih.gov/pmc/arcles/PMC7190065 11 WHO Global Health Esmates 2019 htps://www.who.int/data/gho/data/themes/mortality-and-global-healthesmates/ghe-leading-causes-of-death 12 Meghji J, Mormer K, Agus A, Allwood BW, Asher I, Bateman ED, et al. Improving lung health in low-income and middle-income countries: from challenges to soluons. Lancet. 2021;397:928-40. htps://www.thelancet.com/journals/lancet/arcle/PIIS0140-6736(21)00458-X/fulltext 4  pMDIs are the main inhalaon device used in LMICs as they are less costly, especially when in generic formulaons.13 However, the producon of generic pMDIs in LMICs is made possible through the import of essenal components (for example, the dosing mechanism) and the propellant from high-income countries. The generic inhalers, like the original ethical devices, require approval from regulators in each country in which they are used. The regulatory process involves numerous steps, and it is esmated that transion to novel MDI propellants would likely take at least a decade based on the meline for the transion from chlorofluorocarbon-based MDIs.13, 14 Despite the efforts of the World Health Organizaon (WHO) and several United Naons resoluons to improve access to inhalers for all,15 access to inhalers remains the major barrier to reducing asthma and COPD mortality in LMICs.16 Improving access to inhalers is a priority in recent WHO resoluons, for example WHA66.10 of 2013, the global acon plan for the prevenon and control of non-communicable diseases 2013-2020, subsequently extended to 2030 (WHA72(11) (2019) and the WHO's Implementaon Roadmap 2023-2030 for the Global Acon Plan on the Prevenon and Control of NCDs (75th World Health Assembly 2022). With the planned phasing-out of currently used high-GWP propellants beginning in 2028,17 GINA is concerned that the supply of pMDIs and propellants for LMIC will diminish or stop, owing to inevitable price increases for developing the new products, compeng demand from other sectors for propellant gases for other uses, and lengthy delays associated with obtaining regulatory approval for new medical products within the EU and each country globally (referred to in the IPAC/IPAC-RS submission18). Thus, GINA, as an internaonal non-profit organisaon with a global perspecve, while fully supporng acons to replace harmful propellants and devices, wishes to draw atenon to the serious unintended consequences of the proposed PFAS restricons for paents both within and outside the EU, parcularly for LMICs, given the potenal to exacerbate serious global inequies in health care through major disrupon of the availability and affordability of essenal inhaled medicines. As stated in the United Naons commentary on the Sustainable Development Goals: [e]nding poverty and other deprivations must go hand in hand with strategies that improve health and education, reduce inequality and spur economic growth - all while tackling climate change and working to preserve our oceans and forests.19 13 Woodcock A, Beeh KM, Sagara H, et al. The environmental impact of inhaled therapy: making informed treatment choices. Eur Respir J. 2022;60(1):2102106. htps://erj.ersjournals.com/content/erj/60/1/2102106.full.pdf 14 Wilkinson AJ, Braggins R, Steinbach I, et al. Costs of switching to low global warming potenal inhalers. An economic and carbon footprint analysis of NHS prescripon data in England. BMJ Open. 2019;9(10):e028763. 15 United Naons General Assembly Resoluon 66/2 of 2011. Polical Declaraon of the High-level Meeng of the General Assembly of the Prevenon and Control of Non-communicable Diseases.; United Naons General Assembly Resoluon 70/01 of 2015. Transforming our world: the 2030 Agenda for Sustainable Development. 3. United Naons General Assembly Resoluon 74/2 of 2019. Polical Declaraon of the High-Level Plenary Meeng on Universal Health Coverage: resoluon adopted by the General Assembly. 16 Stolbrink M, Thomson H, Hadfield RM, et al. The availability, cost, and affordability of essenal medicines for asthma and COPD in low-income and middle-income countries: a systemac review. Lancet Global Health 2022;10:e1423-42. 17 European Commission. Proposal for a regulation of the European Parliament and of the Council on fluorinated greenhouse gases, amending Directive (EU) 2019/1937 and repealing Regulation (EU) No 517/2014. COM(2022) 150 final. European Commission, 2022. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52022PC0150 18 Internaonal Pharmaceucal Aerosol Consorum (IPAC), Internaonal Pharmaceucal Aerosol Consorum on Regulaon and Sciences (IPAC-RS). Preliminary joint comments to ECHA REACH on proposal to restrict PFAS. May 2023. 19 The United Naons Sustainable Development Goals Project. htps://www.unsdgproject.com/unpacking-thegoals.html 5 Conclusion GINA submits that the proposed ban on propellants which are essenal for funcon of pMDIs will have a profoundly negave effect on paents with asthma (parcularly young children and the elderly) or COPD who rely on this treatment, and will severely exacerbate inequalies in healthcare globally. For these reasons, we request 12-year derogaon for the current high-GWP propellants (HFC-134a and HFC227ea) and exempon or indefinite derogaon for the future low-GWP propellant HFO-1234ze(E)), because of the lack of currently available alternaves and the long me to develop, test, regulate and manufacture new opons for safe delivery of essenal medicines. We urge all involved in regulatory discussions relevant to medical inhalers to priorise the health of those within and beyond Europe - including people with asthma in LMICs, who already bear the brunt of impact of environmental degradaon. 6