Per- and polyfluoroalkyl substances (PFASs) are considered the most significant human-made environmental pollutants with adverse impacts on human and animal health. Multiple studies currently indicate a far higher concentration of PFASs in the environment and far worse health implications than previously assumed. Consequently, five member countries have submitted the broadest, most restrictive proposal that has ever been made in the European Union. The proposal entails direct consequences for the use of PFASs in primary packaging and delivery devices for pharmaceuticals.
Accordingly, it should not only be important for the industry to evaluate the risks related to using PFA-based components, but it should be equally important to assess whether these substances are needed, considering the consequences they are known to cause.
Environmental, Human and Animal Health Consequences
PFASs are a group of man-made organic compounds with a carbon chain in which hydrogen atoms are entirely or partially substituted by fluorine atoms (see Figure 1). The carbon-fluorine bond is incredibly strong, which makes the substances highly stable but also very persistent. This is why they do not degrade easily in the environment or by waste incineration. Because of this extreme persistency, the European Chemical Agency (ECHA) defines PFASs as “forever chemicals,” that is, any substance that contains at least one fully fluorinated methyl (CF3-) or methylene (-CF2-) carbon atom without any H/Cl/Br/I attached to it (1).
Figure 1 Carbon Chain of PFAS
Figure 2 Effects of Exposure to PFASs in human health (2)
Studies have shown that PFASs have already contaminated rainwater, groundwater, soil, sediment, biota, drinking water and food crops. When humans and animals are exposed to and consume PFASs, the substances accumulate and, due to their endocrine-disrupting behavior, they are considered a major health liability. PFASs are linked to a lowered immune system, elevated cholesterol levels, liver damage and various kinds of cancer, among other conditions (see Figure 2).
Proposal for a Restriction of PFASs in the EU
In February 2023, five member countries of the European Union submitted a restriction report to the ECHA proposing a substantial restriction under Annex XV of the Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) regulation for the use of all PFASs variants, thereby listing PFAS as substances of very high concern.
The technical dossier defines “substances containing at least one fully fluorinated methylene -CF2- or methyl -CF3 carbon atom" in alignment with OECD, which is a significantly wider scope than the previous restriction approach of independently regulating single subgroups of PFASs. Therefore, this recent restriction proposal will include and impact the use of all PFAS-based coatings.
The proposal has recently been in public consultation, and once the many comments have been processed, then, the final draft will be presented to the European Commission for their implementation opinion, after which a corresponding sunset date (date of last use) will be set (3). When the restriction of perfluorooctanoic acid (PFOAs) and perfluorooctanesulfonic acid (PFOSs), subgroups of PFAS, was implemented in June 2020, the sunset date for medical devices was set to June 2025 (4,5).
This proposal restriction of PFASs contains a transition period of 18 months and two restriction options:
- Option 1 – No derogation period after the transition period
- Option 2 – Either a 5-year or 12-year derogation period after the transition period
As the commission also must consider the socioeconomic consequences of such a proposal, the proposal group suggests that Option 1 is most unlikely. The more likely second option is based on a subcategorization of the use-cases of PFASs, where each use-case is evaluated, for example, by yearly usage, essentiality and alternatives, and then a derogation period is proposed to be applied to the respective subject. Consequently, Option 2 ultimately entails a sunset date after 6.5 years or 13.5 years from the implementation of the restriction.
PFASs in Primary Packaging and Delivery Devices
Stoppers and plungers used as closures for vials, cartridges and prefilled syringes are typically made of (halogenated) butyl rubber. These kinds of closures often require a coating to prevent extractables from leaching into and adversely interacting with the drug product. These coatings often also enhance mechanical behaviors by preventing stickiness and improving the friction and gliding capability on movable parts like plungers for prefilled syringes and cartridges and stoppers for vials (6).
These coatings are typically made of polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), polychlorotrifluoroethylene (PCTFE), or similar fluoropolymer-based variations that contain -CF2- or -CF3 groups and hence are PFAS (7).
Currently, various branch organizations and companies are trying to argue for and justify the continued use of PFAS in drug products, medical devices and primary packaging. Arguments are made that each subgroup of PFAS should be separately assessed, that exemptions should be made under the term “essential use” and/or with the reasoning that no feasible alternative exists. While the use of -CF2- or -CF3 groups in drug products are not technically the same, (8) there are some relevant counterarguments against the broad use of PFAS in the other use-cases:
- The submission group states that there are simply too many subgroups of PFASs and they fear that many new subgroups would emerge, regrettably substituting one PFAS with another, and since much evidence indicates that all PFA variations (with few exceptions) are consequential, it would be an insufficient approach to containing the risks.
- The submission groups’ expert panel explained during the online consultation session on April 5, 2023, that the “essential use” concept is not an actual defined implemented criterion, so it would require a recast of the REACH regulation and, therefore, cannot be used as a definition to avoid a restriction policy for any use-case subject.
- There are commercially available feasible alternatives for pharmaceutical delivery devices and primary packaging, e.g., PFAS-free feasible alternative container–closures, including vial stoppers, rigid needle shields and plunger stoppers for prefilled syringes (9), all based on virtually chemically inert thermoplastic elastomer materials that do not require a coating.
One could argue that the coatings used in and on devices and the primary packaging are seldom the direct cause of the accumulation of PFASs in humans and animals. Materials used for components and devices for primary packaging are thoroughly studied for biocompatibility, extractables and leachables. In addition, various potential toxicities are studied and evaluated, and there is constant vigilance and patient-centric risk evaluations.
Nevertheless, new studies are continually being published, indicating that an increasing number of the worldwide population have severe accumulated levels of PFASs in the circulatory system— levels considered far beyond safe. Initially, the regulators tried to prevent this alarming development by lowering tolerable intake levels and banning various subgroups of PFASs. However, it has been deemed insufficient unless PFASs, in general, are fully restricted.
Furthermore, the primary source of PFAS contamination comes from manufacturing, industrial use and waste disposal sites. Therefore, one could equally argue that it is not a question of how PFASs are used, but the fact that they are produced and used, which is endangering the environment and human and animal health.
Despite the vivid ongoing debate, the fact remains that the proposal has been submitted and under consultation comments are being processed, which means the risks related to the restriction of PFAS-based products are present.
De-Risking the Future Through Alternatives to PFAS-based Products
With the coming regulatory change, most coatings may be banned, just as PFOSs and PFOAs were banned in medical devices. Adjacent to the restriction of PFASs, there are expected to be no general exemptions but a derogation period after a transition period.
When pharmaceutical companies choose the supply format and the primary packaging for a drug product, it is intended to be on the market for a long time. Consequently, as the restrictions impact the coating in primary packaging, e.g., on container–closure systems for prefilled syringes, cartridges and vials, businesses should aim to de-risk and seek alternatives to their use.
Clearly, the pharmaceutical industry should care about the use of PFAS and, in due time, prepare for the coming ban of PFAS. Furthermore, the pharmaceutical industry’s continuing support of and contribution to the 17 sustainable development goals of the United Nations (10) should be taken into account. Overall, the restriction proposal should raise some questions for consideration:
- What can we do to prevent the use and spread of PFASs?
- Are PFAS-based coatings in primary packaging really a necessity when there, in many cases, are feasible alternatives?
- Do we not want to contribute to eliminating the environmental consequences of PFAS-based products?
Most companies are putting considerable effort into corporate environmental awareness, minimizing their environmental footprint and implementing various sustainability programs. So why not also be proactive — de-risk and turn this challenge into a value proposition in the presentation and marketing of drug products in PFAS-free primary packaging?
- European Chemical Agency (2021), “Why we care about ‘forever chemicals’ and why you should too”, accessed 22-06-2023, https://chemicalsinourlife.echa.europa.eu/why-we-care-about-forever-chemicals-and-why-you-should-too.
- European Environment Agency, Briefing no. 12/2019 – “Emerging chemical risks in Europe — ‘PFAS’ – PDF”, TH-AM-19-014-EN-N – ISBN 978-92-9480-196-8 – ISSN 2467-3196 – doi: 10.2800/486213, HTML TH-AM-19-014-EN-Q – ISBN 978-92-9480-195-1 – ISSN 2467-3196 – doi: 10.2800/02904
- European Chemicals Agency (2023), “Restriction on the manufacture, placing on the market and use of PFASs”, accessed 22-06-2023, https://echa.europa.eu/restrictions-under-consideration/-/substance-rev/72301/term
- Commission Delegated Regulation (EU) 2020/784 of 8 April 2020 amending Annex I to Regulation (EU) 2019/1021 of the European Parliament and of the Council as regards the listing of perfluorooctanoic acid (PFOA), its salts and PFOA-related compounds (Text with EEA relevance), C/2020/1973, ELI: http://data.europa.eu/eli/reg_del/2020/784/oj
- Regulation (EU) 2019/1021 of the European Parliament and of the Council of 20 June 2019 on persistent organic pollutants (recast) (Text with EEA relevance.), PE/61/2019/REV/1, ELI: http://data.europa.eu/eli/reg/2019/1021/oj
- Carolin Richter, Cornelia Lipperheide, Uwe Lipke, Alf Lamprecht, “Impact of extractables from rubber closures on protein stability under heat stress”, European Journal of Pharmaceutics and Biopharmaceutics, Volume 130, 2018, Pages 22-29, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2018.06.009.
- Olivia Henderson, "Primary Container and Closure Selection for Biopharmaceuticals." Formulation and Process Development Strategies for Manufacturing Biopharmaceuticals (2010): 884.
- European Federation of Pharmaceutical Industries and Associates (EFPIA) and Animal Healt Europe, “EFPIA (Representing European Pharmaceutical industry) and AnimalHealthEurope (representing Animal Health Industry) (2022) position on use and risk of “per- and polyfluorinated alkyl substances” (PFAS) in Europe, in the light of an emerging Restriction under REACH”, accessed 22-06-2023, https://www.efpia.eu/media/636866/pfas-position-_-efpia-and-animalhealtheurope-january-2022.pdf.
- According to https://www.aseptictech.com/en/ (2023), https://www.aptar.com/wp-content/uploads/2020/07/pds_formulations_for_pfsandcartridges.pdf (12/2016 - version 1), https://injecto.eu/pfas-free-plungers/ (2023), accessed 22-06-2023
- United Nations, accessed 05-07-2023, https://sdgs.un.org/goals