Florian Schindler is head of Business Development, ACTEGA GmbH.

Florian Schindler

Needle of a syringe protrudes through the rubber cap of a vaccine vial with red cap. Focus on the rubber stopper, shallow depth of field |Image Credit: © Henk Vrieselaar – stock.adobe.com

Pharmaceutical packaging, and primary packaging in particular, which is in direct contact with the dosage form (or could potentially come into contact with it), is often much more than mere repositories. It can have an influence on the quality, effectiveness, and safety, as well as applicability, of pharmaceuticals, which cannot be underestimated. Typical examples include injection bottles with sealing plugs used as both repositories and for applying medication. Butyl rubber (e.g., bromobutyl and chlorobutyl, the standard material for manufacturing stoppers) is increasingly viewed with skepticism due to its energy-intensive production, its non-recyclable nature and halogen-containing composition. Therefore, a look at alternative materials, such as thermoplastic elastomers (TPE), is worthwhile, especially with regard to the current per- and polyfluoroalkyl substances (PFAS) debate.

Pharmaceutical stoppers are rather small and inconspicuous, but carry enormous responsibility.Primarily used as closures for injection and drug vials, they are subject to complex and highly regulatory requirements.Stoppers used for parenteral applications (i.e., for injectable and infusion-ready drugs) are in direct contact with the product.Therefore, they must adapt perfectly to the product to ensure its integrity at all times.Annex 9 of the World Health Organization (WHO) 

Guidelines for the Packaging of Medical Products 

(1) stipulates, “The kind of packaging and the materials used must be chosen in such a way that the packaging itself does not have an adverse effect on the product (e.g., through chemical reactions, leaching of packaging materials or absorption), the product does not have an adverse effect on the packaging, changing its properties or affecting its protective function.”

In addition, good container closure integrity (CCI) is essential (i.e., to prevent the leakage of liquids and to maintain the sterility of the vial contents).Furthermore, pharmaceutical closures must meet the relevant requirements of the market in which they are to be offered.The most important chemical requirements can be found in Section 3.2.9 of the 

) (2–4). To meet the criteria of protection, safety, compatibility, and function, a variety of physical and mechanical material properties, as well as processability and sterilizability, must be ensured.Physical-chemical and functional tests are used to check for modifications, penetrability, fragmentation, and self-sealing.

Rubber has long been the primary material for pharmaceutical closures due to its (excellent) mechanical properties in terms of sealing and flexibility.However, the manufacturing and processing is energy-intensive, expensive, and wasting resources. Certain degradation and reaction products can be formed during the manufacturing process, which can then find their way into the final product.Furthermore, synthetic butyl rubber is not recyclable and causes many emissions due to its CO

There has long been a search for more sustainable solutions.Thermoplastic elastomers play a key role here - without containing PFAS.They can be processed using the widely used injection molding process and enable faster, more energy-efficient production.TPEs have the required soft-elastic and sealing properties and meet all the requirements of medical-grade plastics, such as tested biocompatibility according to ISO 10993 and USP Class IV.The recyclability of thermoplastic elastomers makes them a sustainable alternative.TPEs can be reused at the end of their life cycle and integrated into new products.This contributes to reducing waste and conserving natural resources.A defined level of purity can be confirmed, given that no conventional cross-linkers like sulfur or zinc are used, as would be the case with vulcanized rubber. This significantly reduces the likelihood of interactions with certain sensitive pharmaceutical compounds.

Substitution of PFAS-containing rubber with TPE

PFAS were and are considered indispensable in the pharmaceutical industry, particularly in primary packaging materials such as stoppers and plungers, as they offer exceptional chemical stability, inertness, and functional advantages.However, the risks posed by their persistence and potential toxicological effects are increasingly bringing their use into the focus of regulatory and social debates.For example, the European Chemicals Agency (ECHA) is seeking a comprehensive ban on PFAS in various applications, including packaging materials (5).In the United States, FDA is increasingly reviewing the safety of PFAS in materials that come into contact with pharmaceuticals.International standards for pharmaceutical primary packaging materials may become more stringent in the future to limit the use of PFAS.

PFAS are a group of synthetic chemicals widely used in various industries for their unique set of properties, as well as their resistance to heat, water, and oil. According to recent estimates, this group of substances includes more than 10,000 different substances (the Organization for Economic Co-operation and Development [OECD] identified approximately 4700 PFAS. the US Environment Protection Agency (6) identified 12,034 substances as PFAS). PFAS were developed in the mid-20th century and quickly found applications in numerous products (e.g., pharmaceutical packaging where PFAS may be used to treat rubber components). PFAS are considered ‘forever chemicals’ because PFAS are almost impossible to break down, and studies have shown that they have contaminated rainwater, drinking water, and groundwater. Worldwide reports of PFAS contamination have linked these substances to a range of problems for humans and the environment. Some PFAS chemicals have been proven to cause diseases such as cancer, liver damage, hormone disruption, and weakening of the immune system (7).

Although medical devices, certain protective equipment, and 

 diagnostics according to the Medical Device Regulation are currently exempt from the bans, some manufacturers have begun to develop alternative materials and coatings to avoid the use of PFAS. Thermoplastic elastomers free of per- and polyfluoroalkyl substances and perfluoroalkoxy alkane polymers are already in use in the medical and pharmaceutical industry, for example, for pharmaceutical closures. The advantages of PFAS-free TPEs include high purity, safety, compliance with strict legal regulations, sustainability, and versatility.

TPEs in medical applications, such as pharmaceutical stoppers for injection and medication vials, will drive material change in the coming years and—especially PFAS-free—are the alternative of the future.

1. WHO. Annex 9 Introductory Note, Paragraph 8, Guidelines on Packaging for Pharmaceutical Products. WHO Technical Report Series, No. 902, 2002. 

https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/regulatory-standards/trs902-annex9.pdf?sfvrsn=82b4c57d_2

https://www.biomed.co.th/downloads/EP7-3.2.9-Rubber-closures.pdf

3. Mangus, J. Japanese Pharmacopeia Updates–Are You Ready? Blog. 

https://www.westpharma.com/zh-cn/blog/2015/august/japanese-pharmacopeia-updates-are-you-ready?srsltid=AfmBOop_mBNnlgE0F_MB-smnCS2LgEE5MxGUhQfbf-pJwoM6dlPB33qc

https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/381_elastomeric_closure_for_injections_rb_notice.pdf

5. ECHA. ECHA Publishes PFAS Restriction Proposal. Press Release. Feb. 7, 2023. Echa.europa.eu. 

https://echa.europa.eu/de/-/echa-publishes-pfas-restriction-proposal

6. OECD Environment Directorate. Chemicals and Biotechnology Committee. Toward a New Comprehensive Global Database of Per- and Polyfluoroalkyl Substances: Summary Report on Updating the OECD 2007 List of ... 2018 (accessed October 2023).

7. Fraunhofer. Replacement of Polymeric PFAS in Industrial Applications with Harsh Environments, IWM Report 1191/2024, Fraunhofer. 

https://publica-rest.fraunhofer.de/server/api/core/bitstreams/d2768dfe-1bb8-480f-ac67-2f4c61146b5f/content

Articles

Pharmaceutical packaging, particularly primary packaging, plays a crucial role in maintaining the quality, effectiveness, and safety of pharmaceuticals. Traditional materials like butyl rubber are under scrutiny due to environmental concerns, prompting a shift towards sustainable alternatives such as thermoplastic elastomers (TPEs). TPEs offer advantages like recyclability, energy-efficient production, and compliance with medical standards. The ongoing debate over per- and polyfluoroalkyl substances (PFAS) highlights the need for PFAS-free materials in pharmaceutical applications. TPEs, free from PFAS, are emerging as a promising alternative for pharmaceutical closures.

Thermoplastic elastomers (TPE) offer a PFAS-free solution for stoppers in parenteral packaging, ensuring a safer and more sustainable product.