BSE / TSE and their relevance for primary packaging in the pharmaceutical industry
The safety of medicinal products is a crucial factor in the pharmaceutical industry. One of the most important challenges is the prevention of contamination by bovine spongiform encephalopathy (BSE) and related transmissible spongiform encephalopathies (TSE). These diseases, which are caused by prions, are potentially dangerous not only for animals but also for humans, particularly through the transmission of the pathogen via contaminated pharmaceutical products. Primary packaging materials such as rubber stoppers, plungers and vials play a key role in the safety of pharmaceuticals. These materials are in direct contact with the drug and can be a potential source of BSE/TSE risk if they are made from animal derivatives.
Definition
- BSE (Bovine Spongiform Encephalopathy): A neurological disease in cattle caused by prions. Prions are infectious proteins that are incorrectly folded and force other proteins to fold in a similar way.
- TSE (Transmissible Spongiform Encephalopathies): A group of related diseases that occur in various animal species and may be transmissible to humans (e.g. Creutzfeldt-Jakob disease).
Transmission routes
BSE/TSE is not transmitted by conventional microorganisms (such as bacteria or viruses), but by prions. These are extremely resistant to sterilization procedures and chemical treatment.
BSE/TSE in the pharmaceutical industry
The pharmaceutical industry is affected because many manufacturing processes and materials use animal derivatives, including
- Gelatin: In capsules or as a stabilizer in vaccines.
- Tallow derivatives: As a component of lubricants or additives in the production of rubber stoppers and other packaging materials.
- Cholesterol: In lipid formulations or cell culture media.
Primary packaging materials such as rubber stoppers, plungers or vials play a central role in the safety of pharmaceutical products. These packaging components can indirectly contribute to BSE/TSE risks, especially when materials of animal origin are used.
Rubber stoppers:
Rubber stoppers are commonly used in glass vials to seal liquid or freeze-dried pharmaceuticals. Animal derivatives such as stearic acid or tallow derivatives are occasionally used in the manufacture of elastomers for rubber stoppers. These substances serve as:
- Lubricants: To improve the processability of elastomers.
- Plasticizers or stabilizers: To adjust the material properties.
If these animal derivatives come from sources at risk of BSE/TSE, there is a risk that they contain prions.
Plungers:
Plungers used in prefilled syringes or autoinjectors are also made of elastomeric materials that may contain animal derivatives. These can be a potential source of contamination during manufacture, storage or through direct contact with the drug.
Vials:
Glass vials themselves do not pose a direct risk of BSE/TSE as glass is inorganic. However, coatings, cleaning agents or other components may contain animal derivatives and thus increase the risk.
The risks posed by BSE/TSE have led to comprehensive regulatory requirements in the pharmaceutical industry. These requirements affect both active ingredients and packaging materials.
EU regulations:
The European Medicines Agency (EMA) has issued guidelines to minimize BSE/TSE risks. These include in particular EMA/410/01, which defines requirements for the evaluation of animal derivatives:
- Proof of origin: Animal materials must originate from regions that are considered BSE/TSE-free.
- Documentation: Manufacturers must trace and document the entire supply chain.
- Risk classification: Materials are divided into risk classes depending on which animal tissue was used (e.g. brain or tallow).
US FDA:
The FDA requires manufacturers to test all materials that come into contact with drugs for potential BSE/TSE risks. In the Guidance for Industry on TSE Risks, the FDA requires:
- Complete elimination of materials from sources at risk for BSE/TSE.
- Testing for the absence of prions in packaging materials.
ISO standards:
ISO standards for primary packaging materials (e.g. ISO 8871 for elastomers) stipulate that materials must be tested for BSE/TSE risks. This applies in particular to rubber stoppers and plungers that come into direct contact with the medicinal product.
Several strategies are used in the pharmaceutical industry to minimize the risk of BSE/TSE in primary packaging materials.
Material substitution:
- Use of synthetic materials: Tallow derivatives are replaced by plant-based or synthetic alternatives.
- Elimination of animal additives: Manufacturers increasingly rely on chemically defined materials without animal derivatives.
Strict supplier control:
- Proof of origin: Materials of animal origin must come from countries classified as BSE-free by the World Organization for Animal Health (OIE).
- Certification: Suppliers must guarantee that their products do not contain any substances containing prions.
Sterilization and cleaning procedures:
- Validated processes: Although prions are resistant to standard sterilization processes, special high-temperature processes can increase safety.
- Cleaning: Coatings or lubricants used in the manufacture of vials and stoppers must be free of animal residues.
Risk-based assessment:
- Production risk analysis: Manufacturers assess each primary packaging product for potential BSE/TSE risks.
- Prion-free testing: Analytical methods are used to detect traces of animal materials.
Challenges:
- Costs: The substitution of animal materials and the implementation of strict testing processes increase production costs.
- Technical limitations: Some synthetic alternatives do not offer the same performance as materials with animal derivatives.
- Regulatory diversity: Different requirements in different countries make standardization difficult.
Future prospects:
- Innovation in materials: The development of new, fully synthetic elastomers and coatings will continue.
- Automated testing processes: Advances in analytics enable more efficient testing for BSE/TSE risks.
- Global harmonization: Regulatory requirements could be standardized internationally to make it easier for manufacturers to comply.
BSE/TSE poses a significant challenge to the safety of medicinal products, particularly when using primary packaging materials such as rubber stoppers, plungers and vials. Although these materials are often only indirectly linked to animal derivatives, their manufacture and use require strict controls to minimize the risk of prion contamination. Through regulatory measures, material substitutions and innovative technologies, the industry is working to eliminate this risk and ensure the safety of medicines worldwide. The future will be characterized by synthetic materials and standardized testing procedures that provide a high level of safety while being cost effective.
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