By Laurent Berliet and Luisa Bernuzzi
In the pharmaceutical industry, controlling the sterility, safety and performance of products is a critical challenge. Among the essential components that contribute to the quality of a product, the elastomers, which constitute plungers, stoppers, injection ports and tubing, often play a discreet but absolutely decisive role.
Available in a wide variety of packaging formats — vials, pre-filled syringes, cartridges, injection devices and infusion systems — these materials ensure container closure integrity, protection against contamination and compatibility with formulations, including the most sensitive ones. Their widespread use is explained not only by their unique mechanical and chemical properties, but also by their direct contribution to the stability of the drug and patient safety.
At the heart of the manufacturing, packaging and administration processes, elastomers represent a strategic element in the sterile product production chain, where every detail can have an impact on the final quality.
Validation of elastomer sterilization process is an essential step. It demonstrates, through robust scientific data, that the method used — whether it is steam sterilization or ethylene oxide sterilization — is effective, reproducible and compatible with the materials.
Validation is based on several standards that define the requirements for demonstrating process lethality and sterilization cycle compliance.
ISO 11138-7: Sterilization of health care products — Biological indicators — Part 7: Guidance for selection, use and interpretation of results
ISO 17665: Sterilization of health care products — Moist heat
ISO 11135: Sterilization of health care products — Ethylene oxide
United States Pharmacopoeia
European Pharmacopoeia
Biological indicators (BIs), compliant with ISO 11138, are used as challenge organisms to demonstrate process performance under worst-case conditions. These BIs must be placed in the “hardest-to-reach areas”, locations that present the greatest challenge to sterilant penetration, to ensure that sterilization is effective, and the cycle is validated in compliance with international standards.
ISO 11138-7: 2019 Sterilization of health care products - Biological indicators - Guidance for the selection, use and interpretation of results
5. Characteristics of biological indicators
5.3.2 The resistance characteristics of a test organism in suspension can be considerably changed upon deposition on or in carriers. Several factors can influence the resistance characteristics, such as the surface on which the suspension is inoculated (e.g., solid materials, viscous products or fluids), the way the spores are dispersed and otherwise treated, the method of drying, etc.
USP NF
(1229.1) Steam Sterilization by direct contact (Official as of 01-Aug-2013)
Component Mapping
Items that are steam sterilized can be quite complex and may have interior void volumes, obscured surfaces, crevices, and difficult-to-reach product contact surfaces that must be sterilized. The ability of saturated steam to penetrate the wrapping materials or containers and to reach the surfaces should be established for each item.
European Pharmacopoeia
5.1.2 Biological Indicators and related microbial preparations used in the manufacture of sterile products (Official as of July 1, 2017)
2. Biological Indicators for sterilisation processes
Spores inoculated into a product or onto surfaces are known to react differently to sterilising conditions as compared to biological indicator units. In these cases, commercially available biological indicator units may not be suitable to test sterilisation effectiveness and an inoculated test product/item prepared from a well characterised spore suspension may be a better model to evaluate the effectiveness of the sterilisation cycle.
Elastomeric components, such as pharmaceutical closures, remain particularly challenging from a process perspective. Their intrinsic properties can significantly affect sterilization performance. Microporosities, surface roughness, as well as the internal structure of the polymer, may trap residual air, slow down heat diffusion or limit access to the sterilant, making sterilization more difficult to validate than for smooth, metallic or perfectly non-porous surface.
This complexity can be increased by the presence of a coating, which forms a lubricating sheet that can encapsulate or partially protect against possible contaminants. Such a hydrophobic barrier can further reduce the efficiency of sterilant penetration, thus accentuating the challenges related to the validation of elastomers sterilization.
In this context, the use of standard biological indicators (e.g. Mesa Strips, EZTest®), although compliant with ISO 11138, does not always reflect the unique challenge of elastomers: spore strips do not replicate the true complexity of the elastomer. This can lead to overestimating the effectiveness of the process on these materials.
Consequently, conducting a D value study based on the direct inoculation of the challenging microorganism on the elastomer, becomes an essential element in the development of the proper sterilization process.
The D-value is used to quantify the time required to reduce a given microbial population by a factor of 10 under actual process conditions, provided that the microbial inactivation kinetics is linear. By measuring these kinetics directly on the elastomeric material, it becomes possible to obtain a much more accurate view of the effective microbial resistance within this type of porous and complex support.
These D-value studies may also reveal a possible tailing effect, characteristic of nonlinear lethality due to the substrate.
Surface contamination may in fact vary depending on the quality and homogeneity of the surface. Spores that are well exposed on the surface can be easily reached and destroyed by steam, spores trapped within porosities or micro-cracks may be more difficult to inactivate.
Understanding and evaluating these characteristics is essential to support the development of an appropriate sterilization cycle and validation strategy using a biological indicator that truly represents the challenge represented by the device itself.
The comparison of this experimental D-value, obtained through direct inoculation, with that provided by standard biological indicators is then a crucial tool to judge the relevance of using a BI to develop an overkill sterilization cycle (i.e. the typical cycle for an elastomeric material).
If the D-value obtained is lower than or similar to that of the biological indicator, then the BI can be considered as representative of the "worst case" and will constitute a real reference for validation.
On the other hand, if the study reveals a resistance of a direct inoculation greater than that of a biological indicator, then the latter will not be representative and will remain an insufficient challenge for cycle validation; the inoculated elastomeric product will become a “custom BI” for assessing sterilization cycle efficacy. In this case, direct inoculation of the elastomer is preferred to reproduce, as closely as possible, the actual conditions of microbial exposure and the specific interactions between the contaminant, the material, and the sterilizing agent.
This approach ensures a more robust validation, taking into account the true complexity of the elastomers and the limitations of standard indicators.
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