Martell Winters- Director of Science, Nelson Labs; Adam Staples- Department Scientist, Nelson Labs.
Introduction
Sterility assurance is a critical aspect of pharmaceutical manufacturing, which commonly includes single-use systems. Single-use systems offer numerous advantages, including reduced contamination risk, increased operational efficiency, and improved flexibility. However, ensuring the sterility of these systems requires careful consideration of various factors. In this overview, we will delve into the key topics that pharmaceutical manufacturers should be aware of when addressing sterility assurance for single-use systems.
1. Regulatory Guidelines
Pharmaceutical manufacturers must stay abreast of regulatory guidelines set forth by authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the International Organization for Standardization (ISO). These guidelines provide the framework for sterilization validation, including the choice of methods, acceptable sterility assurance levels (SALs), and documentation requirements.
2. Sterilization Methods
Different sterilization methods are available for single-use systems, and each has its own advantages and limitations. Steam sterilization (autoclaving) is commonly used in the pharmaceutical industry due to its effectiveness, low cost, and compatibility with various materials, but is not commonly used for single-use systems due to the high temperatures required and the impact on many polymers that are part of the systems. Although other common sterilization methods like ethylene oxide (EO) and electron beam irradiation could be explored, the complexity and density of the single-use systems creates difficulties in using these methods. The most common methods used are gamma and X-ray irradiation, and they have served the single-use systems industry well for many years. Manufacturers should understand the strengths and limitations of each method and select the most appropriate one for their specific single-use systems. Since radiation sterilization is the most common method applied to single-use systems, most of the information below will be focused on radiation.
3. Material Compatibility
Single-use systems consist of various components, such as tubing, filters, and connectors, made from different materials. Manufacturers must evaluate the compatibility of these materials with the chosen sterilization method to ensure that sterilization does not compromise their integrity or performance. Compatibility testing may involve assessing factors such as material stability, leachables, and changes in physical or mechanical properties. This evaluation might influence whether the sterilization process could include some overkill, or should be optimized to result in a more gentile cycle for the materials.
4. Validation Studies
Validation studies are crucial for establishing appropriate sterilization parameters for single-use systems. These studies involve determining the ideal combination of temperature, time, and pressure (for most sterilization processes), or the minimum radiation dose to achieve the desired sterility assurance level (SAL). Validation protocols should include worst-case scenarios and stress conditions to ensure the robustness of the sterilization process.
5. Bioburden Assessment
Bioburden refers to the microbial load present on single-use systems before sterilization. For radiation sterilization, conducting a thorough bioburden assessment is essential for determining the initial level of contamination and establishing an appropriate sterilization dose. This assessment involves sampling, enumeration, and some degree of microorganism characterization which might include identification of microorganisms present, as well as evaluating the potential influence of bioburden on the sterilization process.
6. Sterility Assurance Level (SAL)
The SAL is a measure of the probability of a product remaining non sterile after sterilization. Expressed as 10-n, where “n” represents the desired level of sterility assurance, manufacturers must define the appropriate SAL based on the risk associated with the specific application. The chosen sterilization method must be capable of achieving the selected SAL, which is typically 10-6 (1 in a million), but alternative SALs can be selected under certain circumstances (see AAMI ST67 and ISO 19930).
7. Dose Mapping
Dose mapping studies are essential for verifying the uniformity of radiation sterilization throughout the entire single-use system. Particularly important for large or complex systems, dose mapping involves placing radiation sensors (called dosimeters) at various locations within the system to ensure that all areas receive the minimum sterilization dose. This process helps identify potential low dose areas that may require adjustments in the sterilization process.
8. Product Integrity Testing
After sterilization, it is crucial to assess the integrity of single-use system components to ensure they have not been compromised. Product integrity testing may involve evaluating parameters such as seal strength, particulate matter, leachables, and container closure integrity. These tests help confirm that the single-use system remains intact and capable of maintaining its sterile condition.
9. Residuals and Residues
Many sterilization processes can leave behind residual sterilization agents or reaction by-products on single-use systems. One of the benefits of radiation sterilization is that there are no residuals, so no testing regarding that topic is necessary. When using sterilization processes other than radiation, manufacturers must assess the presence and impact of these residuals to ensure they comply with safety and quality standards. Residual testing may involve chemical analysis and toxicological evaluations to verify the absence of harmful residues that could pose risks to patients or affect product stability.
10. Packaging and Storage Considerations
Packaging and proper storage are critical for maintaining the sterility of single-use systems until their intended use. Manufacturers should consider the influence of packaging materials on sterilization processes, as well as factors like moisture control, gas permeability, and compatibility with the chosen sterilization method. Although packaging can have an influence, such as those just listed, on most sterilization methods, rarely does packaging have any influence in radiation sterilization.
11. Verification of Sterility
Users of single-use systems often are asked, or desire, to verify the sterility of the single-use systems they are using. Performing tests for sterility on some systems does not verify the sterility of other systems they use, and is not the appropriate way to address this question. The proper way to verify sterility is to perform a technical diligence audit of the single-use system supplier, ensure the sterilization process is validated and maintained per an appropriate method (usually an ISO standard), and demonstrate that the sterilization process has been correctly applied (usually through a review of the certification of irradiation).
Conclusion
Sterility assurance is an essential aspect of ensuring the safety and efficacy of single-use systems in pharmaceutical manufacturing. The eleven topics discussed in this overview can help pharmaceutical manufacturers navigate the complexities of sterilization validation effectively. Staying up to date with regulatory guidelines, understanding sterilization methods, assessing material compatibility, conducting validation studies, and performing rigorous product testing are key steps in ensuring appropriate sterility assurance of single-use systems.
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