Releasing Sterile Product from a Validated Sterilization Process
Derek J. Prince, Ph.D.
Prince Sterilization Services, LLC
July 14, 2022
Releasing sterile product from a validated terminal sterilization process does not require the performance of a compendial sterility test such as that outlined in USP <71> Sterility Tests or EP 2.6.1. Sterility. The only way to achieve a proper sterility assurance level (SAL) on a pharmaceutical product or medical device is through exposure to a validated sterilization process that is designed to deliver the appropriate lethal conditions to the specific product. The compendial sterility tests are not designed nor intended to make the determination of whether or not the entirety of a sterilized batch of products/devices is sterile. While not the intention of this article, the limitations of the sterility test are well defined and accepted . Below is an excerpt taken directly from USP <71> Sterility Tests.
“These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process or of the aseptic processing procedures.” .
With respect to the International Organization for Standardization (ISO), ISO ANSI/AAMI/ISO 14937: 2009/(R)2013, Sterilization of Healthcare Products – General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process for medical devices, clearly lays out acceptable practices for releasing product from sterilization:
“If a sterilization process operating within specified tolerances has been demonstrated to be both effective and reproducible, confirmation that the process parameters were within specification limits is taken as evidence of the adequacy of the process.
Various pharmacopoeias specify tests for sterility that can be applied to a sample withdrawn from a batch of product that has been exposed to a sterilization process. The value of conducting such tests for sterility is limited because of the insensitivity of the method. This International Standard does not require the conduct of a test for sterility.” .
The language is clear. Under cGMP (current Good Manufacturing Practices), the only way to assure sterility is through use of a validated sterilization process. This process allows product to be released based on the sterilization cycle conforming to predetermined critical process parameters (CPPs). While not the same, it is similar to that of a parametric release program. In a chapter that we authored titled “Sterilization by Heat” published in the sixth edition of Block’s Disinfection, Sterilization, and Preservation textbook, we discuss these concepts in more detail. In summary, parametric release is the acceptance of the attainment of sterility in a sterilization load, without the use of BIs or end-product sterility testing. This type of verification mechanism requires that the sterilization cycle first be designed and validated to achieve the desired SAL. Batches or lots of terminally sterilized products can then be released according to the critical process parameters defined during validation .
For our reader’s convenience, as it is often challenging to navigate the various regulatory/industry standards related to these topics, we conclude this article with additional references related to the subject:
- Food and Drug Administration, Guidance for Industry, Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes, “Parametric release is defined as a sterility assurance release program where demonstrated control of the sterilization process enables a firm to use defined critical process controls, in lieu of the sterility test, to fulfill the intent of 21 CFR 211.165(a), and 211.167(a).”…“Meeting the requirements of the parametric release process can provide greater assurance that a batch meets the sterility requirement than can be achieved with a sterility test of finished units drawn from the batch.” The document also states that, “Sterility testing by cultivation of finished units drawn from the batch is limited in its ability to detect contamination because of the following: (1) the small number of samples required for testing, which restricts the ability to capture those microorganisms dispersed in a large volume, and (2) the limited ability of the prescribed culture media to stimulate growth of all potential microorganisms. Typically, these tests will detect only major errors in the manufacturing process that result in contamination of a large number of product units. However, data derived from in-process controls of a validated terminal sterilization process can provide more accurate information regarding product sterility because the probability of product bioburden surviving the sterilization process in any single unit of a product can be calculated to be less than one in a million.” .
- USP <1222> Terminally Sterilized Pharmaceutical Products – Parametric Release, “Appropriately designed, validated, and controlled sterile product manufacturing systems are capable of exceptionally consistent performance in the preparation of products that have a probability of a nonsterile unit (PNSU) of ≤10−6. The exceptionally low probability of microbial presence in products manufactured using these systems renders the analytical methods described in Sterility Tests (71) statistically ineffectual.” .
- According to the Japanese Task Force on Sterile Pharmaceutical Products Produced by Terminal Sterilization, “Sterile pharmaceutical products processed by terminal sterilization procedures are required to achieve a sterility assurance level (SAL) of less than 10-6. The sterility of products can only be ensured by a validated and comprehensively and consistently-controlled terminal sterilization process, which provides a greater level of sterility than that achieved by the Sterility Test. Thus, it could be considered a scientifically valid rationale to apply the parametric release to sterile pharmaceutical products that have a high level of SAL.” The document also states that, “The appropriate use of a sterilization method controlled by parametric release is dependent on the compliance with all of the following conditions: 1) The mechanism of sterilization has been fully clarified. 2) Key parameters for physical control of the sterilization process are established and are measurable for analysis. 3) The sterilization process can be validated using appropriate biological indicators (BIs). 4) Sterilization processing can be performed in an efficient and reproducible manner.” .
- Annex 17: Real Time Release Testing (RTRT) and Parametric Release states that “Under RTRT, a combination of in-process monitoring and controls may provide, when authorized, substitute for end-product testing as part of the batch release decision.” It continues, “An end-product test for sterility is limited in its ability to detect contamination as it utilises only a small number of samples in relation to the overall batch size, and secondly, culture media may only stimulate growth of some, but not all, microorganisms. Therefore, an end-product testing for sterility only provides an opportunity to detect major failures in the sterility assurance system (i.e. a failure that results in contamination of a large number of product units and/or that result in contamination by the specific microorganisms whose growth is supported by the prescribed media). In contrast, data derived from in-process controls (e.g. pre-sterilization product bioburden or environmental monitoring) and by monitoring relevant sterilization parameters can provide more accurate and relevant information to support sterility assurance of the product.” .
Prince Sterilization Services, LLC offers contract steam, low temperature hydrogen peroxide, and dry heat sterilization and depyrogenation services to the pharmaceutical, medical device, and related health care industries. In addition, Prince also manufacturers the SteriKit®, a pharmaceutical quality kit containing ready to use vials, seals, and stoppers. Customers may supply their own components for us to process or use components that we have in stock. Prince is FDA registered, ISO 13485:2016 certified, and cGMP compliant. If you have any questions about this article or our services and products, please reach out through our websites contact page.
- Sutton, S. 2011. Sterility Tests IN Rapid Sterility J. Moldenhauer (ed) PDA/DHI Publ pp 7-24.
- USP 43, NF 38, <71> Sterility Tests (2022)
- International Organization for Standardization (ISO), (ISO) ANSI/AAMI/ISO 14937: 2009/(R)2013, Sterilization of Healthcare Products – General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process for medical devices
- BLOCK, McDonnel & Hansen, 2020, 6th ed., Disinfection, sterilization, and preservation, Lippincott, Williams and Wilkins pp 589-607.
- Food and Drug Administration, 2010, Parametric Release – Guidance for Industry, Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes.
- USP 43, NF 38, <1222> Terminally Sterilized Pharmaceutical Products – Parametric Release (2022)
- MHLW Task Force: Sterile Pharmaceutical Products Produced by Terminal Sterilization. Office Communication from the Compliance and Narcotics Division, PMSB revised on November 9, 2012.
- EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines for Good Manufacutring Practice for Medicinal Products for Human and Veterinary Use, Annex 17: Real Time Release Testing and Parametric Release, 2018.