Top 3 Sterilization Validation Methods For Medical Devices
How does the United States Food and Drug Administration (FDA) define sterile?
Under the strictest definition of sterility, an item or product is sterile when there is a complete absence of viable microorganisms (bacteria, yeasts, viruses, and molds). For regulatory purposes, sterility is defined by acceptance criteria based on calculated contamination probability. An acceptable level of contamination risk for most items is the probability of contamination for one in a million products. However, sterility criteria may be more stringent or lax depending upon the intended use of the medical device or product. Please see our sterilization comparison chart for more information on which sterilization method is best for your medical device.
What are sterilization validations, and why are they important?
Since the sterility of a medical device or product is based on acceptance criteria, the process that a product or device undergoes to become sterile must be validated to prove that sterility acceptance criteria are consistently met. Sterility can be assured only by using a validated sterilization process under current good manufacturing practices (cGMP). Sterility cannot be demonstrated by reliance on periodic sterility testing of final products alone. Thus, sterilization validations are tests that accumulate data about a sterilization process and statistically prove that the sterilization process can consistently sterilize medical devices or products under “worst-case scenario” conditions.
The control of sterilization processes involves:
- Sterilization process development: an evaluation of factors such as the stability and compatibility of product materials to the sterilization method, expected pre-sterilization bioburden, and control parameters for sterilization equipment.
- Sterilization process parameter identification: determine the sterilization cycle parameters and sterility acceptance criteria needed for the bioburden of product, properties of the materials, and intended use of the sterile item.
- Sterilization demonstration: a demonstration that proves the operating capability of the sterilization process and equipment at the desired parameters.
- Statistical proof of sterility consistency: the execution of replicate studies that employ actual product or simulated product with biological indicators to prove the expected lethality of the sterilization process.
- Sterilization process monitoring: a plan for monitoring and maintaining the equipment and environment for the validated process during routine operation.
- Sterilization acceptance criteria assurance: implement systems to assure that the microbial content of products, devices, and materials is within predetermined limits before and after the sterilization process. Revalidate sterilization processes periodically.
How are sterilization validations performed?
Knowledge of sterilization technologies, instrumentation, and equipment is needed to control and verify sterilization process metrics appropriately. Appropriate biological indicators are selected and placed at strategic locations to cover “worst-case” microbial scenarios. Sterilization validations require multiple formally documented stages. General principles for validation programs (cleaning validations and the like) are applicable to all sterilization processes. Each sterilization mode (e.g., dry heat sterilization, steam sterilization, ethylene oxide sterilization, vapor sterilization, liquid phase sterilization, sterilization by filtration, and radiation sterilization) has individual criteria that must be met. The first sterilization validation stage is the process development stage. In the process development stage, operating parameters and controls used for the sterilization process are investigated and selected. The next stage is the installation qualification stage, which ensures that equipment controls and instrumentation are installed and calibrated appropriately. As part of the installation qualification, systems to regulate steam, water, and air should be verified and documented. The third sterilization validation stage is the operational qualification stage. Operational qualification makes sure that installed equipment functions within the set sterilization process parameters. After the operation of the equipment is verified, the performance qualification stage begins. Performance qualifications assess the sterilization of materials, items, and biological indicators that pass through the sterilization process under validation. Performance qualifications measure sterilization cycle controls and the effectiveness of the sterilization cycle in overcoming worst-case biological challenges. Often, worst-case biological challenges are bacterial spores. The fifth and final sterilization validation stage is the routine process control stage. This final stage ensures that sterilization processes are continuously monitored and controlled to maintain the efficacy of product sterilization.
How to perform sterilization validations for microbial inactivation processes?
In order to pass sterilization validation acceptance criteria, sterile processes must have a one in a million probability of unit contamination (or less). Sterility acceptance criteria are also known as sterility assurance levels (SALs). Further, PNSU is a common abbreviation for the probability of a nonsterile unit. Sterilization validations for microbial inactivation processes can be performed via three techniques: overkill methods, bioburden-biological indicator methods, and bioburden-based methods. All three techniques are equally accurate. The overkill method is the simplest. However, it is the most stressful for sterilized materials. The bioburden-based method requires the greatest method control but allows sterilized materials to undergo the least stressful conditions. All three sterilization validation techniques are described in greater detail below. Note that filter sterilization of liquids and gases differs from other sterilization modes since it removes microorganisms vs. inactivates them. Thus, the three sterilization validation techniques detailed in this article do not apply to sterilization validations of filter sterilization processes.
#1: Overkill Sterilization Validation Method
The overkill method is preferred for medical devices and items unaffected by the sterilization processes due to its simplicity. Items that could be damaged by extended sterilization process exposure should not be assessed via an overkill method. With an overkill method, the destruction of a high concentration of resistant microorganisms (bacterial spores) supports killing the bioburden present during normal medical device or item sterilization. An overkill validation is passed if any of the following criteria are met: a defined minimum lethality, a defined set of method conditions, or confirmation of minimum log reduction of a resistant biological indicator.
#2: Bioburden-Biological Indicator (Combination) Sterilization Validation Method
A combination bioburden-biological indicator sterilization validation is an approach where the partial destruction of a resistant biological indicator can be used to demonstrate the ability of the sterilization process to reliably destroy the routine bioburden present during medical device (or product) sterilization. A combination approach requires detailed knowledge of the anticipated product bioburden, biological indicator populations, and the relative resistance of the anticipated bioburden and biological indicator populations.
#3: Bioburden-Based Sterilization Validation Method
The bioburden-based method is used when material stability is poor or when no suitable biological indicator microorganisms are available to use with the sterilizing process. Traditionally, radiation sterilization processes are validated using a bioburden-based method. In a bioburden-based method, bioburden samples from the device or product are routinely evaluated for resistance to the sterilization process. Lack of device resistance to the sterilization process can then be utilized to demonstrate its effectiveness. For this sterilization validation method, routine monitoring of the product bioburden population (and any resistance to the sterilization process) is required.
Summary
Since the sterility of a medical device or product is based on acceptance criteria, the process that a product or device undergoes to become sterile must be validated (through a sterilization validation) to prove that sterility acceptance criteria are consistently met. Sterility can be assured only by using a validated sterilization process under current good manufacturing practices (cGMP). Sterilization validations have five stages: process development, installation qualification, operation qualification, performance qualification, and process control. Validated sterilization processes must undergo recertification on a regular basis. Additionally, though the easiest sterilization validation technique for microbial inactivation processes, the overkill method is not preferred for all sterilization processes. Sometimes bioburden-based or bioburden-biological indicator combined methods for sterilization validation assessment are preferred. Overall, ensure you choose a contract testing organization that can provide appropriate sterilization validations for your unique medical device or product needs.
Ethide Labs is a contract testing organization specializing in Sterilization Validations & Bioburden Testing. Ethide Labs also offers Microbiology Testing, Bacterial Endotoxin Testing, EO Residual Testing, Sterility Testing, Cytotoxicity Testing, Environmental Monitoring & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1229> Sterilization of Compendial Articles. Rockville, MD, USA. 2021. (USPC <1229>).
