Ionizing irradiation, typically gamma, has been the most used method of sterilization and bioburden control for single-use bioprocess systems for more than 20 years. Still, there remains some confusion around the need for sterile or bioburden-controlled systems and how to achieve it.
Our latest blog explains the difference between a validated sterile claim and a low or zero bioburden microbial control claim on single-use systems and where each fit into biopharmaceutical manufacturing processes.
Validated Sterility
Sterile claims within drug product and medical device regulations require a validated sterility assurance level (SAL) of 10-6 or better. This statistical approach requires a demonstrated (validated) chance of a non-sterile event being less than one in one million.
For any process that claims to be sterile, there is generally a combination of controls in place to establish and maintain the “sterile envelope.” For such a process, the sterility of the single-use system is required. It is expected that a validated sterilization process with an SAL of 10-6 is in place. Examples of processes that claim to be sterile are those where the drug product is unable to be terminally sterilized. These are drug products that are heat-labile or the active product is too large to be sterile filtered without significant step yield loss. Additionally, products that are terminally sterilized by filtration process systems downstream of the final filter need to have a sterile claim.
Bioburden-Controlled Processes
Following a risk-based approach, many bulk drug substance bioprocesses do not claim to be sterile, but instead are low bioburden or bioburden-controlled processes. The risk to the process and final product quality for such a process is dependent on the low bioburden contribution from process systems. Generally, the bioburden is low or zero, and additional controls are in place to ensure that the final product quality is under control, such as defined hold times and temperatures, and the use of bioburden-reducing filters. These bulk processes often employ sterilizing grade filters throughout the process. The sterile filters are expected to yield a low or zero bioburden filtrate, yet they are not validated to do so since the filtrate is not claimed to be sterile. Remember that zero bioburden does not equate to a sterile claim given the requirements for an SAL of 10-6.
ISO 11137 — VDmax 25 Method
The most common validation method for sterilization of single-use systems is the ISO 11137 Vdmax 25 method. At a high level, this method allows a sterile claim based on a verified received dose of 25 kGy or greater for systems with less than 1,000 colony forming units (CFU) per system. ISO 11137 requires quarterly dose audits and bioburden assessments.
In practice, the sterilization process is dependent upon the density of the package to be sterilized, the received dose and the bioburden being less than 1,000 CFU per unit. Practices vary regarding the assessment of the bioburden from a minimum frequency of quarterly as required by ISO 11137, up to and including lot-specific bioburden assessments, with destructive testing of a limited number of products from the lot to be sterilized.
The Vdmax 25 method is convenient for single-use system manufacturers that routinely manufacture similar products from the same components with consistent bioburden. It offers flexibility within limits to achieve a sterile claim. For manufacturers that frequently manufacture a wider variety of single-use systems or are faced with components that may not fall within the scope of their existing validation, irradiating these systems at greater than 25kGy is another option.
Single-use systems that have been irradiated at greater than 25kGy but do not carry a sterile claim are analogous to sterilizing grade filters for low bioburden processes. It is expected that the single-use system carries zero bioburden, which is sufficient to support the low bioburden process, but which is not sufficient to support a process with a sterile claim.
In summary, components or systems requiring zero or low bioburden when applied to a nonsterile process do not need to be validated as sterile, but simply validated as microbially controlled.
