Is parametric release an appropriate control strategy for sterile drug products that are not terminally sterilized?
No. Parametric release is only appropriate for terminally sterilized drug products. Although both terminally sterilized and aseptically processed drug product batches are required to meet the sterility test requirement (see 21 CFR 211.167(a)) before release to the market, there are inherent differences between the production of sterile drug products using terminal sterilization and aseptic processing.
Products that are terminally sterilized are rendered sterile in their final, sealed units by sterilizers. Discrete physical parameters are continuously measured and controlled with robust precision and accuracy during processing.
Additionally, parametric release incorporates a sterilization load monitor that is integral to satisfying the requirement for a sterility test (see § 211.167(a)) by confirming that the load has been exposed to the prescribed physical conditions.
This allows manufacturers to couple adherence to sterilization cycle parameters with a load monitor to determine thermal lethality, thereby directly confirming sterility and substituting for the sterility test.
In contrast, aseptic processes do not subject the final, sealed drug product to a sterilization cycle, and monitoring the sterility hazards to drugs manufactured throughout aseptic manufacturing operations relies on indirect measurements. Sterilization processes (e.g., filtration) for the drug occur before further manipulations that are performed in Class 100 (ISO 5) environments where transient events can present hmicrobial contamination risks during the manufacturing process. Consequently, indirect measurements used in aseptic processing provide limited information to conclude whether a batch is sterile.
Even contemporary aseptic operations conducted in closed RABS and isolators can experience sterility and media fill failures, despite the substantial robustness of these technologies over traditional cleanroom and open RABS operations.
The sterility test is therefore an essential element to monitor the state of control of an aseptic operation, and it is the last step in a series of fundamental, required controls that collectively contribute to the minimum assurance that a given manufacturing operation produced a drug that meets its sterility claim.
References:
- 21 CFR 211.167(a): Special testing requirements
- 21 CFR 211.113(b): Control of microbiological contamination
- FDA Guidance for Industry, 2010, Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes
- Compliance Policy Guide Sec. 490.200 Parametric Release of Parenteral Drug Products Terminally Sterilized by Moist Heat
- Storage Condition of Pharmaceutical Products
- Different Sampling Strategies in Pharmaceutical Industry
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