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Sec. 460.800 Parametric Release - Terminally Heat Sterilized Drug Products (CPG 7132a.13)

BACKGROUND:

In 1985, FDA approved supplemental new drug applications for certain large volume parenteral drug products, which substituted parametric release for routine lot by lot end-product sterility testing.

Parametric release is defined as a sterility release procedure based upon effective control, monitoring, and documentation of a validated sterilization process cycle in lieu of release based upon end-product sterility testing (21 CFR 211.167). All parameters within the procedure must be met before the lot is released.

POLICY:

This policy applies only to parenteral drug products which are terminally heat sterilized. It does not apply to products sterilized by filtration or ethylene oxide. This policy does not preempt requirements of Section 505 of the FD&C Act. Approved supplements providing for parametric release are required for holders of new drug applications. (21 CFR 314.70(b))

Parametric release, in lieu of end product sterility testing, is acceptable when all of the following parameters are met and documented.

1. The sterilization process cycle has been validated to achieve microbial bioburden reduction to 100 with a minimum safety factor of an additional six logarithm reduction. Cycle validation includes sterilizer heat distribution studies, heat distribution studies for each load configuration, heat penetration studies of the product, bioburden studies, and a lethality study referencing a test organism of known resistance to the sterilization process. All cycle parameters must be identified by the manufacturer as critical (e.g., time, temperature, pressure) or non-critical (e.g., cooling time, heat-up time). Under parametric release, failure of more than one critical parameter must result in automatic rejection of the sterilizer load (see paragraph D concerning biological indicators). (21 CFR 211.113(b))

2. Integrity for each container/closure system has been validated to prevent in-process and post-process contamination over the product's intended shelf-life. Validation should include chemical or microbial ingress tests utilizing units from typical products. (21 CFR 211.94)
3. Bioburden testing (covering total aerobic and total spore counts) is conducted on each batch of presterilized drug product. Resistance of any spore-forming organism found must be compared to that of the organism used to

validate the sterilization cycle. The batch is deemed non-sterile if the bioburden organism is more resistant than the one used in validation. (21 CFR 211.110)

4. Chemical or biological indicators are included in each truck, tray, or pallet of each sterilizer load. For chemical indicators, time/temperature response characteristics and stability are documented and for each sterilization cycle minimum degradation values are established. Chemical indicators cannot be used to evaluate cycle lethality.

Documentation is required for biological indicators (BIs). Documentation for each BI lot shall include an organism's name, source and D-value, spore concentration per carrier, expiration date, and storage conditions. BIs can be used to evaluate cycle lethality where equipment malfunction prevents measurement of one critical cycle parameter. If more than one critical parameter is not met, the batch is considered non-sterile despite BI sterility. (21 CFR 2311.165(e) and 211.167)

Issued: 10/21/87