Dr. Tsuguo Sasaki, GMP Expert, Office of Compliance and Standards of the Japanese Pharmaceuticals and Medical Devices Agency
(PMDA) advocates that F° ≥ 2 min would be a reasonable expectation for parametric release. The authors strongly agree and would favor a harmonized
regulatory approach in which any firm with acceptable GMP compliance that submitted an application for a product sterilized
at a process lethality of F° ≥ 2 min would be granted parametric release for its product without any added expectations. This proposal is radical only
because existing regulatory policy fails to properly consider true medical risk.
Parametric release simply means releasing product without having subjected it to a compendial sterility test. The real question
is what value the performance of a sterility test on a process offers. Given the low sensitivity and statistical sampling
limitations of the sterility test, it has limited value and really should be called a test for gross product contamination.
It is rarely failed when applied to aseptically produced products and simply has no value when used to test products sterilized
in their containers.
Lower temperature heat treatments would provide significant safety benefit to products that are filled in human-scale cleanrooms.
The benefit of these treatments would diminish in instances where advanced aseptic processing technologies, such as isolators,
closed restricted access barrier systems, or some blow, fill, and seal processes are used. The authors postulate that comparable
approaches could be used with radiation sterilization where low-dose exposures would provide similar advantages to patient
safety. ISO 11137-2 provides for developing relatively low does processes based upon bioburden number and resistance (1).
Recommendations and experience from Japan
PMDA's Dr. Sasaki shared with the authors some basic concepts from Japan's Guideline on the Manufacture of Sterile Drugs by Terminal Sterilization, which is expected to be issued in 2012. This document will consist of a narrative section and annexes. The following information
reflects general recommendations for low F° terminal sterilization and will be presented in one of the guideline's annexes:
- Minimum F° is 2.0.
- Cleanliness of filling area is Grade A, and surrounding areas are Grade B. (Grade C may also be used but personnel microbial
monitoring would be expected to meet Grade B levels.)
- Average presterilization bioburden should be less than 1 colony-forming unit (cfu)/product unit.
- Bioburden should be evaluated for heat resistance.
- Grade A is used for filling, but media fill testing is not required.
Low-dose terminal sterilizational is in widespread use in Japan. Dr. Sasaki provided some data regarding its application in
Japan during 2005–2010 from 13 different manufacturers (see Table 1). Nearly 80% of the roughly 2.8 trillion units manufactured
by terminal sterilization were subjected to F° of two minutes or less. Quite clearly, these low lethality sterilization processes would not be allowed were they not safe
Table I: Application of low-dose sterilization from 13 manufacturers in Japan from 2005–2010.