The re-examination of the regulatory philosophies that underpin sterile-product manufacturing is long overdue. There is a
failure to recognize that postfill heat and radiation treatments could provide additive safety benefits and that these adjuncts
to aseptic processing may be applicable to a significant range of products. A process need only be as lethal as necessary
to destroy the bioburden present. The current gulf between aseptic processing and terminal sterilization can be bridged as
the information from Japan clearly illustrates. At the same time, these data indicate that true terminal sterilization can
be applied far more frequently than it is currently by the industry if one considers that low lethality processes can yield
safety levels that are so good that further improvements would provide only theoretical medical benefit.
What has to happen other than this re-examination of the fundamental regulatory philosophies for sterile-product manufacturing?
The authors suggest the following:
Item 1. The realization that most medically significant organisms die at temperatures and conditions far lower than where modern
industry considers that sterilization begins.
Item 2. The universal recognition that the F° principal has tremendous value and relevance and that there is nothing magical about 121.1 °C as a minimum target temperature
Item 3. Increased awareness that parametric release should require evidence only that a process does not benefit from the application
of the compendial sterility test as a quality-release requirement.
Item 4. Awareness that Item 3 requires disavowal of the notion that there is a test to prove sterility or that such a test could
be devised. No microbial test, be it growth-based or rapid, has a limit of detection of zero. It is impossible to prove a
Item 5. Understanding and accepting the clear scientific principal that neither safety nor sterility hinge upon the ability to kill
Geobacillus stearothermophilus spores per article. Organisms isolated from extreme environments, such as hot springs and other geothermal features, are not
and cannot be medically significant.
Item 6. We can learn from the extensive experience of Japan with respect to lower lethality terminal sterilization.
The authors urge broad international discussions on sterile- product manufacturing and strongly suggest that these discussions
be undertaken with the understanding that patient safety must be evaluated from a medical perspective only and not from the
viewpoint that begins and ends with current regulatory paradigms. Many modern-day sterile-product manufacturing paradigms
are mistaken and unduly inflexible. The result is a stifling of innovation and an overreaction to misperceived risk while
thwarting simple steps that would add safety and reduce cost.
The authors thank PMDA's Dr. Sasaki for the information he provided for this article and for the many discussions that have
been instrumental in exploring the options examined in this article.
James E. Akers*, PhD, is president of Akers Kennedy and Associates, PO Box 22562, Kansas City, MO, 64113, AKAincKC@aol.com
James P. Agalloco is president of Agalloco & Associates. He is also a member of Pharmaceutical Technology's editorial advisory board.
*To whom all correspondence should be addressed.
1. ISO, ISO 11137-2 Sterilization of Health Care Products. Radiation (Geneva, 2012).