ASEPTIC PROCESSING: ONE - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 226

• Ensure that regulatory review, compliance, and inspection policies are based
on state-of the-art pharmaceutical science.
• Enhance the consistency and coordination of FDA's drug quality regula-
tory programs, in part, by further integrating enhanced quality systems
approaches into the Agency's business processes and regulatory policies
concerning review and inspection activities.”

This document has had a profound impact on the pharmaceutical industry, and
not the least of it was the acknowledgement that evaluation and minimization of
patient risk would play a much larger role in future compliance considerations.
Concurrent with the release of this major CGMP document, FDA released new
aseptic processing guidance [22]. The aseptic processing guidance, while claimed
by FDA to be risk-based, lacks clarity as to the principles of risk assessment
and mitigation to be followed. ¶ Nevertheless, risk-based thinking is now the
order of the day within FDA, and increasingly across the global pharmaceutical
community [23].
Aseptic processing is a logical candidate for formalized risk assessment, and
due credit must be given to Dr. Whyte of the University of Glasgow. His landmark
papers in this area set the stage for virtually all of the subsequent efforts [24-26].
Central to much of Dr. Whyte's work is the following equation:
Number of microbes deposited on a product = C

× × × × ×

S Pd Pa A T,

where: C

= concentration of microbial contamination on, or in, a source

(number/cm 2 , or number/cm 3 )

S = surface material, or air, that is dispersed or transferred, from the

source in a given time (cm 2 /s for surfaces, and cm 3 /s for air
dispersion); could also be concentration per frequency of
occurrence

Pd = proportion of microorganisms dispersed that are transferred to the

area adjacent to the product

Pa = proportion of microorganisms that arrive at the adjacent area

carrying microorganisms in the concentration C that are deposited
per unit of the product area (/cm 2 )

area of surface onto which microbes are deposited (cm 2 )

=

A

time, during which transfers occur(s); could also be frequency of
occurrence
The logic inherent in this calculation is irrefutable; and provided the various
parameters can be accurately measured, the contamination rate can be precisely
determined. Unfortunately, the first four variables in the equation defy
estimation, let alone determination with any precision. The inability to place
metrics on these elements dramatically reduces the utility of the equation

T =

¶ The 2004 Aseptic Guidance had been initially developed well before the risk-based CGMP initiative,
and lacks meaningful risk-based thinking. Its publication on the same day appears to be more a
forced coincidence than a meaningful effort on the part of FDA to provide a truly risk-based aseptic
guidance.