Page 89 - Assurance of Sterility for Sensitive Combination Products and Materials

Aseptic processing 75

contamination of the sterile product and components. This differs from fin-
ished product sterilization or terminal sterilization, where the objective is to
eliminate the microbiological contamination in the product. The prevention
of contamination is best achieved through a science and risk-based eval-
uation of the product and process. This evaluation and analysis should be
designed to identify and understand the potential sources of contamination.
Understanding the product needs allows for thoughtful design of the pro-
cess. Understanding the variation and limitations of the process allows for
the design of effective control strategies to address variation and minimize
process weakness, thus reducing process risk. The use of risk-based thinking
has long been encouraged by global Health Authorities. The US FDA men-
tions it in its 2004 white paper on GMPs for the 21st century and the EU
suggests it as a means for process control extensively in its 2017 proposed
revision to Annex 1 [4, 18].
Quality risk management involves the use of science and risk-based
decision-making. These are methods of critical thinking that help identify
risk, causes of risk, and means to reduce risk [21]. The best way to achieve
aseptic process control and prevent contamination is to fully understand the
capabilities, limitations, and variables of the aseptic process. Product testing,
process monitoring, and aseptic process simulations have a role in assuring
process control and product quality. Their capability to do so is limited by
the process complexity, inherent variation, and lack of established correla-
tions between the observed and actual performance of the aseptic process.
Assurance of effective process control can only be truly achieved through
risk and science-based aseptic process design practices.
Five simple rules can help meet this objective:
1. Understand the effects of process steps on other quality attributes of the product.
Identify the contamination-related quality attributes or requirements for
the product. Know if the product must be sterile, low bioburden, or
endotoxin-free. Map the process steps to determine what impact each
step has on the establishment of aseptic process or the prevention of
microbiological contamination.
2. Recognize that failures are the result of unforeseen or under-addressed process
variables. Understand the capability, limitation, and variability of the
process steps designed to control, measure, and prevent contamination.
While risk is defined as the severity of a hazard times the probability of
occurrence times the likelihood of detection of a failure, the best means
to reduce risk remains the reduction of the probability of occurrence.
Understanding the variability of the process will allow for the imple-
mentation of more effective process controls.