Page 207 - Assurance of Sterility for Sensitive Combination Products and Materials

186 Assurance of sterility for sensitive combination products and materials

As noted at the onset of this clause, it is not the process simulation sam-
ple sizes alone that provide confidence in sterility; it is the entirety of ISO
13408 requirements and related process engineering.

7.3.4 Point estimates and confidence bounds—Terminal
sterilization; bioburden-based approach
This is a terminal sterilization example of point estimates and confidence
bounds from quantifiable aspects of the terminal sterilization validation pro-
cess. As summarized in Chapter 3, the development, validation, and routine
control of a sterilization process start with product definition, that is, defining
the product and the microbiological condition of the product. Product manu-
facturing controls and product bioburden monitoring are required to fulfill this
requirement. The sterilization process is then defined to actively reduce the mi-
crobial load with the sterilization process in order to achieve the specified SAL
(PNSU* in this chapter). This process is then validated; routine controls and
monitoring are implemented; product release criteria established and means to
maintain process effectiveness implemented. The only part of this process that is
involved in the analysis of this clause is a bioburden-based radiation sterilization
process definition method, Method 1. The remainder of the standard cannot be
statistically analyzed but is the entirety of what assures sterility.
The previous two examples are based on nonparametric statistical
analysis. The following two Terminal Sterilization examples are based on
parametric analysis, where the analysis is based on an assumed underlying
distribution. In each example, the Method is broken down into two parts,
Parts A and B, and statistics are defined for each part to make the analy-
sis more understandable. Only a relatively small portion of the underlying
mathematics is included to give the reader a sense of the math but to allow
the flow of the chapter to progress without interruption.
The specific method used in this clause is a radiation sterilization
bioburden-based Method, Method 1, from ISO 11137-2:2013 Sterilization
of health-care products—Radiation—Part 2: Establishing the sterilization dose. It
is for a product with an assumed true average bioburden of 3.5 to pro-
vide an example of the confidence bounds for a bioburden-based validation
method. An assumed average bioburden of 3.5 has been chosen because the
low value highlights concepts of the statistical analysis in this scenario, that
is, differentiation of doses selected from Table 5 of Method 1. This Method
provides a path to establish an acceptable radiation dose to generate a tar-
geted PNSU*. A schematic representation of the procedure described in
Method 1 is provided below in Fig. 7.6.