Page 184 - Assurance of Sterility for Sensitive Combination Products and Materials

166 Assurance of sterility for sensitive combination products and materials

microbial population has served patients well for decades. Decadal studies
have not linked terminal sterilization as a contributor to patient infection
rates [1–3] except when it was not correctly validated or failed to be ex-
ecuted properly. Aseptic processing (Chapter 4), with terminally sterilized
components being manufactured in controlled environments to exclude
microbial contamination, is designed for products that cannot be termi-
nally sterilized and has also served the industry well for decades. The use
of terminal sterilization with alternate sterility assurance levels (SALs) (for
b
simplification, PNSU*s in this chapter ) is another option for products that
−6
cannot be terminally sterilized at a PNSU* of 10 . Terminal sterilization
−4
−6
with SALs >10 (e.g., 10 ) has recently been expanded upon in the ISO
standards (Chapter 9). Packaging as a sterile barrier system or container
closure (Chapter 5) is well-established to maintain sterility over the shelf
lives of products. The objective of this chapter is to support innovation in
sterility assurance to enable patient-centric health-care product innovation
(Chapters 2 and 8). This goal is achieved by providing an objective view of
patient risk as it relates to health-care facilities (Chapter 6) and the quan-
tifiable aspects of packaging, aseptic processing, and terminal sterilization
ISO standards.
A brief introduction to patient risk concepts from ISO 14971:2007
Medical devices—Application of risk management to medical devices as applied to
sterility assurance is provided in Section 7.1. To make the statistical analysis
of this chapter accessible to most readers, a non-statistician’s introduction
to statistical sampling and confidence bounds as it applies to sterility as-
surance is provided in Section 7.2. Section 7.3 is a novel statistical analysis
c
of the risk associated with the quantifiable components of standards used
in different sectors of the sterility assurance industry including packaging,
aseptic processing, and terminal sterilization (a bioburden-based method
and an overkill method). For readers not inclined to learn statistics or wade

b See Chapter 1, Introduction, for a discussion of the use of the sterility assurance terms across
sectors of the sterility assurance field, including sterility assurance level (SAL) and proba-
bility of a non-sterile unit (PNSU). As noted in this discussion, different terms are used in
different sectors and it is technically inappropriate to use any given term in looking at the
quantifiable aspects of sterility assurance across all sectors. Hence, a term PNSU* is coined
for this chapter. PNSU* denotes the point estimate and confidence estimates of quantifiable
aspects of sterility assurance in any given sector.
c ISO, PDA, and Pharmacopeia standards apply, especially for aseptic processing; for ease of
comparison, quantifiable aspects of ISO standards will be analyzed in this chapter.