Page 202 - Assurance of Sterility for Sensitive Combination Products and Materials

182 Assurance of sterility for sensitive combination products and materials

sample size of 30 shown in Fig. 7.4. In practice, these controls have been
successful. Testing extreme numbers of samples to demonstrate a PNSU*
−6
of 10 is not practical or necessary. Confidence in the packaging materials
and the maintenance of sterility is not achieved by just performing product
integrity testing, as noted at the onset of this clause. Confidence in the seal
strength is obtained using parametric methods under worst-case conditions.
Receiving inspections at the pouch vendor ensure that the film is consis-
tent. Process controls ensure that the seals are consistent. The packaging
validation sample size is just one part of a larger system. It is the entirety of
product design control, production controls and the ISO 11607 require-
ments that ensure that the packaging is fit for its purpose.

7.3.3 Point estimates and confidence bounds—Aseptic
processing
ISO 13408-1 Aseptic processing of health-care products—Part 1: General re-
quirements and ISO 13408-7 Aseptic processing of health-care products—Part 7:
Alternative processes for medical devices and combination products provide exten-
sive procedures for controlling the environment and the work practices that
are used to manufacture product aseptically. PDA and various Pharmacopeia
also have requirements and guidance that are commonly used in the indus-
try. The ISO standard is used in this analysis for consistency with the analysis
of the other industry sectors. As summarized in Chapter 4, the assurance
of sterility in aseptic processing is based on characterization and control of
the manufacturing environment and equipment; personnel training, gown-
ing and general health requirements; and manufacturing aseptic technique.
Process simulation requirements are provided to qualify the process, with
appropriate tests for sterility. Point estimates and confidence bounds from
sample sizes used in process simulations are analyzed in this chapter. Sterility
assurance, however, is achieved by adherence to the entirety of the ISO
aseptic processing standard. The other portions of the standard are vital to
assure sterility but they cannot be analyzed for statistical performance.
The standard makes it clear that the objective is to achieve zero process
simulation contaminated units. The procedure also clearly reinforces the
importance of investigating any contaminated unit and correcting all root
causes.
The relevant information for the statistical calculations is contained in
Table 1 of ISO 13408-1:2008. This table has been copied in Table 7.6 and
three additional columns have been added when compared to the standard.
The number of tests per process simulation was multiplied by the number of