Pharmaceutical Manufacturing Handbook: Production and

culminate in the incubation of the media - fi lled containers with success defi ned as a
limited number of contaminated units in a larger number of fi lled units. The result
is a contamination rate for the media fi ll, and not a direct indication of the level of
sterility assurance afforded to aseptically processed materials using the same procedures.
At the present time, the level of sterility provided to aseptically processed
materials cannot be measured. The FDA and EMEA have harmonized their expectations
relative to process simulation performance, but they have also asserted that
the goal in every process simulation is zero contamination [1, 2] . This formalized
expectation and recognition that patient safety should always be preeminent have
resulted in substantial improvements in aseptic processing technology over the last
20 years.
2.1.12
TERMINAL STERILIZATION
TERMINAL STERILIZATION 131
Terminal sterilization is a process by which product is sterilized in its fi nal container.
Terminal sterilization is the method of choice for products that are suffi ciently
stabile when subjected to a compatible lethal treatment. Because the process utilized
is expected to be lethal to the microorganisms present, is highly reproducible,
and generally readily validated, there is a clear preference for its use [1, 40, 41] .
The predominant method for terminal sterilization is moist heat, and a substantial
percentage of sterile products are processed in this manner. (Estimates range
from 5 to 15% of all sterile products are terminally sterilized.) The sterilization often
requires the attainment of a balance between sterility assurance and degradation of
the material ’ s essential properties [42] . The overkill sterilization method is preferred
for heat - resistant materials, and may be usable for terminal sterilization where the
formulation can tolerate substantial heat input. The bioburden/biological indicator
approach uses less heat input but requires increased control over the titer and
resistance of the bioburden organisms present.
The large - volume parenteral (LVP) industry sometimes uses dedicated nonaseptic
fi lling systems for its containers prior to subjecting them to terminal treatments.
These LVP systems may approach the aseptic designs described earlier, but they are
not supported by the same levels of environmental monitoring nor process simulation.
Application of terminal sterilization at small volume parenteral producers may
be done after the product is aseptically fi lled, although this practice is usual only
where the fi rm produces predominantly aseptically fi lled products and would not
have a fi lling system dedicated to terminally sterilized formulations. Product
that will be subject to terminal sterilization may be fi lled under clean conditions
with reduced environmental monitoring and control. However, control of total
particulate levels requires unidirectional airfl ow for critical fi lling or assembly
processes.
Terminal sterilization is most commonly accomplished by moist heat. Terminal
sterilization by other means is certainly possible, and a very limited number of parenteral
drugs are treated with dry heat or radiation after fi lling. There is growing
interest in the use of radiation, including low - energy E - beam, as a terminal treatment
suggesting more products will be processed in this manner.
Although there are numerous advantages to terminal sterilization, there can be
very good reasons for aseptically fi lling products that are stabile enough to be com-