Biomedical Engineering Reference
In-Depth Information
SALs can be used to describe the microbial population that was destroyed
by the sterilization process. Each log reduction (10
−1
) represents a 90% reduc-
tion in microbial population. So, a process shown to achieve a “6-log reduc-
tion” (10
−6
) will reduce a population from a million organisms (10
6
) to very
close to zero, theoretically. It is common to employ overkill cycles to provide
the greatest assurance of sterility for critical products such as implantable
devices.
SALs describing the “
Probability of a Nonsterile Unit
” (PNSU) are expressed
more specifically as PNSU in some literature.
Generally, 25 kGy can achieve sterility with a SAL of 10
-6
. Even with ele-
vated bioburden levels, bioburden reduction can be achieved with lower
probabilities of sterility (e.g., SAL of 10
-5
or 10
-4
). Products irradiated to such
SALs are still sterile but have higher probabilities of nonsterility and may
not meet standards for validated sterile claims as specified in industry stan-
dards for sterilization of health care products.
Gamma irradiation also causes ionization and excitation of polymer mole-
cules. Some polymers show higher resistance to irradiation-induced changes
than others; all polymers are affected to some degree. Repeated irradiation of
single-use systems or components should be avoided, as the effect is cumulative.
The concepts and protocols described in the current industry standards
for sterilization of health care products by gamma irradiation are applicable
to disposable bioprocess systems as well. There is the requirement of the val-
idation of the efficacy and reproducibility of the sterilization process, based
on determination of average bioburden and subsequent sterility testing of
systems after minimal radiation dose exposures. Systems validated as ster-
ile are also subject to routine audits involving bioburden and sterility test-
ing. Components or systems requiring zero or low bioburden when applied
in nonsterile processes do not require a validated sterile claim and may be
qualified as microbially controlled.
It is important to establish where a full validation of the container is
required. Cell culture bioprocess is divided into several processing stages:
upstream, harvesting, cell separation, depth filtration, and membrane filtra-
tion. In the downstream stage, the target molecule is subjected to a series of
separation, purification, and concentration stages applying chromatography
and membrane filtration to ultimately produce a purified bulk drug product.
This is followed by a final formulation stage where the purified bulk (API or
biological) is transformed to a stable formulation and sterilized by filtration
(or filled aseptically in sterile containers). All stages where the process is
claimed to be sterile would require a validation but not to processes listed as
“microbially controlled,” even though they may have low or no burden. It is
obvious that these stages of preparation of biological drugs cannot be done
under sterile conditions and thus generally do not require sterility validation,
and the manufacturer should not claim the process as sterile and instead
they should be listed as operated under a high degree of microbial control, as
