Biomedical Engineering Reference
In-Depth Information
can be provided by gamma irradiation without sterilization validation. This
is important to reduce the time burden of validation.
In upstream processing, bacterial (e.g.,
Escherichia coli
) cell cultures tend
to be operated in short time frames and are fairly resistant to overgrowth,
because of genetic coding of antibiotic resistance and the media contains
these antibiotics, by low levels of contaminant bacteria. It may be prudent to
classify the bioreactor as microbially controlled and not sterile, allowing the
manufacturer to not perform any validation of gamma-sterilized systems.
This may not, however, be the case when operating mammalian cell cultures
that run for a longer time, weeks at a time. Here, the bacterial contamination
can be serious, and sterilization validation may be required and validation
necessitates complying with regulatory compliance.
Cell harvesting and downstream processing steps are rarely validated
for sterility due to complexities and/or limitations of their equipment, and
especially during process development. The process equipment is generally
chemically disinfected or sanitized and maintained as microbially controlled
for zero or low bioburden. Intermediate holds are kept at low temperature
to prevent microbial contamination. In cases where these process steps are
not claimed to be sterile, it is unnecessary to validate the sterility of single-
use systems for preparation of process buffer feed solutions or intermediate
holds. Buffer solutions or intermediates are filtered through irradiated bio-
burden reduction filter systems, as microbially controlled feeds are generally
suitable for process steps not validated as sterile.
Even at the stage of final formulation and filling, it is not necessary to
claim sterile processing as a nonsterile finished bulk API is subsequently
processed with sterilization. The only steps requiring disposable systems
to be validated as sterile are in the preparation of sterile API and the aseptic
filling of sterile containers; that is, if the fluid is to be claimed as sterile, then
the single-use system it is filled into must have that validated claim.
Several industry standards are used for sterilization validation of gamma-
irradiated health-care products. The three parts of ANSI/AAMI/ISO
11137:2006 are
• Part 1: Requirements for Development, Validation, and Routine
Control of a Sterilization Process for Medical Devices specifies
requirements for development, validation, process control, and rou-
tine monitoring in the radiation sterilization for health-care prod-
ucts. Part 1 applies to continuous and batch-type gamma irradiators
using the radionucleotides 60 Co or 137 Cs, and to irradiators using
a beam from an electron or x-ray generator.
• Part 2: Establishing the Sterilization Dose describes methods that
can be used to determine the minimum dose necessary to achieve
the specified requirement for sterility, including methods to sub-
stantiate 15 or 25 kGy as the sterilization dose.
