ADDRESSING TECHNICAL DIFFICULTIES WITH TESTING OF SINGLE-USE SYSTEMS
Because of their size and complexity, single-use systems can present some technical difficulties when assessing bioburden
and sterility after irradiation. Fortunately, the standard provides some practical strategies by allowing for the grouping
of similar products into families so that validation only needs to be performed with a worst-case or representative unit.
Product families are defined by common nature and source of raw materials, components, and product design and size, along
with assembly process, equipment, and environment. A single master product can then be identified or constructed to be the
representative or worstcase version of all the products in the family. Sterilization of comparable products in the family
can then be rationalized as equivalent to the validated master product.
Although this reduces the number of different systems that need to be qualified, bioburden recovery and sterility testing
of large complex systems can still present formidable technical challenges. Therefore, it is common to only validate the sterility
of the internal product fluid-contact pathway (with closures at any ports or openings). The system exterior and inner packaged
space, which receives the same radiation dose, can be considered microbially controlled, but not validated as sterile.
To further ease the technical challenge of aseptic handling for bioburden and sterility testing, the master product can also
be broken into smaller subunits, termed sample item portions (SIPs). These can be tested separately and have their mean bioburden
and sterility results combined to establish the validated sterilizing dose for the fully configured system.
RADIATION STERILIZER — DOSE MAPPING AND QUARTERLY AUDIT
Cobalt 60 can be stored safely in a pool of water, while the chamber above the pool is surrounded by a thick concrete barrier
that prevents gamma rays from escaping when the gamma source is elevated into the irradiation chamber. Product intended for
sterilization is packaged, palletized, and transported into the irradiation chamber using a conveyor.
Once a minimum sterilizing dose is established for the master product, a pallet-load configuration and density is established.
Dose-measuring devices called dosimeters are distributed throughout the packaged load to confirm that the minimum sterilizing
dose is reached throughout the batch. Because the received dose can vary based on density, materials are typically qualified
to withstand up to 50 kGy to ensure the minimum sterilizing does can be achieved throughout the batch. On a quarterly basis,
the process is audited by, again, determining bioburden in 10 current product, master product or SIP samples. Verification
dose-sterility tests are conducted on 10 additional samples.
STERILE PRODUCT DOCUMENTATION
The sterilization validation and irradiator batch-data support both the supplier's claim for sterility for the singleuse system(s)
and the user's claim for cellculture process control and finished-product sterility. Several documents serve to support both
system and finished product sterile claims. First, the supplier should provide a letter explaining the rationale for the sterile
claim of each specified system by part number, based on actual or master product validation. Suppliers can insert a Certificate
of Quality within the unit packaging stating that the product is sterile after irradiation. External irradiation indicators
that change colour upon exposure are not sufficiently quantitative to confirm sterility. A summary Sterilization Validation
Report supporting the minimum sterilizing dose, as well as the Dose Mapping Study Report and most current Quarterly Dose Audit
Report generated by the irradiator, should be provided by the system supplier. Original data and irradiator certificates,
however, may only be available during supplier audit. Lastly, the supplier should provide a Certificate of Irradiation for
the system lots in the batch, certifying the minimum dose recorded by the batch dosimeters.
This combination of sterilization validation rationale, minimum dose-sterilization validation, batch load dose map, batch
irradiation dose certificate, and quarterly dose audit serves to support the ongoing sterility of the single-use system and
the sterile products produced with them.
Jerold Martin is senior vice-president of Global Scientific Affairs at Pall Life Sciences, Port Washington, NY, and chairman of the Board
and Technology Committee at Bio-Process Systems Alliance, tel. 516.801.9086. email@example.com
1. AAMI/ANSI/ISO 11137:2006, "Sterilization of health care products — Radiation — Part 1: Requirements for the development,
validation and routine control of a sterilization process for medical products; Part 2: Establishing the sterilization dose;
Part 3: Guidance on dosimetric aspects," (2006).
2. American Association of Medical Instrumentation, "Sterilization of health care products—Radiation—Substantiation of a
sterilization dose—Method VDmax," Technical Information Report TIR33:2005 (2005).
For further information on this topic, see BioProcess Systems Alliance, "Guide to Irradiation and Sterilization of Single-use
Systems," available at
as well as an educational webinar by J. Martin, and M. Senescu, "Sterilization of Single-use Systems by Gamma Irradiation,"