Sterile connectors and disconnectors
Sterile connectors and disconnectors are often employed downstream of final sterilizing filters and could potentially contribute
particles from the fluid path into final dosage containers. To control this risk, suppliers should sample and inspect molded
parts for visible particulates upon receipt, and may also subject samples of assembled connectors and disconnectors to rinse
analysis for microscopic particulates. Sterile connectors and disconnectors should be validated to not be significant sources
of particles during actuation. When installed on single-use systems, sterile connectors and disconnectors can again be screened
for visible particulates. Optically-clear connectors and disconnectors can facilitate the observation of visible particles
that may be in the fluid path.
Tubing and fittings
Tubing and fittings are typically not manufactured with specific claims for particulate cleanliness. However, as with biocontainer
films, their manufacturing processes (i.e., extrusion and molding) are not intrinsically particle generating, and particulate
contamination can be minimized if manufactured and packaged under controlled, clean conditions. Incoming tubing and fittings
from qualified suppliers can be screened for visible particles on a sampling basis, and then rescreened more thoroughly during
assembly into single-use systems. Visual inspection for particles within tubing and fittings can be limited, however, by translucency
or opacity of the tubing material. Additional testing for particulates in lot samples of tubing and fittings may be performed
as part of the quality control procedures for assembled single-use systems.
Assembled single-use systems
Even where particulate matter in single-use components is minimized, there remains a risk for particles entering the fluid
path from the cutting of tubing and insertion of hosebarbs into tubing. Systems can be assembled in a Class 10,000 cleanroom,
but tube cutting and assembly methods should also be qualified by the supplier to demonstrate that visible particles are not
generated and introduced into the fluid path during system assembly.
To assess the particulate quality of assembled tubing systems, some system suppliers have established quality-control programs
where single-use system lot samples, or master systems with "worst case" tubing connections and component combinations, are
subjected to rinse fluid analysis for particles. Results can demonstrate that the fluid path rinse fluids meet USP <788> limits
for microscopic particles and quantify any visible particles detected.
Plug-and-play versus pre-use flush
Many drug developers have embraced the plug-and-play concept of single-use systems to mean that pre-use flushing of the fluid
path can also be eliminated. Whether or not flushing of single-use final filtration and/or filling systems is required to
minimize particles in the fluid path must be determined by the end user, as defined by process requirements for drug product
quality. Where flushing with water for injection or buffer is desired, systems can be designed with flush collection bags
and protocols to minimize residual fluid path hold-up volumes that could dilute initial drug product effluent. Where sterilizing
filters are installed, this same procedure can be applied for wetting the filter before pre-use integrity testing, an increasing
requirement for the marketing of drug products to some European countries. Alternatively, where appropriate, filters and the
downstream fluid path can be flushed with product to minimize losses. Sterilized sterilizing grade filters can be pre-use
integrity tested "product wet" with the flush going to initial filled containers that may be used for quality control weight/volume
checks or formulation analysis. In that way, initial flush can be accommodated to minimize particles without separate loss
of product.
Particulate quality of post-filtration single-use system fluid paths for final filtration and filling should be considered
as part of design requirements. Assessments of recoverable particle sizes and levels should be made in advance of clinical
and GMP production.
If you are considering single-use disposable systems for final filling or any other applications, please email me your questions
or suggestions for future Disposable Advisor topics.
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. jerold_martin@pall.com
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