FINAL PRODUCT PARTICULATE QUALITY

According to most GMPs worldwide, injectable drug products are required to be essentially free of visible particles. USP General Chapter <1> Injections states, "Each final container of all parenteral preparations shall be inspected to the extent possible for the presence of observable foreign and particulate matter (otherwise termed 'visible particulates') in its contents. The inspection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates" (1). Similarly, the European Pharmacopoeia (2.9.20) states, "Injectable solutions, including solutions constituted from sterile solids intended for parenteral use, should be essentially free from particles that can be observed on visual inspection" (7).

The observation of a "visible particle" during inspection of filled drug product will depend on the drug, and container clarity, lighting, particle size, optical density, refractive index, color and contrast, and operator or automated inspection sensitivity and reliability. "Essentially free" is also not defined. Because only those individual drug product containers observed to contain visible particles are subject to rejection, limits can vary for the number of unacceptable drug product containers with one or more visible particles per batch, which can be rejected to meet an interpretation of "essentially free of visible particles" for released dosage units. Whether the regulatory expectation of "essentially free of visible particles" applies to particles recovered from single-use fluid paths that may or may not be ultimately visible in drug products, and to what level, is open to interpretation.

Suppliers' procedures, processes, and qualifications of single-use systems to minimize particulate contamination vary with components and systems.

Filters

Sterilizing-grade filters are typically preflushed during manufacturing to wet prior to 100% integrity testing. This flushing also serves to minimize downstream particles. Preflushing of particulate filters used as final filters should be confirmed with the supplier. Final filters and re-usable downstream fluid paths or containers are also flushed by users before filling of drug product containers to further minimize particulate and leachable contamination before final drug filling. This flushing may be done for various other reasons, including pre-use integrity testing of the sterilized filter, priming of the filling lines, and checking for final container fill weights and other quality control tests. Filter manufacturers typically recommend that final filters and their associated downstream fluid paths be flushed with a suggested liquid volume before filling of final dosage containers to minimize leachables and downstream particles that would otherwise be introduced into injectable drug products. Initial filter or system flushing is optional per FDA GMP, but indirectly required by EMA GMP Annex 1, which specifies that the sterilized filter should be integrity tested before drug product filtration. Such integrity testing requires inline flushing to wet the filter, which would also serve to minimize downstream particulates if the flush effluent is discarded before finished drug product filling.

FDA GMP requires that the final filters used to manufacture injectable drugs are "non-fiber-releasing" in accordance with US CFR Title 21, Parts 210.3 (b) and 211.72 (6–8). While this requirement originates from the time when filters contained asbestos fibers, it helps ensure that sterilizing grade filters contribute a minimum amount of fibers of any kind (typically from nonwoven polyester or polypropylene support layers). Filter manufacturers may certify that either the finished element or just the membrane meets this requirement. Downstream cleanliness of supplied cartridges, especially those only claiming the membrane is "non-fiber-releasing" versus the finished cartridge, should be assessed as part of product qualification and selection. Filter samples from each manufacturing lot may also undergo effluent particulate analysis by the supplier.

Despite these effluent cleanliness qualifications, users should recognise that filters are subsequently dried, packaged, shipped, unpacked, handled, and installed prior to use. All these manipulations carry the potential for visible particles to be generated after the manufacturing flush and quality control tests. Visual inspection of the downstream core of a filter capsule for particles is not possible; thus, most filter manufacturers recommend filters to be flushed prior to use to ensure minimum downstream particles and leachables prior to drug product filling.

Biocontainers

Unlike the manufacture of filters, film extrusion is not an intrinsically particle-generating process. Films used to manufacture biocontainers are typically handled in a Class 10,000 cleanroom where fluid contact surfaces are minimally exposed to a controlled environment. During biocontainer assembly (seam and port welding), sealed biocontainers are typically subject to inspection for visible particles. Samples of assembled biocontainers may also be subjected to rinse and analysis per USP <788> (2). Biocontainers integrated into single-use systems may be further screened for visible particles during system assembly. Visibility of particles may vary with film clarity.