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, colour 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.
Singleuse component particulate quality
Suppliers' procedures, processes and qualifications of single-use systems to minimise particulate contamination vary with
components and systems.
Sterilising-grade filters are typically preflushed during manufacturing to wet prior to 100% integrity testing. This flushing
also serves to minimise 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 minimise particulate and leachable contamination before final drug filling. This flushing
may be done for various other reasons, including pre-use integrity testing of the sterilised 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 minimise 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 sterilised filter should be integrity tested before drug product filtration. Such integrity testing requires
inline flushing to wet the filter, which would also serve to minimise 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 sterilising 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.
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 10000 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.
Sterile connectors and disconnectors
Sterile connectors and disconnectors are often employed downstream of final sterilising filters and could potentially contribute
particles from the fluid path into final dosage containers. To control this risk, suppliers should sample and inspect moulded
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.