Biopharmaceutical and vaccine manufacturers are increasingly considering the use of single-use systems for final formulation
and filling. These applications have stimulated many questions about the particulate quality of single-use systems and their
suitability for use under GMP. Particles in singleuse systems have not historically been an issue because most applications
were for media or buffer preparation, intermediate hold, or other applications upstream of final filters. Recently, however,
drug developers and manufacturers have begun to apply single-use technology to final formulation and filling, which are downstream
of final filters. In this column, I will summarize the regulatory requirements for particles in finished drug products, discuss
how they can be related to quality requirements for particles from final filters and single-use system fluid paths, and suggest
what suppliers and users can do to ensure that finished drug products meet the regulatory requirements for particulate quality.
Existing drug and biologics GMP regulations and guidelines that address particulate quality apply either to the external cleanroom
environment or to the finished drug product itself, after filling in its final dosage container. In addition to the inspection
of final dosage units for visible particles (e.g., per USP <1> Injections), injectable drug products are also subject to lot
sample testing for microscopic particles (e.g., per USP <788> Particulate Matter in Injections) (1, 2). Similar tests exist
under the European Pharmacopoeia 2.9.19 and Japan Pharmacopoeia 6.06 (3, 4). For global harmonization, these tests have also
been incorporated into International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH) Q4B (5).
In contrast to finished injectable dosage units, process equipment, including single-use systems, is not directly regulated
under drug or biologics GMP. Consequently, there are no regulations or guidelines for the particulate quality of final filter
effluents, single-use filling equipment fluid paths, final bulk drug containers, or even finished drug product dosage containers
prior to filling. By themselves, these components and systems do not fall within the scope of GMP regulations, which focus
on finished drug products.
However, regulatory authorities recognize the potential influence of the process equipment fluid path when in contact with
final bulk drug formulation. For example, US 21 CFR Part 211.65 states, "Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug
products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity
of the drug product beyond the official or other established requirements"(6).
While particulate quality of process equipment is not specified, drug manufacturers must ensure that process equipment does
not adversely impact the quality of the final drug product. This requires the single-use system user to establish that reasonable
controls are in place to ensure that process equipment does not cause the drug product to fail particulate quality specifications.