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Jerold Martin was the senior vice president of global scientific affairs at Pall Life Sciences and chairman of the Board and Technology Committee at Bio-Process Systems Alliance.
The author looks at strategies to minimize particle levels in the finished product when using single-use technologies downstream of final capabilities.
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.
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.
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.
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.
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. firstname.lastname@example.org.
1. USP 34–NF 29 General Chapter <1>, "Injections."
2. USP 34–NF 29 General Chapter <788>, "Particulate Matter in Injections."
3. EurPh, 5.0, 2.9.19 "Particulate Contamination: Sub-Visible Particles" (EDQM, Strasbourg, France, 2005), 253–255.
4. Japan Pharmacopoeia XV, 6.06, "Foreign Insoluble Matter Test for Injectables," in General Tests, Processes, and Apparatuses Section, p. 110–113.
5. ICH, Q4B, Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions — Annex 3 Test for Particulate Contamination: Subvisible Particles, General Chapter (Jan. 2009).
6. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington DC), Part 211.65, "Equipment."
7. EurPh, 5.0, 2.9.20, "Particulate Contamination: Visible Particles" (EDQM, Strasbourg, France, 2005) 255–256.
8. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.72 "Filters."