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Jerold Martin, senior vice president global technical affairs, at Pall Life Sciences, explains the importance and impact of single-use systems in sterile environments.
Single-use systems have only recently been introduced into final-filling cleanroom environments. A key strength is their recognition as “closed systems” by drug manufacturers and regulatory authorities. Many drug and vaccine manufacturers see this as a great opportunity to work in non-classified or lower-classified areas (e.g., Grade C or D/Class 100,000/ISO 8), and some have already applied this approach in new facilities and expansions. A key enabler of single-use systems in final-filling areas has been the innovative development of sterile connectors, which enable sterile connections in nonclassified environments. These sterile connectors are valued as providing higher assurance of containment than traditional aseptic connections that must be performed under Grade A/Class 100/ISO 5 conditions. Although perhaps having minimal impact on existing cleanroom facilities, these advanced capabilities are stimulating designers of new aseptic filling facilities to consider reduction in cleanroom spaces and classifications, greatly reducing the potential cost to put up new aseptic filling suites.
Implementing single-use systems in a new cleanroom facility can enable reduction in the size of the cleanroom by allowing for downgrades at every stage, working in grey areas for most of the process and limiting Class A (Grade 100, ISO 8) areas to around the filling needles. This is further facilitated through the use of complementary technologies within cleanrooms, for example, single-use port approaches on isolators that enable single-use system integration into Grade 100 areas. The primary benefit of these technologies is a reduction in controlled environment class and areas, which can greatly decrease facility build cost and time, as well as labour resources, time and the costs of environmental monitoring, maintenance and other ongoing quality control activities.
Closed systems eliminate the risk of external contamination—including chemical, microbial or particulate. Sterile connectors have been shown to maintain sterile pathways even when externally contaminated with up to one million bacteria per unit and in bacterial aerosols far higher than would occur even in an uncontrolled environment. Because clean sterile fluid pathways are maintained independent of the environment, classified cleanroom conditions are only needed at points of filling. Conservative practices and tradition may preclude complete elimination of controlled spaces, but single-use systems will enable manufacturing in smaller and lower classification areas, greatly reducing facility construction and operating costs. Regulatory acceptance of sterile connection technologies is increasing at the pace of single-use technology implementation, such that in the coming years, both the user base and data for sterile connector technology will only further increase.
In existing facilities, it is common for biopharmaceutical manufacturers to develop a “hybrid” system of both existing stainless steel and new single-use components. In build-outs or new facilities, particularly at small to moderate scale, more single-use is being introduced. At the larger scale, hybrid systems again dominate with large fermenters, chromatography columns and tangential flow filtration (TFF) systems continuing in stainless steel, while buffer and intermediate/final product hold tanks and filters are introduced as single-use systems. These hybrid systems will be used in large volume production facilities for quite some time, particularly in the downstream area despite progress made in operation technologies such as single-use TFF. Most biosimilar production today is focused on large volume drugs where stainless steel will still predominate, especially for large bioreactors and chromatography columns. In filling areas, however, we are seeing a lot of interest in single-use formulation and filling systems, but we have to take into account the large installation base of stainless steel filling equipment.
Functionally, manufacturers integrate stainless steel and single-use components or systems using linking technologies that are typically steam sterilisable (“steam-to” or “steam-through” connectors). The linking technology is steamed with the stainless portion of the process. Then the single-use flow path (which is typically pre-sterilised by autoclave or gamma irradiation) is opened to the stainless portion.
Regulatory requirements are spelled out in existing GMP documents: process equipment and bulk drug product containers must not adversely affect final drug product quality or safety. Drug manufacturers must demonstrate that single-use systems used in aseptic environments do not introduce leachables, particles or microbes to the drug product that could compromise the product or patient safety. Hurdles include understanding how supplier extractables data, when suitable, can be applied to assess potential toxicity of leachables, while minimizing or even eliminating the need for additional testing, and how and when additional leachables testing should be applied. Drug manufacturers also need to better understand how to apply extractables and leachables data in the context of final dosage levels and understand potential toxicological impact (or, more commonly, substantiate the absence of toxicity above established safety threshold levels). Microbial safety (i.e., sterility) is ensured by validated sterilisation using gamma irradiation, but drug manufacturers need to know what supplier documentation must be submitted to regulatory agencies and understand how the valid sterilized state is maintained for each batch of single-use equipment. Particles from single use systems are generally controlled by in-line filters, but in final filling manifolds and aseptic systems without sterilizing filters, control of particles by the component and assembled system supplier, as well as implementation of flushing protocols where appropriate, must be considered. Another potential hurdle is understanding how to flush and perform integrity tests on in-line sterile filters prior to use when required. Lastly, as there is currently no test to ensure the leak or microbial barrier integrity of assembled single-use systems, components and assembly must be designed and controlled to minimize risk of leaks, and users must learn to trust these assurances in the absence of an on-site pre-use system integrity test correlated to microbial barrier performance. These are key areas where drug manufacturers must work with their supplier partners to design single-use systems and operating procedures that facilitate appropriate use and meet quality and safety requirements.