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    Single-Use Technology For The Most Extreme Processes

    Source: CPC
    By: Michael Francis, Product Manager at Colder Products Company

    Single-use technology (SUT) has afforded drug manufacturers greater flexibility, but downstream processing for biologic drugs often requires the use of harsh chemicals that can damage SUT components. During filtration and chromatography, chemicals like sodium hydroxide, dimethyl sulfoxide (DMSO), benzyl alcohol, and others can compromise the structural integrity of SUT tubing and connectors, leading to leaks and spills and increasing the likelihood of leachables contaminating the drug product.

    For manufacturers that have identified and characterized their preferred SUT equipment and methods, it can be frustrating when a new drug project is incompatible with the system and materials in place. Searching for a new connector that can withstand harsh chemicals adds time, cost, and uncertainty to a project. Companies may find what they are looking for in the moment but sacrifice the assurance of supply chain security or the comfort of familiarity and ease of use.

    When a client approached CPC about a project that required a more robust connector, designers researched novel materials and identified a polymer that allowed us to reproduce one of our AseptiQuik connectors to handle the rough downstream chemicals. The result ensured the client still had a market neutral supply chain and the same functionality of the connectors to which they had grown accustomed.

    Sterility And Closed Systems: A Challenge Under Any Circumstances

    Biologic drug development demands sterility for success and safety. Biologics also are notoriously expensive to make. The further they progress in the manufacturing process, the higher their value climbs, and by the time they reach downstream processes like chromatography, the financial consequences of a batch lost to contamination can tally in the millions of dollars.

    Traditional methods of sterility assurance involving clean rooms and laminar flow hoods placed great time and cost burdens on companies. SUT systems have largely replaced or at least augmented these processes over the past couple decades, but the development of SUT components also is continually evolving as the industry identifies the challenges and shortcomings that available products and practices pose. For example, tube welding – one of the most common methods for securing closed, sterile SUT flowpaths – still presents the potential for leaks, spills, and contamination by leachables, and can be very demanding in terms of time and the costs of equipment, components, and maintenance. When SUT systems fail and leaks or spills occur, companies do not just lose millions in product. They lose time and momentum as they analyze their procedures, materials, vendors, and the chemicals they are using. If the chemicals cannot be changed, then the company must make changes elsewhere, which can create unforeseen delays.

    Sterile connectors are among the great advances in SUT. CPC’s AseptiQuik connector portfolio was developed to address the inconsistencies in size, functionality, compatibility, quality, and sustainability of commercially available connectors. Among other novel designs intended to address the problems of tube welding and unreliable SUT components, CPC developed the AseptiQuik line of genderless connectors to assure fast, easy, secure connections and quick assembly.

    These polycarbonate connectors have enjoyed great success on the market, having largely withstood many of the most common chemicals used in downstream processing. They form fast, sterile connections in a way that ensures the interior of the flowpath is never exposed to the exterior environment. However, a client recently approached CPC about a project that demanded the use of at least eight fermentation or purification chemicals that would test or exceed the limits of what our connectors could tolerate. Other commercially available connectors, made of polyethersulfone (PESU) – a material more chemically resistant than polycarbonate but not as mechanically strong – still were not sufficient for the project’s demands. As the AQG line had become an integral part of their SUT system, they feared the loss of familiarity and a reliable supply chain.

    What was required was a plastic material that, like polycarbonate, was strong enough to hold up against handling, processing, and shipping, but also chemically inert so that it could handle the corrosive substances that would flow through it. The material also had to meet regulatory standards for plastic purity.

    Identifying And Testing For The Right Fit

    The client specifically required a connector with greater chemical compatibility for buffer prep, liquid transfer in chromatography process and column storage, and freeze-thaw applications. So, CPC sought to reproduce the AseptiQuik G connector using a polymer material that would enable broader compatibility. CPC worked with polymer suppliers to identify several BPA-free biologic polymers that could meet mechanical stability and chemical inertia standards, with low levels of extractables. Fifteen material candidates were evaluated and scored on a material matrix of 10 different characteristics, including their physical attributes, regulatory compliance, and supply chain reliability. Based on that review, CPC narrowed the field to two finalists – PESU and polyphenylsulfone (PPSU). Developers then employed creep rupture, water burst, sideload, and tensile testing.

    For the creep rupture test, AseptiQuik G (AQG) connector sets made of both materials were conditioned at 40 degrees Celsius for seven days at 75 psi. All PPSU sets passed while all PESU sets failed within 24 hours. 

    Sets of both candidate materials and polycarbonate connectors were then capped and pressurized with water until burst failure, in both virgin and post-gamma formats. Table 1 shows the results of the PPSU vs. PESU for water burst. The mode of failure also showed that PPSU connectors functioned better in failure than PESU. When the PPSU connectors eventually yielded to pressure, their latches disengaged at the bases but never broke, whereas the latches on PESU connectors broke at the base.

    Table 1

    Material % Higher than PESU
    Virgin - Pre-sterilized
    PPSU +20%
    Gamma Irradiated
    PPSU +30%

    In side-load-to-break testing, both materials were exposed to side load at the hose-barb termination, again in both virgin and post-gamma formats. PPSU outperformed polyethersulfone, while PESU was found inferior to both other materials. CPC observed generally similar outcomes in tensile-to-break tests: PPSU was found decisively superior to PESU. The results of the side-load and tensile-to-break tests can be seen in table 2 and table 3.

    Table 2

    Material % Higher than PESU
    Virgin - Pre-sterilized
    PPSU 158%

    Table 3

    Material % Higher than PESU
    Virgin - Pre-sterilized
    PPSU 35%

    Once PPSU was confirmed to be the mechanically best material against PESU, the next step was to verify its chemical compatibility in dynamic testing situations. To accomplish this, a test was constructed to judge the AseptiQuik polycarbonate next to the PPSU material. Five connected sets of the AQG polycarbonate were attached in series with five sets of the AseptiQuik G PPSU connector. Then a chemical solution was pumped through all ten sets at approximately 1.0-1.2 GPM and the sets were observed for any leaks. The duration of the test as well as the chemicals tested were chosen based on industry feedback of the common chemical application concentrations and durations. After the chemical exposure, the connectors were subjected to hydrostatic and water burst testing to test the mechanical strength after exposure. The AQG PPSU passed all chemical exposure and had a higher average burst strength than the AQG polycarbonate which had mixed results. The below diagram shows a mock-up of the test setup and table 4 shows the chemicals which were tested.

    Table 4

    Chemicals Duration PPSU Results
    1N NaOH 1 month Pass
    0.5M phosphoric acid 1 month Pass
    10% acetic acid 1 week Pass
    1% acetone 1 week Pass
    DMSO 25% 24 hours Pass
    30% PS80 24 hours Pass
    10% Triton-X 24 hours Pass
    2% benzyl alcohol 1 month Pass
    1M sodium carbonate 1 month  Pass
    20% EtOH 1 month Pass

    Choosing The Next Generation

    Designing and commercially producing a new connector is not as easy as simply making the same device out of new material. Following the selection of polyphenylsulfone for the new connector model, CPC undertook the rigorous validation processes for new injection molds for the PPSU resin and the CPC manufacturing process using PPSU components. We then executed design verification testing for product specification claims on pressure, temperature, sterilization, and backwards compatibility with the base polycarbonate version of the connector.

    The AsepitQuik G and the AseptiQuik L Product lines are available in PPSU, and are interchangeable with their series connectors when needed for harsh downstream processing. The AsepitQuik PPSU is fully compatible with the respective AseptiQuik G and AseptiQuik L series, as the fit and function are identical, with the same Flip-Click-Pull assembly operators have come to prefer. The material is USP Class VI compliant and, like polycarbonate, it can withstand gamma irradiation (tested at greater than 50 kgy) for sterilization purposes, as well as freezing down to -80 degrees Celsius. It is now commercially available with termination sizes from 1/4-inch to 3/4-inch flow path for AseptiQuik G, and from 3/4-inch to 1 1/2-inch flow path for the AseptiQuik L. The product can be differentiated by a purple pull tab.

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