Pharmaceutical Technology - May 2019

Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 17 major risk for product development is subvisible particles. However, failing subvisible particles requirements on stability is a negligible risk for most protein formulations containing polysorbate and given adequate particle characterization," he observes. The presence of leachables and API im- purities can be further challenges. Other failures concern patient-related issues. "Patients can have difficulty using the combina- tion product (user handling), and these issues should be considered as testing failures," Schoen- knecht says. High injection forces, long injection times, and general issues with gripping the sy- ringe are examples. Testing of empty sterile sub assemblies Testing empty syringes prior to filling presents a few challenges that largely relate to the fact that only one part of the combination product (sterile barrel) is being tested, according to Eon. "The impact of the drug product on the func- tionality of the syringe cannot be evaluated prior to filling, but testing is still needed to confirm the intended purpose for the combination drug product," he explains. Specif ic tests that should be performed on empty syringes include: • Glide force testing to evaluate syringe lubri- cation (ISO 11040-4) • Pull-off force testing of the tip cap or the needle shield (ISO 11040-4) • Flange break resistance testing (ISO 11040-4) • Luer cone breakage resistance testing (ISO 11040-4) • Needle penetration testing (ISO 11040-4, ISO 7864, ISO 9626, and DIN 13097-4); • Needle pull-out force testing (ISO 11040-4) • Luer lock adapter collar pull-off force testing (ISO 11040-4) • Luer lock adaptor collar torque resistance testing (ISO 11040-4) • Luer lock rigid tip cap unscrewing torque testing (ISO 11040-4). Retention volume and deliverable volume are also tested for prefilled syringes. The retained volume is important because it will affect the fill volume and filling tolerances during manufac- turing, according to Sacha. This method can be challenging to implement, however, because vari- ances in the values obtained during testing occur between analysts and are affected by how the tip cap is treated during the test. "All of these tests give only information about the quality and performance of the container it- self, though," agrees Schoenknecht. "Final proof of a specific container closure system for a given drug product, consisting of the container with closures and liquid fill (drug formulation), suited to fulfill the requirements can be made using tests performed on the final combination prod- uct," he asserts. Schoen k necht a lso stresses t hat dev ice de- velopment should be driven by human factor studies (user requirement studies) that lead to design input requirements. "Performance tests such as breakout- and extrusion-force measure- ments should be executed against the user re- quirements, which should take into account the capabilities of the intended patient population/ group," he explains. Functionality testing Functionality testing (e.g., gliding force, mechani- cal resistance, opening force, etc.) involves exami-

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