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18 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m Prefilled Syringes nation of the force required to initiate movement of the plunger and the pressure required to main- tain the movement; the test is usually destructive. As a result, it is only performed with a reduced inspection plan (S-4) and limited sample popu- lation, which leads to a higher beta risk for the customer, according to Eon. Carrying out these tests requires a clear un- derstanding of the testing requirements listed in the cited ISO standard and the capability to implement and qualify the test methods in accor- dance to GMP standards, according to Schoen- knecht. "Injection-force, break-loose force, and glide-force measurements can be particularly challenging because they depend closely on the inner diameter of needle, which can vary within tolerances," he says. A key source of failure in functional tests is in- sufficient application of silicone oil in the barrel of the syringe, according to Sacha. "Insufficient application of the oil can make it difficult to start movement of the plunger and can cause the plunger to halt during movement through barrel, which is known as chattering," he explains. Container closure integrity testing "Sterility is the most important critical quality at- tribute of a parenteral/sterile drug product. Con- tainer closure integrity (CCI) testing (ISO 11040- 4) is one of key tests to be performed to ensure the combination product is in full GMP compliance, guaranteeing sterility," asserts Schoenknecht. CCI is required to ensure microbiological qual- ity and thus sterility until point of use. CCI testing eva luates the adequacy of con- tainer closure systems to maintain a sterile bar- rier against potential contaminants. Currently, regulatory guidance around CCI testing is am- biguous and provides limited details on how to properly assess CCI, according to Eon. He does note, however, that revisions to regulations (e.g., the new EU Annex 1) are being made to ensure a common understanding of expectations in rela- tion to CCI testing. Schoenknecht adds that the limitations of the individual technologies need to be understood and the most suitable methods selected and quali- fied for a given product. "The best solution is to have a holistic sterility/CCI strategy that follows a quality-by-design approach and comprises a phase-appropriate testing strategy," he observes. Issues with existing methods vary depending on the method. Some, such as dye-penetration testing, leak testing, and microbiological ingress testing, are destructive to the samples being tested. "These probabilistic methods also rely on a statistically representative number of samples from the batch and assume that any defect is uniformly present throughout the batch. All decisions are therefore made based on the small number of samples re- moved from the batch," Sacha comments. With others it can be difficult to demonstrate the sensitivity of the CCI test method, particu- lar with respect to the positive control, accord- ing to Eon. Traditionally dye ingress, which is probabilistic, also has poor sensitivity, accord- ing to Schoenknecht. Deterministic methods are non-destructive and can be used to test every unit from the batch. These methods include vacuum/pressure decay testing, high-voltage leak detection, and analysis of the head space within the syringe, according to Sacha. New technologies on the horizon for 100% CCI inspection based on x-ray imaging