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16 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m Prefilled Syringes Testing must be compliant with existing test and release methods for empty containers and for containers filled with the drug product solution. As such, both drug and device regulations apply to prefilled syringes. The regulatory landscape for combination products is complex and prod- uct/country specific, according to Schoenknecht. In the United States, for example, several parts of 21 Code of Federal Regulations (1) (211 cGMP for finished pharmaceuticals, 314 drugs, 600 bio- logics, and 800 devices) are applicable. There are separate requirements outlined in the European Union (EU) Medical Directives (2) and proposed revisions to EU GMP guidelines Annex 1 (3). While International Organization for Stan- dardization (ISO) standards are important in- struments for harmonization, health authorities do not necessarily support or enforce them, but use them as a guidance for internal regulation development, according to Schoenknecht. "As an example, FDA guidance on GMP requirements for combination products (4) cites several ISO standards, such as ISO 11040," he says. In general, test methods are defined in ISO 11040-4, Part 4 (Glass barrels for injectables), Part 5 (Plunger stoppers for injectables), Part 6 (Plastic barrels for injectables), and Part 8 (Requirements and test methods for finished prefilled syringes). Other tests are outlined in ISO 80369 for small bore connectors for liquids and gases in health- care applications: Part 1 (Small bore connectors) and Part 7 (Connectors for intravascular or hy- podermic applications, which have replaced ISO 594-1 and -2), according to Eon. For glass prefilled syringes for biologics, the re- quirements are based on technical report num- ber 73 from the Parenteral Drug Association (5), Eon adds. With respect to inspection of prefilled syringes, ISO 2859 (Sampling procedures for inspection by attributes package) and ISO 3951 (Sampling procedures for inspection by variables) are applicable. "The PDA technical report comes from industry, with key users of prefilled syringes in the pharmaceutical community teaming up with the vendors of those containers to create a document that serves the industry as a white paper. It describes in broad detail what needs to be considered for the successful combination of a prefilled syringe with biologics and what enables combination with a drug-delivery device," says Schoenknecht, who is one of the co-authors of the report. Numerous opportunities for QC failure Given that so many different tests must be con- ducted on empty syringes and syringes filled with product, it isn't surprising that there are many opportunities for these complex systems to fail to meet quality requirements. Cosmetic defects such as scratches are common. These units are rejected because it can be difficult to determine if a scratch is only at the surface of the material or if it is a crack. Insufficient con- tainer siliconization can result in failure during break-loose and extrusion-force measurements and actual product use. For needle syringes, in- sufficient needle pull-out forces can occur due to weak needle assembly and imperfect adhesive polymerization control. For filled syringes, failures depend on the drug product design (e.g., the formulation), the syringe process design, and the careful assessment of in- terplays, according to Schoenknecht. "One point of concern being controversially discussed as a