|ToF-SIMS analysis of vial for contamination.|
Pharmaceutical companies with parenteral (injectable) products usually start to get serious about determining the container and closure systems at the time of clinical testing. As these products become increasingly more complex, and the regulatory demands placed on their packaging continue to rise, it is much more difficult to preserve the stability of a modern biotech product over its entire lifetime than traditional chemical ingredients. More testing is the order of the day.
The selection of the container system depends on several important factors. Drug administration factors include drug indication, stability (lyophilized vs. liquid) and sensitivity (metals, organics, salts, water/oxygen). Container-specific factors include cosmetic appearance, filling equipment, chemical durability (risk of glass delamination or pH shift), sealability and use (staked needle vs. Luer lock/Luer cone). Manufacturability considerations are also a factor.
The physical integrity of the drug product during filling processes is critical, involving testing for contaminants, leachates or non-soluble integration products. There is also the possibility of contamination during storage caused by (among other factors) outgassing from secondary packaging materials like shrink-wrap. Due to this variety of aspects, it becomes evident that testing utilizes a wide range of methods and analytical tools, such as spectroscopy, chromatography, scanning electron microscopes and other highly sophisticated instruments (Figure). In addition, there is testing of the closure integrity (dye ingress, helium leak testing, endotoxin) and dispensing action of the assembly (force and pressure testing, optical microscopy, biological sterility).
Container strength testing should be a part of all container selection criteria. Regardless of whether or not the container is a standard or custom-designed vial, cartridge, or syringe, the design has likely been checked for high stress points through the use of finite element methods (FEM). While the materials used in parenteral pharmaceutical containers (glass, cyclic olefin polymers) have strength well above applied forces, the strength of these containers depends on the surface quality and location of applied force. Glass containers that experience a significant amount of glass-to-glass or glass-to-metal contacts can experience enough reduction in glass strength to noticeably increase the number of glass container breakage events.
For auto-injectors, the containers should be assessed to determine if they can withstand the supplied delivery force (spring, gas) to a desired failure rate of few ppm across multiple lots of the container to ensure minimized risk of failure of the device in the field. For syringes, the containers should be assessed across multiple lots at the flange, body and cone. Samples are subjected to overloading until it causes breakage. Thus the container defect rate under “normal” conditions can be estimated with high confidence based on these statistical evaluations. A typical syringe requires at least three testing geometries (flange, body and cone).
Testing is best done by laboratories in accordance with good manufacturing practices (GMP), such as those laboratories accredited based on the DIN EN ISO 17025 standard. Also advantageous is using laboratories that have experience in assessing the materials used in manufacturing and troubleshooting the cleaning/filling processes of pharmaceutical packaging. Containers testing such as these are offered by SCHOTT Pharma Services, backed up by more than 125 years of accumulated knowledge of specialty glass and other materials development, manufacturing, and processing. Unlike most of the other pharmaceutical analytical laboratory service providers, being a sister company to a manufacturer of pharmaceutical packaging, they are also familiar with the entire process chain that ranges from selection/analysis of the raw materials to the filling process, sterilization, and use.