By Alexis Kopp, Technical Account Specialist, West Pharmaceutical Services, Inc.
Sterilization, process control and validation issues at drug manufacturers have all generated FDA warning letters for concerns that include inadequate aseptic processing operations, human error, high endotoxin levels, microbial contamination and insufficient sterility testing. All critical process steps in the manufacturing of a drug product, including packaging and testing, must be validated and controlled. The integrity of a drug product may be compromised at different points in the process, and the proper preparation of the container closure system (CCS) contributes to achieving sterility and quality assurance.
Container closure systems for parenteral products most commonly utilize elastomeric components. Historically, preparation processes for elastomeric components have been validated and controlled by drug manufacturers. To alleviate drug manufacturer’s validation efforts, elastomeric component suppliers can provide washed, depyrogenated and siliconized ready-to-sterilize (RS) products in packages suitable for sterilization. Component suppliers are providing further relief with ready-to-use (RU) products, which are commercially available in multiple types and sizes, and their use is growing steadily. RU components are provided sterilized and in packaging that has been validated to withstand transportation and maintain sterility over time. The drug manufacturing process can be validated to include RU components, and for drug product manufacturers that choose fully validated RU components, the risk to sterile drug product quality can be mitigated.
The ideal sterilization process destroys all microorganisms rapidly with minimal adverse impact on the chemical and physical properties of the elastomeric closure. Developing and validating an acceptable sterilization process is critical to the protection of the drug product. Typical sterilization methods include moist heat (i.e., steam), dry heat, ionizing radiation (gamma or e-beam) and gas (typically EtO – ethylene oxide). Dry heat requires temperatures and duration well beyond conditions that are feasible for typical pharmaceutical elastomers and therefore is not a viable option. Gases are frequently used for medical devices, but this sterilization method is not popular in pharmaceutical applications due to increased concerns with possible residuals that could adversely affect drug products. Moist heat and ionizing radiation are commonly used but have pros and cons that should be examined on a case-by-case basis.