by Daniel Prince
FDA has published guidance for industry to assure patient safety public that glass containers such as vials, beakers and rubber stoppers be clean. Gibraltar provides vials that meet these requirements and is an outsourcing destination for the washing of containers and closures with USP/EP Water for Injection (WFI) as well as being a FDA registered laboratory to certify that the materials processed at Gibraltar are pyrogen-free and particulate–free.
Containers/Closures: For an example of products that are certified to meet this requirement see, https://www.gibraltarlabsinc.com/sterikit-product/
| Section 211.94 (drug product containers and closures) states that “drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.” It also states that “Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.”
Section 211.113(b) requires “validation of any sterilization process” as part of designing procedures “to prevent microbiological contamination of drug products purporting to be sterile.” |
1. Preparation
Containers and closures should be rendered sterile and, for parenteral drug products, pyrogen-free. The type of processes used will depend primarily on the nature of the material comprising the container and/or closure. The validation study for any such process should be adequate to demonstrate its ability to render materials sterile and pyrogen-free. Written procedures should specify the frequency of revalidation of these processes as well as time limits for holding sterile, depyrogenated containers and closures.
Presterilization preparation of glass containers usually involves a series of wash and rinse cycles. These cycles serve an important role in removing foreign matter. Rinse water should be of high purity so as not to contaminate containers. For parenteral products, final rinse water should meet the specifications of Water for Injection, USP.
The adequacy of the depyrogenation process can be assessed by spiking containers or closures with known quantities of endotoxin, followed by measuring endotoxin content after depyrogenation. The challenge studies should be performed with a reconstituted endotoxin solution applied directly onto the surface being tested and air-dried. Positive controls should be used to measure the percentage of endotoxin recovery by the test method. Validation study data should demonstrate that the process reduces the endotoxin content by at least 99.9% (3 logs).
Glass containers are generally subjected to dry heat for sterilization and depyrogenation. Validation of dry heat sterilization/depyrogenation should include appropriate heat distribution and penetration studies as well as the use of worst-case process cycles, container characteristics (e.g., mass), and specific loading configurations to represent actual production runs. For example, This service is offered at Gibraltar https://www.gibraltarlabsinc.com/services/microbiology/depyrogenation-services/
Pyrogen on plastic containers can be generally removed by multiple WFI rinses. Plastic containers can be sterilized with an appropriate gas, irradiation or other suitable means. For gases such as EtO, the parameters and limits of the EtO sterilization cycle (e.g. temperature, pressure, humidity, gas concentration, exposure time, degassing, aeration, and determination of residuals) should be specified and monitored closely. Biological indicators are of special importance in demonstrating the effectiveness of EtO and other gas sterilization processes.
Rubber closures (e.g., stoppers and syringe plungers) are cleaned by multiple cycles of washing and rinsing prior to final steam or irradiation sterilization. At minimum, the initial rinses for the washing process should employ Purified Water USP of minimal endotoxin content, followed by final rinse(s) with WFI for parenteral products. Normally, depyrogenation is achieved by multiple rinses of hot WFI. The time between washing and sterilizing should be minimized because moisture on the stoppers can support microbial growth and the generation of endotoxins. Because rubber is a poor conductor of heat, extra attention should be given to the validation of processes that use heat to sterilize rubber stoppers. Validation data should also demonstrate successful endotoxin removal from rubber materials.
A potential source of contamination is the siliconization of rubber stoppers. Silicone used in the preparation of rubber stoppers should be rendered sterile and should not have an adverse effect on the safety, quality, or purity of the drug product.
Contract facilities, such as Gibraltar, that perform sterilization and depyrogenation of containers and closures are subject to the same CGMP requirements as those established for in-house processing. The finished dosage form manufacturer is responsible for the review and approval of the contractor’s validation protocol and final validation report.
Reference: Sterile Drug Products Produced by Aseptic Processing Draft. See Appendix for full guidance.