21 CFR 211.80(a) states that “There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.”
21 CFR 211.80(b) states that “Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.”
21 CFR 211.84(d) states, in part, that “Samples shall be examined and tested as follows: * * * (6) Each lot of a component, drug product container, or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.”
21 CFR 211.94(c) states that “Pharmaceutical 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.”
21 CFR 211.94(d) 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.”
21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
A pharmaceutical drug product produced by aseptic processing can become contaminated through the use of one or more components that are contaminated with microorganisms or endotoxins. Examples of components include active ingredients, Water for Injection (WFI), and other excipients. It is important to characterize the microbial content (e.g., bioburden, endotoxin) of each component that could be contaminated and establish appropriate acceptance limits.
Endotoxin load data are significant because parenteral products are intended to be nonpyrogenic. There should be written procedures and appropriate specifications for acceptance or rejection of each lot of components that might contain endotoxins. Any components failing to meet defined endotoxin limits should be rejected.
In aseptic processing, each component is individually sterilized or several components are combined, with the resulting mixture sterilized. Knowledge of bioburden is important in assessing whether a sterilization process is adequate. Several methods can be suitable for sterilizing components (see relevant discussion in Section IX). A widely used method is filtration of a solution formed by dissolving the component(s) in a solvent such as Water For Injection, USP. The solution is passed through a sterilizing membrane or cartridge filter. Filter sterilization is used where the component is soluble and is likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (or lyophilization) of the component as a sterile powder. However, this method involves more handling and manipulation and therefore has a higher potential for contamination during processing.
Dry heat sterilization is a suitable method for components that are heat stable and insoluble. However, conducting carefully designed heat penetration and distribution studies is of particular significance for powder sterilization because of the insulating effects of the powder.
Irradiation can be used to sterilize some components. Studies should be conducted to demonstrate that the process is appropriate for the component.
Containers and closures should be rendered sterile and, for parenteral pharmaceutical drug products, nonpyrogenic. The process used will depend primarily on the nature of the container and/or closure materials. The validation study for such a process should be adequate to demonstrate its ability to render materials sterile and non-pyrogenic. Written procedures should specify the frequency of revalidation of these processes as well as time limits for holding sterile, depyrogenated containers and closures.
Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles. These cycles serve an important role in removing foreign matter. US FDA recommend use of rinse water of high purity so as not to contaminate containers. For parenteral products, final rinse water should meet the specifications of WFI, USP.
The adequacy of the depyrogenation process can be assessed by spiking containers and closures with known quantities of endotoxin, followed by measuring endotoxin content after depyrogenation. The challenge studies can generally be performed by directly applying a reconstituted endotoxin solution onto the surfaces being tested. The endotoxin solution should then be allowed to air dry. 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 percent (3 logs) (see Section VII).
Subjecting glass containers to dry heat generally accomplishes both sterilization and depyrogenation. Validation of dry heat sterilization and 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. See Section IX.C. Plastic containers used for parenteral products also should be non-pyrogenic. Where applicable, multiple WFI rinses can be effective in removing pyrogens from these containers.
Plastic containers can be sterilized with an appropriate gas, irradiation, or other suitable means. For gases such as Ethylene Oxide (EtO), certain issues should receive attention. For example, 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. EtO is an effective surface sterilant and is also used to penetrate certain packages with porous overwrapping. Biological indicators are of special importance in demonstrating the effectiveness of EtO and other gas sterilization processes. US FDA recommend that these methods be carefully controlled and validated to evaluate whether consistent penetration of the sterilant can be achieved and to minimize residuals. Residuals from EtO processes typically include ethylene oxide as well as its byproducts, and should be within specified limits.
Rubber closures (e.g., stoppers and syringe plungers) can be 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 at least Purified Water, USP, of minimal endotoxin content, followed by final rinse(s) with WFI for parenteral products. Normally, depyrogenation can be achieved by multiple rinses of hot WFI. The time between washing, drying (where appropriate), and sterilizing should be minimized because residual moisture on the stoppers can support microbial growth and the generation of endotoxins. Because rubber is a poor conductor of heat, extra attention is indicated in the validation of processes that use heat with respect to its penetration into the rubber stopper load (See Section IX.C). Validation data from the washing procedure should 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 meet appropriate quality control criteria and not have an adverse effect on the safety, quality, or purity of the drug product.
Contract facilities that perform sterilization and/or depyrogenation of containers and closures are subject to the same CGMP requirements as those established for in-house processing. The finished dosage form manufacturer should review and assess the contractor’s validation protocol and final validation report. In accord with 211.84(d)(3), a manufacturer who establishes the reliability of the supplier’s test results at appropriate intervals may accept containers or closures based on visual identification and Certificate of Analysis review. Pharmaceutical Process Validation
2. Inspection of Container Closure System
A container closure system that permits penetration of microorganisms is unsuitable for a sterile pharmaceutical product. Any damaged or defective units should be detected, and removed, during inspection of the final sealed product. Safeguards should be implemented to strictly preclude shipment of product that may lack container closure integrity and lead to nonsterility. Equipment suitability problems or incoming container or closure deficiencies can cause loss of container closure system integrity. For example, failure to detect vials fractured by faulty machinery as well as by mishandling of bulk finished stock has led to drug recalls. If damage that is not readily detected leads to loss of container closure integrity, improved procedures should be rapidly implemented to prevent and detect such defects.
Functional defects in delivery devices (e.g., syringe device defects, delivery volume) can also result in product quality problems and should be monitored by appropriate in-process testing.
Any defects or results outside the specifications established for in-process and final inspection are to be investigated in accord with § 211.192.
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This Guidance is published by US FDA on September 2004
We also recommend our readers to visit US FDA’S website for undated guidances on sterile drug products