Depyrogenation of Components

Perform one or more cycle development test runs with item used in the load configuration to determine appropriate cycle type, temperature and dwell period, hard-to-heat items or areas, load item preparation, and minimum and maximum load configurations. 

Identify and document the quantity, placement, and physical description of each component to be included in the load configuration. Determine load configurations from Cycle Development Test studies. 

Perform load and chamber temperature mapping and verify that the temperature distribution in the chamber is uniform for the load configuration, and that all measured points within the load configuration receive thermal treatment sufficient for depyrogenation. Perform three (3) runs on the maximum load and a minimum of three (3) runs on the minimum load. 

Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Cycle Development and Performance Qualifications Testing. 

Temperature distribution thermocouples in the heat penetration and distribution test studies for three (3) consecutive runs must be within 5°C of the mean chamber temperature during the dwell period at any one print interval. 

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Washing of components Sterilization of components Depyrogenation of components... 

Sterilization and depyrogenation of containers, closures, equipment, and components... 

FDA guidance The completed batch record supplied with the chemistry, manufacturing, and controls section of the application should identify the validated processes to be used for sterilization and depyrogenation of any container-closure components. This information may be included in the batch record by reference to the validation protocol or SOP. 

Kinetic LAL methods are claimed to increase the efficiency of large-scale testing, probably important when validation of depyrogenation cycles or preparation of components for aseptic processing are required. For all procedures, test validation must be conducted to rule out interference, which may be either inhibition or enhancement. Depyrogenated glassware must be used throughout. 

Validation of support processes. Define test functions and acceptance criteria for critical validation support processes such as washing of components, sterilization of components, depyrogenation, etc. 

Dry heat is used to sterihze and depyrogenate components and drug products. The definition of dry heat sterilization is 170 °C for at least 2 hours and a depyrogenation cycle at 250 °C for more than 30 minutes. Typical equipment includes tunnel sterilizers (force convection, infrared, fiame) and microwave sterilizers. An important aspect is the need to ensure air supply is filtered through HEPA filters. Biological indicators such as Bacillus subtilis can be used to gauge the performance of sterilization. 

Description of any operations or preparations that are performed on a packaging component by the applicant (such as washing, coating, sterilization, or depyrogenation)... 

Ordinarily, present within the preparation area are localized areas of ISO 5 unidirectional airflow (Class 100) utilized to protect washed components prior to sterilization and/or depyrogenation. These areas are not aseptic and should not be subjected to the more rigorous microbial expectations of aseptic processing. They are designed to reduce/eliminate the potential for particle contamination of unwrapped washed materials. Operators accessing these protective zones wear gloves at all times when handling materials. 

Endotoxin is the lipid A component of LPS (see section 2.2.1). It possesses multiple biological properties including the ability to induce fever, initiate the complement and blood cascades, activate P lymphocytes and stimulate production of tumour necrosis factor. Endotoxin is generally released from lysed or damaged cells. Care must be taken to eliminate or exclude such heat-resistant material from parenteral products and their delivery systems through a process known as depyrogenation (Chapter 20). 

Water used for the final rinsing of container components used for parenteral drugs is tested for endotoxins unless such components are depyrogenated subsequently. 

Data should be available that demonstrates a knowledge of the (or endotoxin) loading on components prior to treatment in a depyrogenation process. When a depyrogenation process is used, the data shall demonstrate that the process will remove a greater quantity of endotoxin than may have been originally present in the component or product... 

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