Sterile Filtration Validation

To describe the procedure for validation of the sterile filtration to ensure filter integrity before and after the filtration 

The production manager is responsible for following the procedure. The quality assurance manager is responsible for SOP compliance. 

Perform a test filtration with the selected product samples prior to and after filtration. Results should be examined with regard to chemical stability (i.e., active content, physical, color, etc.). 

Unfiltered and filtered product no chemical and physical difference 

Filter Integrity Test prior to and after Sterilization 

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All production processes, such as ampoule washing and sterilization, solution filtration, equipment set-up and operation, sorting, and freeze-drier cleaning and operation, should be covered in detail in a procedure manual to ensure that all operations are understood as well as carried out properly and uniformly. Cleaning, sterilization, sterile filtration, filling, and aseptic processing operations must be validated. 

The complexity of the sterile filtration operation and the CGMP regulations require the validation of sterilizing filter systems. The validation of a sterile filtration operation can be complex, with many operational parameters and their interactions needing to be identified, controlled, and predicted for each end product to demonstrate that sterility is adequately achieved by the filtration process. In the commonly used steam sterilization process, the heat parameters are identified and in-process controls specified such that a level of sterility assurance can be reproducibly obtained. In steam sterilization, the important parameter of heat, measured by temperature, can be accurately measured and continuously monitored to ensure the operational integrity of the autoclave however, unlike steam sterilization, filtration sterilization cannot be monitored on a continuous basis throughout the process. 

TR 36 Current Practices in the validation of Aseptic Processing, 2002 TR 40 Sterilizing Filtration of Gases, 2005... 

Pharmaceutical products can be sterilized by steam sterilization, dry-heat sterilization, filtration sterilization, gas sterilization, and ionizing-radiation sterilization. The USP provides monographs and standards for biological indicators required to test the validity of the sterilization process. These products must also be tested for pyrogens—fever-producing substances that arise from microbial contamination most likely thought to be endotoxins or lipopolysaccharide in the bacterial outer cell membrane. 

The prime purpose of sterile filtration is to produce a sterile effluent that has not been altered as a result of the process of sterilization. Within these considerations. validation must address the performance of both the filler media and the whole filtration unit including housings, seals, connections, etc., versus its practical application. As with any other sterilization process, the continued effectiveness of sterile filmuion cannot be assumed without confirmation from routine monitoring end-product sterility testing (or testing for nonsteriiity) is unsuited for this purpose. 

There are certain things that must be done by filter users as part of validation before using a particular type of Tiller other tests have to be done before and/or after use of each individual filter and yet other indicators ought to be monitored throughout use of Individual filters. The distinction between validation and routine monitoring is less clear for sterile filtration than for any other sterilization process. 

The integrity of sterilizing fillers is most often validated and routinely monitored by nondestructive methods. The U.S., European, and U.K. guidelines on sterile filtration refer to four methods of integrity measurement filtration flow rate, bubble point tests, diffusion (forward flow) tests, and pressure hold tests. Each of these has its uses in determining that routinely used filters are per-forming to the same standards as those validated for the particular products and processes. 

For sterile filtration, fllterability and validation experiments are typically conducted at the laboratory scale to determine the size of the large-scale system and verify the absolute retention of bacteria with the actual process solution and operating conditions. 

Pharmaceuticals for injection must be presented in a sterile form. Sterility may be achieved by filtration through 0.22 pm filters under aseptic conditions, or by steam, dry heat, radiation or gas sterilisation methods, which may be applied to packaged products. Irrespective of the method, the process must be validated and monitored to assure its effectiveness. As discussed in Chapter 2, this is an example of a process that cannot be assured by verification testing because of its destructive nature. 

Nonaqueous liquids, semi-solids, and dry powders dry heat at 160°C/120 minutes then dry heat under alternative conditions of time and temperature to achieve a sterility assurance level of 10 6 then an alternative to dry heat, e.g., ionizing radiation with a minimum absorbed dose of not less than 25 kGy then a validated alternative irradiation dose (according to ISO 11137) then aseptic filtration and aseptic processing and then the use of presterilized components and aseptic compounding or filling... 

For protein-based drugs, filtration via a 0.2 pm filter is an effective way to achieve sterilization. Factors that determine the filtration efficiency include integrity of the filter, pressure, temperature, how rate, contact time of material with the filter, pH, and viscosity. Validation of filters should include chemical compatibility of the filter with the product and possibility of contaminant from the filters leaching into the product. 

Validation of membrane filtration and direct inoculation sterility test methods... 

Sterilization by filtration is a major unit operation used in aseptic processes. Aseptic processes require the presterilization of all components of the drag product and its container. Then all of the components are brought together in a controlled aseptic environment to create the finished sterile product sealed within its container/closure system. The level of sterility attained by an aseptic procedure is a cumulative function of all the process steps involved in making the product. Therefore, the final level of sterility assurance for such a product cannot be greater than the step providing the lowest probability of sterility. Each step in the aseptic process must be validated to known levels of sterility assurance [43],... 

Filters are used for clarification, removal of small molecules, exchange of buffers, and concentration of product, as well as sterilization and virus removal. A recent review of validation of filtration describes the critical validation issues [29], Filter compatibility is tested with process conditions to avoid nonspecific binding of product to the filter or addition of extractables to the process stream. Extractables are defined and limits established based on final product safety studies. Special considerations apply for sterilizing filters and those that are designed for virus removal. These filters are single use, however, which simplifies the validation effort. 

Unlike sterilizing and virus removal filters, tangential flow filtration (TFF) filters are often reused. Flow and integrity tests are necessary to ensure the filter remains the same after usage and cleaning. Consistency of filtrate and retentate streams is validated using relevant validated assays that are specific for each process and product. 

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