VALIDATION OF ASEPTIC PROCESSING AND STERILIZATIONIn this series of articles we are going to disscus aspects of
Validation of Aseptic Process and Sterilisation routine qualifications and validation study recommendations .
Change control procedures are an important part of the quality systems established by any firm.
A change in facility, equipment, process, or test method should be evaluated through the written change control program, triggering an evaluation of the need for revalidation or requalification.
We have divided topic "Aspects of Validation of Aseptic Process and Sterilisation" in to three parts .
A. Process Simulations :
B. Filtration Efficacy. ( Filtration Efficacy will be discusses in this article )
C. Sterilization of Equipment, Containers, and Closures ,
( In next article we will be writing about this aspect "Sterilization of Equipment, Containers, and Closures ".
B. Filtration Efficacy.
Filtration is a common method of sterilizing drug product solutions. A sterilizing grade filter should be validated to reproducibly remove viable microorganisms from the process stream, producing a sterile effluent ( This article does not address virus removal ).
Currently, such filters usually have a rated pore size of 0.2 μm or smaller (0.22μ and 0.2μ are considered interchangeable nominal pore size ratings ).
Use of redundant sterilizing filters should be considered in many cases. Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions for the material to be filtered and integrity test results of the filters used for the study. Product bioburden should be evaluated when selecting a suitable challenge microorganism to assess which microorganism represents the worst-case challenge to the filter. The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown, harvested and used, is a common challenge microorganism for 0.2 μm rated filters because of its small size (0.3 μm mean diameter). The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product. Bioburden of unsterilized bulk solutions should be determined to trend the characteristics of potentially contaminating organisms.
In certain cases, when justified as equivalent or better than use of
B. diminuta, it may be appropriate to conduct bacterial retention studies with a bioburden isolate. The number of microorganisms in the challenge is important because a filter can contain a number of pores larger than the nominal rating, which has the potential to allow passage of microorganisms. The probability of such passage is considered to increase as the number of organisms (bioburden) in the material to be filtered increases. A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used, resulting in no passage of the challenge microorganism. The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production.
Direct inoculation into the drug formulation is the preferred method because it provides an assessment of the effect of drug product on the filter matrix and on the challenge organism. However, directly inoculating B. diminuta into products with inherent bactericidal activity against this microbe, or into oil-based formulations, can lead to erroneous conclusions. When sufficiently justified, the effects of the product formulation on the membrane's integrity can be assessed using an appropriate alternate method. For example, a drug product could be filtered in a manner in which the worst-case combination of process specifications and conditions are simulated. This step could be followed by filtration of the challenge organism for a significant period of time, under the same conditions, using an appropriately modified product (e.g., lacking an antimicrobial preservative or other antimicrobial component) as the vehicle. Any divergence from a simulation using the actual product and conditions of processing should be justified.
Factors that can affect filter performance generally include (1) viscosity and surface tension of the material to be filtered, (2) pH, (3) compatibility of the material or formulation components with the filter itself, (4) pressures, (5) flow rates, (6) maximum use time, (7) temperature, (8) osmolality, (9) and the effects of hydraulic shock. When designing the validation protocol, it is important to address the effect of the extremes of processing factors on the filter capability to produce sterile effluent. Filter validation should be conducted using the worst-case conditions, such as maximum filter use time and pressure (Ref. 12). Filter validation experiments, including microbial challenges, need not be conducted in the actual manufacturing areas. However, it is essential that laboratory experiments simulate actual production conditions. The specific type of filter membrane used in commercial production should be evaluated in filter validation studies. There are advantages to using production filters in these bacterial retention validation studies. When the more complex filter validation tests go beyond the capabilities of the filter user, tests are often conducted by outside laboratories or by filter manufacturers. However, it is the responsibility of the filter user to review the validation data on the efficacy of the filter in producing a sterile effluent. The data should be applicable to the user's products and conditions of use because filter performance may differ significantly for various conditions and products.
After a filtration process is properly validated for a given product, process, and filter, it is important to ensure that identical filters (e.g., of identical polymer construction and pore size rating) are used in production runs. Sterilizing filters should be routinely discarded after processing of a single lot. However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed. Integrity testing of the filter(s) can be performed prior to processing, and should be routinely performed post-use. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration. Forward flow and bubble point tests, when appropriately employed, are two integrity tests that can be used. A production filter’s integrity test specification should be consistent with data generated during bacterial retention validation studies.
Regulatory Aspects for This article .21 CFR 211.63, 211.65, and 211.67 address, respectively, to the aspects of “Equipment design, size, and location,” “Equipment construction,” and “Equipment cleaning and maintenance.”
21 CFR 211.84(c) mentions, in part, that “Samples shall be collected in accordance with the following procedures: (3) Sterile equipment and aseptic sampling techniques shall be used when necessary.”
21 CFR 211.100(a) mentions , in part, that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart.”
21 CFR 211.113(b) mentions 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.”
