Tuesday, 10 September 2013

Sterile Filters - Regulatory Requirements



 

 
   STERILE FILTERS - REGULATORY REQUIREMENTS
 
 

 
Filtration is a common method of sterilizing drug product solutions. 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.

 
USFDA GUIDANCE REQUIREMENTS

(Ref: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice)
 
1.
Sterilizing grade filter to be validated. 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. The microorganism Brevundimonas diminuta (ATCC 19146) , is a common challenge microorganism for 0.2 μm rated filters because of its small size (0.3 μm mean diameter). 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.
 
2.
Filter validation should be conducted using the worst-case conditions, such as maximum filter use time and pressure.
 
3.
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.
 
4.
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.
 
5.
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.
 
6.
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.

 
EU GUIDANCE REQUIREMENTS

(Ref: Manufacture of sterile medicinal products – Annexure - I)

1.
If the product cannot be sterilised in the final container, solutions or liquids can be filtered through a sterile filter of nominal pore size of 0.22 micron (or less), or with at least equivalent micro-organism retaining properties, into a previously sterilised container. Such filters can remove most bacteria and moulds, but not all viruses or mycoplasmas.
 
2.
Due to the potential additional risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilised micro-organism retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be
carried out as close as possible to the filling point.
 
3.
Fibre-shedding characteristics of filters should be minimal.
 
4.
The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter should be determined during validation and any significant differences from this during routine manufacturing should be noted and investigated. Results of these checks should be included in the batch record.
 
5.
The same filter should not be used for more than one working day unless such use has been validated.
 
6.
The filter should not affect the product by removal of ingredients from it or by release of substances into it.
 

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