asertain Validation Services
As per regulatory requirement, pharmaceutical industry has to provide a high level of assurance that the sterile drug product manufactured through aseptic processing offers the identity, strength, quality, and purity it purports to have or is represented to posses (Ref. USFDA 21CFR 211.100(a)). Consequently it has become increasing critical to establish/quantify the impact on the drug due to its interface with various process components under different process conditions. Sterilizing grade filters are key components of the aseptic process as these not only ensure sterility of the filtered drug but, as they provide a large surface area for drug interface, can also have a significant impact on other parameters such as purity and strength of the drug. mdi offers a wide range of validation services to establish the functionality, testability, and compatibility of the sterilizing grade filters with the drug product. more....
Filter Integrity Test Values Specific to Product
For aseptic processes, filter integrity tests are required to be performed on critical filters immediately before and after batch filtration in order to assure filter efficiency during the filtration process. In order to optimize processing, it may be more convenient to integrity test the filter cartridge wet with the product or process fluid. However, drug products/process fluids due to different components may have different surface tension impacting the drug-filter interface and consequently the integrity test values exhibited by the filter. Thus, it is critical to establish drug product wetted integrity test specifications for the filter. mdi validation services for establishing product specific filter integrity test specifications help correlate product wetted integrity test values with those exhibited with the reference fluid (filter manufacturer specified) which in turn are already correlated to bacterial retention as per ASTM F- 838-05 (Ref. mdi Validation guides). Product wetted integrity test values are compared with reference fluid wetted values for 3 different filter lots and an integrity test ratio so established is used to establish the product wetted integrity test specifications. Special consideration is given to process conditions such as temperature that may also have an impact on filter integrity test values.
Physico-Chemical Compatibility studies evaluate the inter face between filter components and the pharmaceutical product after exposure to "worst-case" fluid and process conditions to ensure that the filter experiences no adverse effects in the pharmaceutical product. The filter is exposed to the process fluid for a specified period under pre-determined conditions that include simulated filter sterilization conditions, exposure times exceeding the maximum process time, temperatures exceeding maximum process temperature, and differential pressures that exceed process pressures.
Compatibility is determined by comparing:
1. Integrity test results using the reference fluid
2. Flow Rates
3. Membrane Thickness
4. Pore Morphology
Tests are performed on the filter prior to and after worstcase exposure.
Leachables are compounds that leach out from the filter into the drug product under normal process conditions, whereas extractables are compounds extracted from the filter in solvents exhibiting varying physicochemical properties, under conditions designed to maximize extraction. Potential sources of extractables/ leachables from a filter can be membrane filter components such as plasticizers, surfactants, antioxidents, residual solvents, device support layers, and plastic components such as end caps, housings, cages, O-rings etc. Although it is recommended to establish the quantum of leachables from a filter in direct interface with the drug product or its placebo, sometimes due to possible drug component interference it is not possible to accurately do so. In such cases, model solvent streams, selected on the basis of their ability to simulate the extraction abilities of different drug components, are used to carry out extractable studies under simulated worst case process conditions.
It is critical that filters are selected to minimize adsorption and loss of product components. Laboratory-scale filter tests are used to generate adsorption profiles to help with filter selections and process qualification. Process conditions such as temperature and filter fluid contact time (flow rates) are simulated as these may have an impact on adsorption.
USFDA CDER guidance document on Sterile Drug Products Produced by Aseptic Processing as well as PDA Technical Report No. 26, Revised 2008 on Sterilizing Filtration of Liquids, stress on establishing documented evidence for the sterilizing grade filter to reproducibly remove bacterial contamination from the process stream.
microbial retention studies qualify the filter under test to repeatedly produce a sterile filtrate with the drug product under simulated worst case process conditions.
The drug product or simulant is inoculated with the challenge organism at a concentration >1x107 viable organisms/cm2 of filter area and the test is performed on filters from three different lots, with at least one having a pre-filtration physical integrity test value at/or near the filter Manufacturer's specified limit.
This involves establishing the viability of the test organism in the drug product and testing the filter for bacterial retention test under simulated process conditions.
Test Organism Viability Study
Establishes whether the drug product is bactericidal to the test organism under simulated process conditions of temperature and contact time. This in turn helps establish the test methodology for the bacterial challenge/retention studies.
Bacterial Retention Study
For non-bactericidal drug products the filter is challenged with the test organism suspended in drug product. For bactericidal products viability studies are carried out with modified formulation, modified process conditions, or in product surrogate. In such cases filter preconditioning with the product under worst case process conditions is carried out followed by bacterial challenge test with modified formulation/process under which test organism viability has been established.