Filter Validation

Typically, initial filter screening is performed on a scaled-down device (47 mm disc) installed in special media: this type of test is useful to determine the correct sizing of the process filter and/or potential prefilter combinations to optimise total flow.

To predict performance on a production scale, constant-flow or constant-pressure filterability tests can be used. Depending on the main process parameter to be applied, the increase in pressure drop as a function of filtration time (constant flow) or the decrease in flow rate as a function of filtered volume (constant pressure) is evaluated.

Using the data obtained from the scaled-down tests, the right full-scale process filter size can be predicted. Critical factors, such as flow rate, pilot pressure or delta P values, product components and temperature, can influence filterability, so must be taken into account.

The small-scale filtration volume must be defined at the beginning of the study test based on the maximum process batch size and EFA of the proposed process filters.

The purpose of compatibility validation studies is to have documented evidence to show that the filtration process, under simulated worst-case processing conditions, does not affect the physical structure of the filter or its ability to perform its stated function; the integrity test, where applicable, is a 'physical test' that relates to microbial retention and is a determinant of compatibility. During a chemical compatibility study, it is necessary to include all components of the filter system under investigation. In addition to the membrane, these include the membrane support materials, the cartridge shell and the housing material.

The purpose of extractables validation studies is to have documented evidence that the filter used in the specific process does not alter the drug product in terms of safety, identity, strength, quality or purity beyond official or other established requirements. Extractables are chemical compounds that can be extracted from product-contact surfaces when exposed to an appropriate solvent under exaggerated conditions of time and temperature. 

The evaluation of the potential presence of extractables/powder substances during pharmaceutical production is an important consideration in assessing the suitability of a process and its equipment (including filters) for a specific application.

The quantity and nature of extractables must be considered and evaluated when determining the suitability of the filter for the intended application. All extractables must have passed USP <88> Class VI tests for elastomers, plastics and other polymeric materials.

The results are presented in terms of extractable Non-Volatile Residues (RINs), understood as the total mass of all non-volatile material in the product: the application of this generic analytical method allows the detection of any unexpected extractables, to confirm that only those substances expected from the filter composition are extracted. Next, the RINs are qualified by infrared spectroscopy based on the characteristic infrared signal generated by chains of different lengths of a single polymer, identifying the functional groups present and the class of the compound.

The test is performed on a set of three cartridges/capsules of different batch/series numbers.

Characterisation and semi-quantitative evaluation of the individual compounds (if present) in the test solution are performed using specific analytical techniques suitable for profiling organic extractables (semi-volatile organic and non-volatile organic compounds).

The objective of adsorption validation studies is to have documented evidence showing that the filter used under the specific process conditions will not bind the drug components, as this may cause the product to fall below the specification for these ingredients; therefore, if an adsorption phenomenon occurs, this must be addressed. The adsorption of target components by the filter (mainly the membrane) will be assessed by comparing the composition of the product before and after filtration, according to the acceptance limits provided by the end-user.

Critical factors such as flow rate, pressure or delta P values, drug concentration, preservative concentration, temperature and pH can influence adsorption, so must be considered.

The analytical method used to quantify the active concentration is provided by the end user.

Depending on the layout of the filtration process, the test could include a step to simulate filtration from the preparation tank to the storage tank or a step to simulate filtration from the storage tank to the filling machine. The test is performed on a small scale using 47 mm membranes representing the filters used in the process by the end user.

The viability of the test organism Brevundimonas diminuta (ATCC 19146) is assessed by direct inoculation into the product and simulant (also called surrogate) fluid (if required) for an exposure time equal to or longer than the maximum filtration time of the process, as well as the washing regimes of the filter capsules used during the bacterial challenge study.

The viability test method is based on the principles described in Parenteral Drug Association (PDA) Technical Report No. 26.

The viability results are used to determine the most suitable method for performing a liquid-phase bacterial challenge test for product- and process-specific filter validation, based on the following definitions:

Non-bacterial

A decrease in viability of microorganisms of less than one log over the duration of the process is defined as non-bactericidal product.

Moderately bactericidal

A decrease in viability of microorganisms of less than one log within 60 minutes and 1 log or more over the process duration is defined as a moderately bactericidal product and may allow a bacterial challenge within the product after recirculation of the product.

Bactericidal

A decrease in the viability of microorganisms of more than one log for a minimum period of 60 minutes is defined as a bactericidal product.

The purpose of bacterial retention validation studies is to have documented evidence that the filtration process will generate a sterile effluent and consistently remove a high level of a standard bacterium suspended in the drug formulation or surrogate fluid under simulated worst-case processing conditions. The bacterial resistance study is performed using a standard bacterium suspended in the drug formulation under simulated worst-case processing conditions and considers the standard method for qualifying microbial retention membrane filters, as described by the American Society for Testing and Materials (ASTM) standard and PDA Technical Report No. 26 guidelines.

The three test filters, or at least one of the batches of membranes used, should have a pre-use physical integrity test value at or near the filter manufacturer's test specification. When this is not possible, the test membranes should be selected from a production lot whose pre-use integrity test values are as low as possible. A fourth line is assembled with a control filter membrane (0.45 μm) that consists of the same filter medium as the test membranes. At the end of the test phase, the entire test effluent is collected through the recovery filter membranes and the appropriate flushing regime is applied. At the beginning and end of the test, a total viable aerobic count (TVAC) of the challenge inoculum is performed.

Pre and post-use integrity testing of sterilising grade filters is a regulatory requirement and forward flow and bubble point tests are the recommended non-destructive testing methods to verify the integrity of sterilising grade filters.

The diffusive/forward flow test quantitatively measures the sum of diffusive flow through the membrane and flow through open pores, while the bubble point pressure depends on pore size and surface interactions between the filter and wetting fluid.

Integrity tests are highly dependent on the physical characteristics of the wetting solution, and even small changes to the test solution can substantially alter integrity test results.

Many pharmaceutical solutions have a significantly high viscosity and/or low surface tension value, due to the properties of an active component of the formulation or clinical requirements. 

Filter manufacturers provide minimum specifications for integrity testing of wetted filters with standard wetting fluids, i.e. water for hydrophilic filters and hydroalcoholic solutions such as IPA/water mixture for hydrophobic filters. These wetting fluids are ideal for integrity tests before use, but after use the filter is wetted with the drug product's process fluid.

Integrity test results obtained using the product as wetting fluid must be compared with those obtained using the reference wetting fluid recommended by the filter manufacturer on the same membranes to determine a product wetting specification. This specification is then indirectly related to the bacterial retention capacity of the filter membrane.