Sterility is one of the most critical quality parameters for injectables, parenteral preparations, biologics, and many other products. It involves the removal of microorganisms and particulate matter from liquids or gases to achieve sterility. When selecting a sterilizing-grade filter, several important factors must be considered, including the material of construction and its compatibility with the fluid being filtered. Validation is a crucial aspect of ensuring the sterility of final dosage forms produced under aseptic conditions. The primary purpose of sterilizing filter validation is to demonstrate and document the effectiveness of the filtration process in achieving and maintaining sterility. The validation process includes various tests and evaluations to ensure the filter's reliability, efficiency, and consistency in removing contaminants.

Choose a Sterilizing-Grade Filter

The purpose of the sterile filtration step is to eliminate any viable microorganisms, excluding viruses, that may be present in the product stock solution. When selecting a sterilizing-grade filter, it is essential to consider several important factors, including the materials of construction and their compatibility with the product. Additionally, process characteristics such as volume, flow rate, differential pressure, temperature, and the chemical properties of the product to be filtered should also be taken into account.

The materials used to manufacture sterilizing filters must be meticulously selected and controlled to ensure compliance with applicable quality and regulatory standards. All materials must be non-toxic and meet USP Class VI and other toxicological criteria. Furthermore, filters must not contain extractable substances that could alter or contaminate the fluid being filtered. This necessitates the careful selection of raw materials, manufacturing equipment, and maintaining cleanliness in the production area to protect the filters from environmental contaminants. Additionally, the appropriate filter support must be chosen to maintain yield and ensure an efficient and reliable filtration process.

The level of sterilization is the first and most critical factor. An ideal sterilizing-grade filter must eliminate all microorganisms present in the fluid without compromising product quality. Bacterial removal can be specified with pore sizes of 0.2 or 0.22 μm (different manufacturers may use these nominal values interchangeably, but what is most important is that they are validated for bacterial retention). For mycoplasma removal, even smaller pore sizes are necessary—0.1 or even 0.03 μm, depending on the manufacturer and validation testing.

After determining the required pore size rating and filter type, it is essential to consider specific fluid properties to select the optimal filtration solution. Whether filtering a simple solution, a highly viscous and concentrated monoclonal antibody, or a complex lipid nanoparticle formulation, each process presents unique challenges. Some filter manufacturers offer single-layer membrane sterilizing filters, while others provide filters with two layers of membrane, which may feature different pore sizes (with a layer of larger pore size media preceding the final sterilizing filter media) or two layers of material with the same pore size. The chemical composition of the process fluid may restrict the choice of membrane material. For aqueous solutions, polyethersulfone is often the preferred option due to its ability to provide high flow rates and excellent dirt-holding capacity.

If the feed is known to have low particle contamination and a relatively low bacterial count, a single-layer filter may suffice. In critical applications where additional safety is necessary, a dual-layer filter with the same pore size rating may be a more suitable option. For feeds with low particle levels but high bacterial counts, employing a dual-layer filter with a larger initial pore size can help prolong the life of the sterilization layer, such as using a 0.45 μm layer followed by a 0.22 μm layer. For feeds with high particle loads, a higher-capacity pre-filter can be incorporated before the final sterilization layer.

Other factors to consider include the required flow rate, batch size, and expected filter life. For low flow or volume requirements, the results of filter selection may not significantly impact performance. However, in situations where these factors are critical, the outcomes of the selection process can make a substantial difference. Single-layer filters typically offer the highest flow rates per filter cartridge; however, depending on the fluid characteristics, they may lead to premature clogging and a reduced service life.

Filter Validation

Similar to other processes in the pharmaceutical industry, filtration processes require validation. Filter validation is the procedure that verifies whether the filters used to sterilize drug products effectively eliminate microorganisms. Employing final filtration as a sterilization method is a crucial stage in the development and production of drug products.

Reference regulations and guidelines for filter validation include:

ASTM F838-15 (ae1): Sterile filters must be validated using a testing procedure that adheres to the protocol outlined in ASTM F 838-15 (ae1) for assessing bacterial retention in filters utilized for liquid filtration. The challenge level should be a minimum of 10^7 microorganisms per square centimeter of filter media.

ASTM F838-20: Standard Test Method for Determining Bacterial Retention of Membrane Filters for Liquid Filtration. This test method assesses the bacterial retention characteristics of membrane filters used in liquid filtration, utilizing Brevundimonas diminuta as the challenge organism. It can be applied to evaluate any membrane filtration system designed for liquid sterilization.

Parenteral Drug Association (PDA): The PDA published an authoritative summary of best practices for sterilizing filtration and its validation in a 1998 publication. Technical Document 26 outlines the fundamental requirements for filter validation used in the sterilizing filtration of liquid products. Sterile filtration validation is conducted to demonstrate that a specific filtration method yields a sterile permeate. This can be achieved by selecting a sterilizing-grade filter that is suitable for the process, ensuring it is nontoxic, integrity-testable, sterilizable, non-adsorptive of formulation components or extractables introduced into the process, and capable of effectively removing bioburden associated with the product. Subsequently, a challenge test is performed using 10^7 colony-forming units (CFU) of Brevundimonas diminuta (ATCC 19146) per square centimeter of filter media under process conditions, and the results are confirmed through testing to ensure the production of a sterile filtrate.

Other Key Considerations for Filter Validation

Integrity Testing: Non-destructive testing confirms that the filter effectively retains bacteria. It is well established that there is a correlation between bacterial retention and non-destructive integrity testing. Sterile filters used for fluid handling can be evaluated for integrity through bubble point testing, forward or diffuse flow testing, or pressure hold testing, depending on the feasibility of each method for the specific application.

Fit for Purpose: This is the most critical consideration when selecting a sterilizing filter, namely "what is the product to be filtered" and "what will the product be treated with". From upstream, downstream and ultimately to final filling, the risk of contamination in both the product and the process conditions increases proportionally. Therefore, it is essential to include filters with appropriate characteristics and sizes in the validation plan. If there are any changes to the process or redesigns of the product, the sterilizing filter must be revalidated. In general, it is necessary to assess whether the filter meets the specific requirements of the product and the process.

Sterilization of Filters: Employ standard operating procedures, laboratory controls, and accuracy and repeatability testing to ensure that the product sterilization process does not compromise the integrity of the filter. Prior to initiating the sterilization stage, it is essential to confirm that the sterilization process is effective and will not damage the filter. Filters can be sterilized using specific methods. Capsule filters may be sterilized through gamma irradiation or autoclaving, while cartridge filters are typically sterilized using a steam-in-place (SIP) operation. The steam utilized must be free of particulate matter, as these contaminants can significantly reduce the filter's service life.

Stability of the Filter Used: It is essential to ensure that the construction of the filter does not negatively impact the filtration process. In some cases, the materials used in the filter's construction can interact with the product, altering conditions in the fluid processing, such as temperature, pH, and physical appearance. This interaction can typically be assessed by collecting data on the fluid processing conditions and analyzing it using statistical methods. It is crucial to verify that the filter does not interfere with or damage the process fluid.

Filter Binding: Filter binding refers to the investigation of whether the product contact surface of the sterilizing filter binds to any component of the dosage form, which could result in product loss during processing. The filter must not remove active pharmaceutical ingredients, excipients, carriers, diluents, proteins, preservatives, or any other components of the dosage form. The binding and adsorption characteristics of filters are assessed during the quality confirmation phase through adsorption analysis to determine if any product contents are partially trapped in the filter.

Compatibility: Ensure that the filter meets the physical requirements of the production process. For instance, conditions such as heat, hydraulic pressure, or chemical exposure can significantly affect the integrity of the sterilizing filter structure. The filter must be appropriately matched to the process and should not dissolve or break under operational conditions. The filter system must undergo quality verification to confirm that all product contact surfaces, including the membrane support layer, filter element, O-ring, and other related components, can withstand the challenges posed by sterilization and production processes. Additionally, biocompatibility and biosafety must be taken into account for filters utilized in pharmaceutical production.

Extractables and Leachables: Extractables and leachables testing is a crucial component of sterilizing filter validation, as it identifies, quantifies, and evaluates the filter as a potential source of physical or chemical contaminants that may migrate into the process stream. Extractables are typically substances extracted from plastic or elastomeric materials under extreme conditions using solvents, while leachables are compounds that leach from these materials into the drug product under standard conditions. Non-volatile residue (NVR) testing is often employed to quantify the amount of such contaminants released from the filter into the process stream. It is essential to identify, quantify, and assess the impact of compounds that pass through filtration and remain in the process stream. The final product should not be adversely affected by the filter.

The SCS-G series filters from Duoning Biotech utilize a high-performance polyethersulfone membrane, which effectively removes a greater number of bacteria and particles at high flow rates while maintaining low pressure drops.

Product Features:

Ÿ   Asymmetric membrane pore structure, with strong dirt holding capacity

Ÿ   100% integrity test to ensure absolute sterilization effect

Ÿ   No foreign substances such as adhesives

Ÿ   Highly durable PES, can be sterilized multiple times

Typical Applications

Ÿ   Buffer filtration

Ÿ   Colloid or viscous liquid filtration

Ÿ   Pre-chromatography/pre-filtration filtration

Ÿ   Pharmaceutical water sterilization filtration

Ÿ   Biological product intermediate and bulk solution filtration

Duoning Biotech's SCF series hydrophobic polytetrafluoroethylene filter products exhibit exceptional natural hydrophobicity, high-temperature resistance, and corrosion resistance. They are widely utilized in the filtration of respirators and highly corrosive liquids.

Product Features

Ÿ   High temperature and steam resistance

Ÿ   Wide chemical compatibility allows for use in various pharmaceutical process filtration applications

Ÿ   Natural hydrophobicity, high flux, and low pressure difference

Ÿ   Strong oxidizing liquid sterilization filtration

Typical Applications

Ÿ   Air filters for sterile packaging

Ÿ   Sterile filtration of corrosive gases

Ÿ   Sterile filtration of compressed air and nitrogen

Ÿ   Sterile filtration of highly oxidizing liquids