When should filter validation be performed?

Irrespective of the clinical phase that a drug product is in, there is an expectation that the end-user provides assurance that the drug product meets the predefined characteristics in terms of identity, strength, quality, and purity (1). For drug products that cannot be terminally sterilized, sterility is typically achieved using sterilizing grade filters. Before the drug product is produced for early phase clinical trials, the rationale for selection of a sterilizing grade filter should be documented as part of the contamination control strategy (CCS) (2). The risk assessment must consider the following:

• Suitability of the filter for pharmaceutical use (e.g. cleanliness, integrity test values correlated to bacterial retention).
• Compatibility of the filter with the drug product/processing condition.
• Potential adsorptive effects of the filter with the drug product such that the drug product may not meet its predefined specifications.
• Extractables (usually based on generic data available from the supplier).

As the drug product progresses through clinical trials, so too does the level of product and process understanding. While it is recognized that product and process related filter validation studies must ultimately be performed, there is no specific guidance that categorically states when such filter validation studies should be performed. Consequently, the decision when to perform filter validation is determined largely by the end-user. While most end-users elect to perform process specific filter validation testing during Phase 3 clinical trials, risk assessment should be used to identify and mitigate any risks that are determined during process development.

Regulatory guidance

For investigational new drugs, FDA guidance provides no expectation that process-specific filter validation is performed for aseptically manufactured drug products sterilized by final filtration, simply stating that they should comply with current good manufacturing practice (CGMP) (3). This means that the clinical batch is produced using a sterilizing grade filter which has an integrity test that is correlated to microbial retention (demonstrated by retention of Brevundimonas diminuta at a concentration ≥ 1.0 × 107 colony forming units per cm² of effective filtration area (≥ 1.0 x 107 CFU/cm²)) (4).

Annex 13 of the EU Guidelines to Good Manufacturing Practice states, ‘During development critical parameters should be identified and in-process controls primarily used to control the process’ and ‘Production processes for investigational medicinal products are not expected to be validated to the extent necessary for routine production but premises and equipment are expected to be qualified’ (5). As with the FDA Guidance for Phase 1 Investigational Drugs, this implies only that use of a qualified (by the filter manufacturer) sterilizing grade filter is required, but control of critical process parameters (CPP) must be demonstrated by the end-user.

However, Annex 13 further states, ‘For sterile products, the validation of sterilizing processes should be of the same standard as for products authorized for marketing.’ We believe that this does not mean that filter validation studies are warranted at this early stage of drug development, when details of the full, scaled up process will be unknown, and there may be insufficient product available to perform a full filter validation. However, it is always good to consult regulatory authorities early to ensure of alignment with current thinking.

With reference specifically to drug product at Phase 2, the FDA Guidance for Industry, INDs for Phase 2 and Phase 3 Studies states, ‘Information related to the validation of the sterilization process need not be submitted at this time’ (6). However, it is expected that as chemistry, manufacturing and controls (CMC) information is developed, this is reflected in annual reports. For Phase 3 drug product, the document goes on to state, ‘Information related to the validation of the sterilization process need not be submitted at this time but should be submitted at the time of an NDA filing.’ This is also reflected in the Guidance for Industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products (7).

Although Quality by Design (QbD) principles should be incorporated into the final sterile filtration process as early as possible, there are usually too many unknown factors related to the scaled-up manufacturing plans to warrant performing process-specific filter validation until the drug product reaches Phase 3 clinical trials. However, if the initial risk assessments performed as part of the CCS indicate a specific risk that needs to be addressed, testing can be performed to mitigate the specific risk identified. In response to this we have developed a program called Sterility Optimization by Assessment of Risk (SOAR) to facilitate risk mitigation prior to performing process-specific filter validation.

What is the purpose of the SOAR program?

Essentially it is to evaluate the risk to sterility of any given set of final sterile filtration conditions prior to performing formal filter validation studies. The importance here is that it allows full exploration of the proposed filter design space at the time of filter selection. Not every process fluid or sterile application will need this detailed level of understanding, however there are significant benefits to considering this during Phase 1 or 2 clinical trials. Our SOAR program is split into the three main areas, as shown in Figure 5.

• Process optimization — looks to assess any potential risk to sterility assurance caused by the intended critical process parameters defined for the manufacturing process.
• Test method development and optimization — allows the validation laboratory to design and qualify new test set-ups which may be required for complex processing operations.
• High risk fluids — recognizing that some fluids, such as liposomes that cannot be terminally sterilized, may present unique challenges for sterile filtration.

 

Fig 1. Elements of the SOAR program for evaluation of sterility assurance

Conclusion

Timing of filter validation studies is ultimately the decision of those developing a sterile drug manufacturing process and would benefit from discussions with the filter supplier and holistic approaches to the assessment of risk similar to that outlined in the SOAR program. With increasingly complex biopharmaceutical manufacturing operations and drug delivery systems, the traditional approach to sterile filtration and subsequent filter validation performed as a one-time event is unlikely to be sufficiently robust to accommodate the current regulatory expectations.

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