The United States, FDA’s Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (cGMP) document states “The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product”. No specific bioburden limits or sampling frequencies are stated. In contrast, the EU guidelines to cGMP state specifically that pre-sterilizing filtration bioburden must be < 10 CFU/100 mL, aseptic processed drugs subjected to sterilizing filtration and terminally sterilized drugs under parametric release must have pre-sterilization bioburden determined for every batch. 

The purpose of Pall’s SOAR program is to evaluate the risk to sterility of any given set of processing conditions prior to performing formal filter validation studies. This is important, as it allows the end user to fully explore the proposed filter design space at the time of filter selection. While not every process fluid or sterile application may need this detailed level of understanding, there are significant benefits to considering this during Phase 2 clinical trials. The program is split into the three main areas: process optimization; high risk fluids; and test method development and optimization.

Although it is widely recognized that product and process related filter validation studies must be performed for aseptic processing, 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. Risk mitigation is central to Quality by Design (QbD) and Quality Risk Management (QRM), and increasingly, ways are sought to build quality into production steps, to reduce risk to the patient. With respect to aseptic processing, this includes a thorough understanding of the design space for sterile filtration.

Although Pall will readily accommodate specific end user requirements for filter validation testing, in accordance with the guidelines indicated in PDA Technical Report 26, Pall recommends that test filters be sterilized using the same method as used in the customer process. A filter that is gamma irradiated may produce a different extractables profile compared to a steam sterilized filter of the same membrane type and configuration. Consequently, to cover these potential chemical differences, two sets of extractables testing would be required.

Although Pall will readily accommodate specific end user requirements for filter validation testing, in accordance with the guidelines indicated in PDA Technical Report 26, Pall recommends that test filters be sterilized using the same method as used in the customer process. A filter that is gamma irradiated may produce a different extractables profile compared to a steam sterilized filter of the same membrane type and configuration. Consequently, to cover these potential chemical differences, two sets of extractables testing would be required.

The purpose of this paper is to outline the approach for performing bacterial retention testing on bactericidal fluids, and to provide the scientific rationale for selection of a surrogate solution when the process fluid is determined to be bactericidal.

Water systems for the production, storage, and distribution of purified water are critical points in pharmaceutical production plants. A key concern of regulatory authorities is the installed vent filter on high purity water-holding tanks. This document provides Pall’s technical recommendations to meet current regulatory requirements on the topic. 

Risk mitigation is central to Quality by Design (QbD) and Quality Risk Management (QRM); one way of capturing the aspects of science and risk for product quality is to adopt a Question based Review – Quality Overall Summary (QbR-QOS) approach. This document provides details about this approach and describes its advantages and benefits to the applicants.

Regulatory agencies expect filter validation studies to be conducted using the worst-case conditions. “Worst-case” refers to a set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions).

This document details factors to consider for filter re-use, defines the potential risks of filter re-use, and outlines a strategy for end-users who wish to justify re-use of sterilizing grade filters in liquid services.