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Single-Use Redundant Filtration
This article identifies a suitable design for redundant filtration operations using single-use technology and standardised assembly components. The design was finalised with input from a global technical and quality team with consideration given to international regulatory requirements. The article also demonstrates the capability of the assembly to withstand the high pressure that is used for integrity testing and drying. Pre-use integrity testing was performed on both filters. Using hydrophilic/hydrophobic filters on the assembly outlet eliminated flush volume limitations caused by catch bag size. Assembly specifications, such as leachables and extractables, hold up volume and flushing requirements, were established for a single-use assembly.
Meeting regulatory expectations
As defined in PDA Technical Report 26, redundant filtration is a "type of serial filtration in which a second sterilising-grade filter is used as a backup in the event of an integrity failure of the primary sterilising filter." The pore size of the sterilising-grade filters may be the same or tighter than the primary filter (1). Other regulatory bodies (e.g., FDA, EMA and SFDA) have also issued their own guidelines for sterile filtration. According to the FDA's aseptic processing guidelines published in 2004, it is recommended that redundant filtration should be considered in many cases where liquid is sterilised by filtration (2). The EMA's 2008 GMP guidelines state that because of potential risks of sterilisation by filtration, a second filtration step as close to the filling point as possible is advisable (3).
Designing a redundant filtration system that meets regulations and recommendations is challenging. For stainless steel systems, the EMA recommends that integrity testing should be performed on sterile filters before use. To do this, filters must be fully wetted without breaching the sterility on the downstream side of the assembly. Many conventional stainless steel facilities employ a "catch can" with a sterile vent filter to collect the initial flush liquid from the wetting step. Prior to use, additional time is required to sterilise, maintain and store the catch can. In addition, use of a catch can constrains the total flush volume that can be used if the filters need to be rewetted (e.g., in a repeated filter integrity test).
Disposable or single-use redundant filtration (SURF) assemblies offer a flexible solution for this relatively complex operation (4). These assemblies can be presterilised by the supplier using gamma irradiation and there is no need for cleaning after use because assemblies are self-contained and entirely disposable.
Proposed single-use process solution: design considerations
This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly
that has greater operational robustness and minimises the risk of product contamination. Below are the major design considerations
for the assembly (see Figure 1):
The catch bag on the first liquid filter is primarily in place to avoid the liquid spill that can occur during venting for water flush and product filtration. With some minor modifications, the catch bags on both the first and second liquid filters can also be used for in-process sampling. The catch bag on first liquid filter and the separate air inlet line (with an air filter near the feed inlet) are additional features that are incorporated to ensure cleanliness and ease of operation.
Pre-use, post-sterilisation integrity testing of a redundant filtration setup can be challenging. With either stainless steel or a singleuse assembly, it is critical to maintain setup sterility during every step. The efficiency of the filter wetting step is also important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. Figure 1 outlines the utilisation sequence for SURF assembly before use. Along with the points mentioned above, operator convenience and regulatory compliance were also considered.
This study identified a suitable design for redundant filtration operations by utilising single-use technology. An optimised utilisation sequence for preparatory steps was designed and tested. Conducting a pre-use integrity test on a pre-sterilised redundant filtration setup can be challenging, but an effective filter wetting step is important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimise product dilution. All preparatory steps and filtration operations can be successfully performed on a single-use assembly. SURF assemblies are robust and efficient disposable solutions for bulk and final fill processes.
Ranjeet Patil process engineer II
Michael Felo applications engineer consultant
George Oulundsen process engineer III EMD Millipore
1. Parenteral Drug Association (PDA), Journal of Pharmaceutical Science and Technology, 62 (S-5), (2008).
2. FDA, "Sterile Drug Products Produced By Aseptic Processing—Current Good Manufacturing Practices (Guidance for Industry)," Sep. 2004 (Rockville, MD).
3. European Commission, "Guidelines to Good Manufacturing Practice—Manufacture of Sterile Medicinal Products," Annex 1, Nov. 25, 2008 (Brussels, Belgium).
4. Lentine et al, Bioprocess International, 4 (6), 44-47 (2006).