This article identifies a suitable design for redundant filtration operations using single-use technology and standardized assembly components. The design was finalized 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 EXPECTATIONSAs defined in PDA Technical Report 26, redundant filtration is a "type of serial filtration in which a second sterilizing-grade filter is used as a backup in the event of an integrity failure of the primary sterilizing filter." The pore size of the sterilizing-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 FDA's aseptic processing guidelines published in 2004, it is recommended that redundant filtration should be considered in many cases where liquid is sterilized by filtration (2). EMA's 2008 GMP guidelines state that because of potential risks of sterilization 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, 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 sterilize, 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 presterilized 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
Many biopharmaceutical companies already use variations of SURF assemblies for final and bulk fill operations. However, preparation and utilization sequences may differ across processes and geographies because of differing national guidelines.
This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly that has greater operational robustness and minimizes 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.