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The authors describe a new assembly for bulk and final drug product filling operations.
Increased regulatory expectations and the need to mitigate risk have popularized the use of redundant filtration for bulk and final fill operations. Single-use redundant filtration (SURF) assemblies are an efficient and flexible alternative to stainless steel systems because they eliminate clean-in-place (CIP), sterilization steps and the associated validation protocols. Preparation time can also be significantly reduced when using single-use assemblies because of their presterilized format and the ease with which they can be handled. Redundant filtration operations in multiproduct facilities can be performed without spending the extra validation time that is often required for non-disposable systems.
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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.
As 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.
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.
Pre-use, post-sterilization 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 minimize product dilution. Figure 1 outlines the utilization sequence for SURF assembly before use. Along with the points mentioned above, operator convenience and regulatory compliance were also considered.
A flushing test was conducted to record the reduction of total organic carbon (TOC) and conductivity with flush volume. The filters and assembly were flushed with deionized (DI) water at a flow rate of 250 mL/min for a total of 20 L. The assembly effluent was sampled at 1 L intervals and tested for conductivity and TOC. Analytical results for flush filtrate samples are summarized in Figure 2. At the end of 20 L reverse osmosis (RO)/DI water flush, TOC and conductivity were 0.231 ppm and1.1 μS/cm, respectively.
Traditionally, the comparison of single-use versus stainless-steel processes is made on the basis of consumable cost versus capital cost, but other costs must also be taken into account to make an accurate comparison, including labour, validation and quality. Selection of the cost minimum option depends on the specifics of the application and accurate accounting of the associated costs of each technology. Labour rates and process costing assumptions are taken from Biosolve cost modelling software (Biopharm Software Solutions). Tables I and II summarize the results of the cost analysis for a typical redundant filtration process using two 10 in. cartridges. The costs assumed here are representative of industry costs; it is assumed that difference in cost for utilities and materials (e.g., CIP solution, water for injection) does not significantly affect the cost comparison. The costs of pump and extractables–leachables validation are similar for both stainless steel and singleuse setup, so these costs were excluded from the analysis.
Table I: Capital and validation cost. Capital and validation costs are taken over 10-year expected lifetime of the facility.
SURF assemblies offer further benefits over stainless-steel setups. Equipment turnover for new products is quicker with single use assembly. For example, additional testing and cleaning time associated with equipment release and documentation is reduced or eliminated if singleuse technologies are used. It also provides more production flexibility because single-use assemblies can be made to order in the size and configuration required with the need for additional equipment or validation. It also eliminates the need to have multiple setups in place to meet the production demands of different products.
Table II: Cost per batch. The cost calculations in this table are based on 12.5 h batch time for stainless steel setup and 6.5 h batch time for single-use assembly. The batch time is lower for single-use assembly due to elimination of preparation steps, cleaning procedure and ease of handling.
This study identified a suitable design for redundant filtration operations by utilizing single-use technology. An optimized utilization sequence for preparatory steps was designed and tested. Conducting a pre-use integrity test on a pre-sterilized 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 minimize 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, is a process engineer II; Michael Felo, is an applications engineer consultant; and George Oulundsen, is a process engineer III, all at 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, (Sept. 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 Intl. 4 (6), 44–47 (2006).