Flow maintenance

PharmTech: How can manufacturers maintain product flow or prevent it from decreasing during adjuvant filtration?

Bromm (Sartorius Stedim): For the manufacturer of the adjuvants, it is important to study and understand the process variables involved in making the adjuvant. The process variables identified to have a significant impact on the filterability of the formulation should be controlled carefully and kept within a narrow operating window. This will enable constant performance of the filtration process within established process parameters.

If a specific flow rate is desired over the duration of a filtration operation where the potential for plugging exists, the filtration operation should be performed under constant flow mode using an appropriately sized filtration area. Product flow can be maintained by increasing the inlet pressure as needed. Throughput of complex biological fluids often benefits from operation in this constant flow mode, as opposed to operating at high initial pressure and allowing flux to decay as the filter plugs.

With adjuvanated vaccines, or similar products at risk for reduced bacterial retention efficiency, preliminary filterability trial performed at the initial stages of process developments can identify filters providing the highest level of sterility assurance for further formulation or process optimization, perhaps including limited microbial challenges to confirm initial suitability. Further filterability studies can then focus on optimizing process time and economy under operating parameters known to further increase bacterial retention likelihood with these highest assurance filters. This will maximize both retention and throughput to provide for successful sterilizing filtration, validation, and processing.

Koklitis (3M): As mentioned, the careful management and control of the operating conditions during process filtration is usually advantageous for achieving consistency and robustness. In addition, the choice of filter membrane type can can contribute to maintaining a consistent flow. An asymmetric membrane structure, with a more open upstream zone, can provide a relatively higher initial flux, for example, which results in higher filter capacity for some process streams.

A higher filter surface area can be obtained per cartridge cylinder by selecting products that use advanced pleat technologies, thus enabling higher throughput without increasing filter system size. This approach may help with filtering highly viscous process streams, such as emulsions.

Powell (Asahi): Large areas of membrane is the brainless solution, but working with filter vendors and doing DOE-based filter screening under the desired, "high stability" API conditions is the better choice.

Just like in horse racing, where some horses perform better than others on different courses, choosing the right filter type or perhaps a cascade of filters can solve the problem and provide a balanced solution to your filtration problem. If your feed contaminant is primarily a slowly precipitating molecule of some sort, a relatively small coarse filter such as a 1 µm or 5 µm might be able to trap it and allow a medium-sized sterile grade filter handle the higher flow rate and process larger volumes.

Depth filters often provide significantly higher capacity than membrane filters so placing them upstream of a sterile grade filter is often a good idea when possible. As with any filter, but especially depth filters, a study of undesired reduction (by binding) in solution components should be considered. Find a balanced approach to this cascade of filters, with each filter sized appropriately to deal with and control the specific contaminant that causes the processing roadblock.

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PharmTech: Manufacturers are increasing the use of oil-in-water emulsions and liposome adj uvants as a cost-effective way to meet worldwide vaccine demand. Can one reduce the time required to filter such adjuvanted vaccines?

Bromm (Sartorius): It is important to select in a filter-screening study the optimal filter or optimal prefilter/final filter combination for the actual adjuvants formulation. This selection helps to achieve moderate process parameters and also to keep filtration time on an acceptable level. The use of prefilters is advisable to reduce the particle challenge for the final sterilizing grade filter and to maintain flow rate on high level consequently reducing filtration time. There is a broad range of membrane- or fleece-based prefilters available providing a broad range of pore size distributions and retention effectiveness which may be beneficial to maintain the performance (i.e., flow rate) of the filtration system on a high level, thus reducing filtration time. Therefore adjuvants filtration must not be necessarily a highly time consuming exercise.

Martin (Pall): Use of appropriate filter sizing allows the user to find a balance between process cost and processing time. Once a suitable filter is selected based on flux properties and bacterial retention assurance, the appropriate filter sizing required to process the fluid in the desired time under available inlet pressure without plugging can be established. Process time for a given batch volume is determined by filter porosity (flux), inlet pressure, and filter area. For a given filter medium, process time can be reduced by increasing available maximum inlet pressure or by increasing filter area. If the time consumption referred to here, is the time requested to optimize and validate a filtration process, then a confident partnership between the filter manufacturer and the vaccine producer at an early stage of process design will help reducing timescales. It can help selecting the filter (membrane type, rating, surface area, filter geometry), the filtration conditions (flow rate, maximum pressure drop, time, temperature), and as far as possible, fluid formulation (adjuvant type and concentration) to get the best compromise in terms of filtration throughput and retention efficiency.

Koklitis (3M): Any adjuvant filtration process step is best approached by initially performing a screening study to correctly size and select an optimal filtration system. The aim is often to provide the shortest processing time subject to whatever spatial and economic constraints exist. Operational time can be saved by taking care not to disrupt emulsions in process streams during filtration, such as avoiding variable feed pressures and any disturbances in flow.

Rabin (Asahi): Choose a filter or filter cascade that is compatible with your adjuvanted vaccine. Understand what the contaminants are. Understand your API in this adjuvanted solution and what it takes to keep it stable. Depth filters typically can provide higher capacity than membrane.