No abstract
Sterile filters are ubiquitous in biopharmaceutical manufacturing processes. Because such filters are in direct contact with the process fluid, profiling of the extractables is of utmost importance. The work presented here reveals the extractables profile from filter cartridges for sterilizing-grade filtration, which were obtained from six different vendors. All filters contain a 0.2 μm polyethersulfone membrane for sterile filtration combined with a polyethersulfone pre-filter with retention rates spanning from 0.4 to 0.6 μm. These filter cartridges are designed for use in stainless steel housings which allow for in-line steam sterilization. A combination of different analytical techniques such as (headspace) gas chromatography-mass spectrometry, ultra-performance liquid chromatography-high-resolution mass spectrometry (electrospray ionization), inductively coupled plasma mass spectrometry, total organic carbon, non-volatile residue, conductivity, and pH value were applied to develop a comprehensive extractables profile on a qualitative and semi-quantitative basis. Pure ethanol and purified water were used as extraction media. The extractables profile consisted of various polyolefin-related extractables, additives such as antioxidants and degradation products thereof, hydrocarbons, and processing aids in addition to membrane-related extractables. Filter cartridges or other filter products for sterile filtration are currently most commonly made of polymeric materials such as polypropylene, and a filter membrane material such as polyethersulfone. These materials will usually release chemical substances upon extraction in the laboratory (), or upon application in biopharmaceutical processing (). Potential extractables and leachables are additives used to tailor the physicochemical properties and to protect the polymeric materials, or degradants of these substances, or they arise from substances used during the manufacturing of the filter cartridges. Multiple analytical techniques were applied here to investigate the concentration and chemical nature of extractables obtained upon application of two distinct extraction solvents. Typical extractables found were antioxidants or releasing agents in addition to compounds originating from the polyethersulfone membrane.
Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. The sterility of such liposome solutions is typically ensured using 0.2 μm-rated sterilizing-grade membranes, but due to the high viscosity and low surface tension of these formulations, they can cause premature blocking and increased risk of bacterial penetration through a 0.2 μm sterilizing-grade membrane. The low surface tension of liposome solutions affects the contact angle with membrane and reduces bubble point, leading to bacterial penetration through the membrane. This poses a great challenge to select an appropriate sterilizing-grade membrane for a given process and for filter manufacturers to develop a sterilizing-grade membrane that specifically addresses these needs. In this study, the influence of different variables that could affect the total throughput and bacterial retention performance of different membrane types on processing of liposome solutions was evaluated. Based on the results, we conclude that the membrane properties, for example, surface porosity, surface tension, pore size, symmetry/asymmetry, hydrophilicity and liposome properties (e.g., composition, lipid size, and concentration) affect bacterial retention and total throughput capacity. Process parameters such as temperature, pressure, and flow should also be optimized to improve process efficiency. Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. Liposome solution cause premature blocking and increased risk of bacterial penetration through a 0.2 μm sterilizing-grade membrane due to their high viscosity and low surface tension. In this study, we demonstrated the total throughput and bacterial retention performance of different sterilizing-grade membranes with liposome solution. Based on the results, we conclude that some sterilizing-grade membranes yield less throughput and bacterial retention compared to other membranes. This is due to liposome formulation and membrane properties. Therefore, it is important to identify the product formulation and membrane properties before selection of a suitable sterilizing-grade filter for a given process application to ensure expected throughput and bacterial retention.
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