In the pharmaceutical, biotechnology, and vaccine industries, filters are key to ensuring product safety. With increasing economic pressure and market competition, these industries are exploring new ways to reduce costs and improve efficiency, one of which is considering the reuse of sterilizing-grade filters. Although these filters are typically designed for single use to guarantee sterility standards for a single batch or production cycle, in practice, they may be used multiple times for cost reasons. However, this practice brings potential risks and poses severe challenges to quality control, as reusing filters can affect product safety and efficacy and may even lead to cross-contamination. Therefore, how to find a balance between cost reduction and maintaining product quality is an important topic in current process optimization.
Reuse of Liquid Filters
In the previous article on "Bacteria-Reduction Filtration," we mentioned three reuse scenarios for liquid bacteria-reduction filters: flushing between batches, flushing and sterilization between batches, and cleaning, storage, and sterilization between batches. In fact, this can be further divided into the following five reuse methods:
• No moving, flushing, cleaning, disinfection, or re-sterilization required.
• Flushing only between different batches.
• Both flushing and re-sterilization between different batches.
• Flushing, cleaning, and re-sterilization between different batches.
• Intermittent use with drying between batches.
Method 1: No Moving, Flushing, Cleaning, Disinfection, or Re-sterilization
The filter is sterilized before initial use and remains in place, with no other operations between batches.
Advantages: External forces on the filter (such as heating, contact with corrosive liquids, etc.) are minimized.
Risk Factors:
• Microbial Survival: Viable microorganisms from the previous batch may remain.
• Membrane Penetration: Prolonged microbial growth could lead to membrane penetration.
• Microbial Penetration: The risk of microbial penetration from prolonged use cannot be assessed by integrity testing alone.
GMP: According to EU and China's 2010 GMP, the filter usage period should not exceed one day.
Method 2: Flushing Only Between Batches
Between each production batch, the filter is flushed only with water or other solvents, with no additional measures taken.
Advantages: Reduces residue of components from the process solution and lowers the risk of cross-contamination between batches.
Risk Factors:
• Microbial Penetration: There is a risk of the membrane being penetrated by microorganisms growing over an extended period.
• Endotoxin Contamination: The downstream solution may be contaminated with endotoxins.
Method 3: Flushing and Re-sterilization Between Batches
Advantages: Can reduce microbial penetration issues caused by prolonged use and help control potential biofilm formation.
Risk Factors:
• Risk of Inadequate Flushing: If the filter is not thoroughly flushed, re-sterilization may lyse microorganisms, leading to elevated endotoxin levels in the next batch.
• Risk of Chemical Degradation: If product component residues are not completely flushed out, the re-sterilization process may trigger chemical degradation reactions, causing additional chemical reactions with the filter.
Supplier Validation: Typically, suppliers have validated that intact filters, wetted only with water, can withstand multiple autoclaving or SIP cycles.
Method 4: Flushing, Cleaning, and Re-sterilization Between Batches
Advantages: Effectively reduces the risk of cross-contamination and microbial by-products.
Risk Factors:
• Limitations of Integrity Testing: Integrity testing may not detect all potential filter issues.
• Chemical Compatibility Issues: Cleaning agents may have incompatible chemical reactions with the filter material.
• Impact of Residues: Residues of product components or cleaning agents may have a more severe impact on the filter during re-sterilization.
Method 5: Intermittent Use with Drying Between Batches
The entire process includes flushing, cleaning, re-sterilization, and drying steps.
Risk Factors:
• Concentration during Drying: During the drying phase, product components, cleaning agents, or other impurities may become concentrated, which could exacerbate chemical reactions.
The above introduces different reuse methods and their pros, cons, and potential risk factors. In various situations, to save on filtration costs, end-users may consider reusing filters. Therefore, all related processes and reuse conditions must be strictly validated to ensure they do not affect the filter's bacterial retention efficiency and the accuracy of integrity testing.
Considerations for Reusing Liquid Sterilizing Filters
Each application has specific requirements and risks regarding bioburden control and sterilizing filtration. In addition to considering process conditions such as flushing, cleaning, re-sterilization, and drying, the suitability of reusing a filter in each application should be evaluated individually based on the sterility assurance level and its impact on the filtrate. Therefore, the criticality of the filtration process should also be part of the risk assessment. Based on the risk assessment, some non-critical process points may not require the highest level of sterility assurance.
Figure 6. Degree of Reuse Risk under Different Application Requirements)
For Filter Cartridges Used in Terminal Sterilization Processes
Since it is not used for sterilizing filtration but serves to reduce the microbial load beforehand, it is not recommended to cross-use filter cartridges between different products.
For these filters used for terminal sterilization and microbial load reduction, current domestic and international regulations and GMP standards do not explicitly prohibit this practice. In fact, filter reuse does exist in industrial practice. If a company decides to reuse filter cartridges, corresponding research and validation work must be conducted, focusing on cleaning validation. Since the filter is not for terminal sterilization, the validation focus is not on microbial retention capability but should be based on the planned usage cycle and the filter's cleaning status, paying special attention to the filter's performance changes before and after cleaning.
Strategy for Reusing Filters in Critical Applications
For sterilizing filters used in aseptic processing, both China's GMP and Europe's GMP have relevant recommendations. EU GMP recommends changing the filter after each batch, while China's GMP stipulates changing the filter within 24 hours, i.e., after each production batch. Although neither recommends reusing sterilizing filters for aseptic processing, it is not an absolute prohibition. If a company insists on reuse, the required work can be complex, so it is not recommended. For filters used at the front end of injectable production to remove visible particles and insoluble particulates, it is recommended to refer to the previously mentioned requirements for terminal sterilization filters and consider and manage the reuse of these filters accordingly.
A final sterilizing filter is typically used in series after a bioburden control filter. Using dual or redundant sterilizing-grade filters (0.2 or 0.1μm) is common. In such a dual-stage filtration system, the upstream filter can be reused while the final filter is used once to achieve a balance between economy and safety; or the final filter from the previous batch can be reused as the upstream filter for subsequent batches. In each application case, the cost savings from reuse must be weighed against the increased risks of premature filter clogging, integrity issues, increased extractables contamination, or bacterial penetration.
*(Figure 7. Reuse Methods in Redundant Filtration Applications)*
Summary
Filter reuse must be strictly controlled to ensure the filter is safe and effective and complies with the manufacturer's recommended usage parameters. Reuse of sterilizing-grade filters must include flushing, cleaning, and re-sterilization, and each step must be designed, constructed, and validated. The grade of water and chemicals used should be documented in detail, and all chemicals and filtrate should be disposed of according to regulations. The reprocessing steps and filter performance test results should be truthfully recorded. Before reuse, the filter must be tested for integrity, absence of pyrogens, removal of residues and by-products from the previous batch, and its performance and time limits must be validated. Validation should consider factors such as pH, viscosity, flow rate, pressure, and temperature, and control methods should be established to ensure the filter does not contaminate subsequent batches. Despite the risks, some pharmaceutical companies, based on established product and process-specific reuse protocols, will reuse sterilizing filters in practice. Specific cases will be detailed in a follow-up.
References
• J. Martin, "Considerations on Re-Use of Sterilizing-Grade Filters", Pharmaceutical Technology, Sterile Manufacturing, Aseptic Processing (2008).
• Martha Folmsbee, Ph.D. & Dr. Gabriele Geerligs, Re-Use of Sterilizing Grade Filters - Considerations and Risk Assessments Technical Rationale.
• US FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing: Good Manufacturing Practice, FDA (2004).
• EU Guidelines to Good Manufacturing Practice - Medicinal Products for Human and Veterinary Use - Annex 1 - Manufacture of Sterile Medicinal Products (2022).
• PDA, "Sterilizing Filtration of Liquids," Technical Report No. 26, PDA (2008).