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12 Pharmaceutical Technology ® Quality and Regulatory Sourcebook eBook March 2024 PharmTech.com Aseptic MAnufActuring operating conditions during steam sterilization, preventing any damage. • Gamma irradiation resistance: Single-use as- semblies utilize filter capsules. These filters are resistant to gamma irradiation up to 50 kGy. The gamma irradiation method is validated to show proof the assembly is sterilized, and the assem- bly and filter membrane are compatible with the sterilization method, without damage. • Minimal extractable substances: Even when used straight out of the box, these filters release extremely low levels of extractables, which have been published and are detailed in qualification documentation from the filter manufacturers. • Mechanical resistance: Modern sterilizing filters can withstand 25,000 pulsations at a pressure dif- ference of 70 psi (5 bar), ensuring their durability and reliability. Such tests are performed by filter manufacturers to assure the product robustness. • Low unspecific adsorption: Most filters have been optimized to greatly reduce the amount of un- specific adsorption, which is of importance to avoid the retention of target proteins or other important fluid components, for example polysorbate. • Optimal total throughputs: Some filters are de- signed to provide the highest possible volume of filtration, effectively reducing the cost per liter of filtered material. Highly asymmetric and heter- ogenous double layer filter designs are through- put focused filter types. • Optimized flow rates: Some filters are engineered to achieve the most efficient flow rates, which can reduce processing times or the required filtration area. In this case, the filters have a high pleat den- sity and therefore effective filtration area and are typically single layer membranes. • Integrity testing: Sterilizing grade filters must be tested for their integrity using non-destructive methods such as diffusive flow, pressure decay, or bubble point tests. These tests have been success- fully used for decades and are a reliable must-do test post-use. • Full qualification documentation: The filters come with comprehensive qualification docu- mentation, which lists a multitude of tests, for example, endotoxin release, Plastic Class VI, etc., ensuring that they meet the necessary regulatory standards. • Individual process validation: The filters un- dergo process validation specific to the drug product being filtered under process conditions, confirming their compatibility, performance, and retentivity. ∙ Every sterilizing-grade filter is individually integrity tested by the filter manufacturer, as a release criterion for the product. ∙ The filter suppliers also recommend necessary shelf-life data for filtration and single-use as- sembly products and validate the packaging and transportation of these components to assure the product are not damaged. Major filter manufacturers have not only improved their production processes to achieve these features but have also collaborated with the biopharmaceuti- cal industry to develop reliable solutions. By invest- ing in research and development, manufacturers have enhanced the safety and economic efficiency of the aseptic filtration process. Filter production processes adhere closely to pharmaceutical quality standards, with input received f rom the pharma- ceutical industry and regulatory authorities (2). This continuous collaboration and adherence to industry requirements have made manufacturers more f lex- ible in meeting the specific needs of the biopharma- ceutical industry. However, the mechanical, thermal, and chemistry improvement of modern sterilizing-grade filters is still not fully recognized by all regulators. Some still hold an outdated and biased perspective, viewing fil- tration as a poorly controlled and unreliable method of sterilization. This does not represent the modern state of the filtration industry, nor recognize and sup- port the necessity of this sterilization method for the biopharmaceutical industry. An example of this view is the generic enforcement of pre-use post steriliza- tion integrity testing, which is considered by some to be a necessary means to enhance filtration processes but often creates a much higher risk to such. Review and discussions of Annex 1 sections Annex 1 section 8.87 states: "The integrity of the ster- ilized filter assembly should be verified by integrity testing before use (pre-use post sterilization test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use" (1). Ex- ecution of this integrity testing requires the sterile filtrate side be manipulated before the filtration pro- cess starts and therefore represents a risk elevation as one cannot assure that there may be an accidental ingress on the sterilized filtrate side due to the ele- vated complexity and potential mishandling. As ment ioned in t he prev ious sect ion, ster i liz- ing-grade filters are much more robust than one is made to believe in section 8.87. The filter installation and steam sterilization are documented in standard operating procedures and performed by end users. Most steam sterilization cycles are automated and at least fully qualified to avoid any excess of tempera- ture or differential pressure/temperature conditions. Assuming a steam sterilization cycle is not run appro- priately, and damage happens to the filter, the dam- age is typically catastrophic and will be detected by