Sterile filtration integrity testing

Filters for use in sterile gas filtration must conform to standards similar to those mandated for sterile hquid filtration. Nondestmctive integrity tests may be apphed. The tests are performed by wetting the filter with an appropriate solvent, commonly 60/40 isopropyl alcohol/water for hydrophobic membranes, and applying air or nitrogen gas at a preset pressure. 

Performed the forward flow integrity test (using WFI as wetting liquid) before and after final sterile filtration according to SOP and per MFM. Forward flow results for final sterile filtration of media fill run 1, run 2, and run 3 are found satisfactory. 

Unlike sterilizing and virus removal filters, tangential flow filtration (TFF) filters are often reused. Flow and integrity tests are necessary to ensure the filter remains the same after usage and cleaning. Consistency of filtrate and retentate streams is validated using relevant validated assays that are specific for each process and product. 

When the filter integrity test fails, the sterile filtration process must be rejected. 

Retention is a function of the pore size distribution of the membrane, solution properties, and operating conditions. For critical applications such as sterile or virus filtration, retention should be tested with the actual solution under different operating conditions. Typically, membrane filters are tested for integrity before use to ensure the required retention is obtained during operation. Integrity tests are based on bubble point or diffusion [6]. 

In a typical application, the filters are sterilized by autoclaving or steaming in place and flushed with water for injection or buffer before filtering the actual process solution. A postuse integrity test is performed after the product solution has been filtered to ensure that the required retention performance was obtained during the filtration process. 

Perform the system integrity test before and after each sterilization program of the filtration system. 

The integrity of sterilizing fillers is most often validated and routinely monitored by nondestructive methods. The U.S., European, and U.K. guidelines on sterile filtration refer to four methods of integrity measurement filtration flow rate, bubble point tests, diffusion (forward flow) tests, and pressure hold tests. Each of these has its uses in determining that routinely used filters are per-forming to the same standards as those validated for the particular products and processes. 

Although it might seem reasonable to consider microfiltration and tighter filtration as sterile and an alternative to conventional sterile filtration, this temptation should be avoided. Because it is not presently possible to test the membrane s integrity, it is impossible to know if larger pores or microscopic tears are present. In fact, we have observed the use of ultrafilters in a sterile filtration application where Zygosaccharomyces present in the permeate at >10 GFU/mL. 

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