Effective filtration is vital to process protection and factors such as filter selection, testing and optimization can have an impact on process risk. Here we examine the factors to consider when implementing normal flow and tangential flow filtration systems into biopharmaceutical manufacturing processes in order to maximize process protection.
Normal flow filtration
With normal flow filtration, the selection of an appropriate filter for the product stream at any given point will primarily be driven by the level of retention required.
In some circumstances, a highly retentive filter such as PROPOR MR may be required to remove diminutive organisms such as mycoplasma from process fluids. However, implementing an extremely retentive filtration step where it is not required will only create an additional burden on the process.
It is therefore important to understand precisely what is appropriate at each stage.
Sterilizing-grade filters such as PROPOR SG and PROPOR HC ranges are frequently employed, and correctly so in many aspects of biopharmaceutical production. However, employing a sterilizing-grade filter where only bioburden control is needed will require an oversized filter stage: this may potentially restrict the process and will create the need for additional filter integrity testing steps.
In many cases, downstream processing stages are not truly sterile — chromatography being the prime example — and therefore in this example, a bioburden control filter such as PROPOR BR will provide sufficient process protection without risking unnecessary additional process operations.
Integrity testing protocols should be designed to provide assurance of filter integrity in accordance with regulatory requirements, but must also be balanced against introducing further process risk. Additional flushing and testing operations may confirm that the filter is still fit for purpose but they can also create a risk of contamination. In addition, from a product safety perspective, the data provided may be redundant when further post-use integrity testing is performed anyway.
Vendor assistance should be requested during filter sizing exercises. The filter supplier may be able to offer additional experience, which can be brought to bear in advising on a specific filter and application pairing: this may not be immediately apparent if the operator only relied upon data from a single bench top capacity study, which would not take into account the effect of long-term process variation upon filter performance.
Operating and testing procedures should be designed to deal with troubleshooting aspects of filter use. If, for example, a filter blocks prematurely due to process variation, or if an integrity test fail result is returned, are these eventualities written into the operator protocols? And has the vendor provided input regarding best practice in each case?
Tangential flow filtration
When utilizing tangential flow filtration, the membrane cut-off used to achieve the appropriate degree of retention or transmission is clearly important.
However, it is always good practice to ensure that the process has been optimized to provide repeatable performance under defined operating conditions. For example, faster processing or better membrane recovery can be achieved through optimization studies. If these studies are not performed, this may have a detrimental effect on process efficiency or even quality.
Module format should also be considered: cassettes and hollow fibres are commonly used but may provide advantages in certain situations arising from process needs.
In some applications, aseptic closed-loop processing may be highly beneficial. For example, some vaccines are too large to be sterile-filtered and therefore processing in a pre-sterilized single-use system is ideal. This means that gamma-stable cross-flow elements with very low extractables content, such as the single-use PROPOR TFF product, are very beneficial.
In any application, process systems should also be designed to maximize product yield through the elimination of unnecessary tubing or pipework and minimizing any potential for product to be lost within the process.
Finally, sterilization methods should be considered. If gamma irradiation is used, a product such as Parker Bioscience’s single-use PROPOR TFF element is required. On the other hand, if autoclave sterilization or caustic sanitization are implemented, products such as the PROPOR TFF autoclavable or reusable elements would be appropriate.
Now watch our webinar to find out more about how to protect your biopharmaceutical manufacturing process.