PUPSIT - A new challenge in GMP manufacturing

PUPSIT performs an integrity test on a filter used in a critical application. The test ensures that the sterilization or installation has not damaged the filter, often at the final stage of product manufacturing.

The primary aim of PUPSIT is patient safety, where the packaged pharmaceutical product must be free of viable microorganisms. However, implementing PUPSIT involves a more complicated process design and operation, which increases the risk of contamination of the filtered product.

“The new revised Annex 1 directives requiring PUPSIT will be a major challenge for our customers. At Colly Flowtech, we have a long experience in helping our customers to solve this type of technical difficulties. We know that our customers want and should focus on developing and manufacturing breakthrough drugs. That's where we can add incredible value by letting Colly Flowtech help design a PUPSIT single-use system that is tailored to the customer's process. Together with our partner Parker, we offer the perfect mix of world-leading filters and technical expertise in single-use system manufacturing. This allows us to meet the customer's needs in an efficient and reliable way,” says Viktor Fredriksson, Product Manager at Colly Flowtech

The challenge of PUPSIT

You need to carefully assess how to include PUPSIT in a process. Design PUPSIT to ensure that sterility on the downstream side of the sterile filter is not affected. There is no universal method, but you can follow some guiding principles to apply PUPSIT:

• Minimize connections on the sterile side to reduce the risk of leakage/entry points.
• Minimize the influence of liquid to wet the filter to reduce product waste.
• Maximize the reproducibility of the wetting process to reduce the need for rework and testing.
• Handle waste liquids and gases efficiently on the sterile side to protect the process fluid.
• Optimize filter integrity testing to reduce the risk of operator error and time that can affect quality and productivity.

What should you consider when implementing PUPSIT?

Design single-use system with as few connections and components as possible, and ensure that they are ergonomic for both installation and operation. The potentially higher pressures associated with the integrity test may require different type of tubing or other system components. 

Filter selection

In addition to the sterile filter, you need to consider whether you need a pre-filter to reduce contaminants that may affect the rinsing of the sterile filter.

You may also need to implement an extra step for sterile filtration to reduce the risk of the post-use integrity test failing. By implementing PUPSIT, you show that the primary filter keeps the integrity at the beginning of the process, and if it works within validated process parameters, this will not change. But you need to weigh the risk of not including extra filtering, as it may be too high. Moreover, adding more filters increases the complexity of the system and extends the sterile pathway within the system.

You may also need to use filtration when gases or other liquids enter or leave the process to maintain the sterile barrier.

Choice of filter integrity test method

Filter manufacturers, and distributors such as Colly Flowtech, have the technical expertise to advise on the best integrity test method for the type and size of filter chosen for the process.

Most common is either the bubble integrity test or diffusive flow integrity test - it is important that the system can withstand the pressures involved in these tests.

PUPSIT is only required on the product sterilizing filter; other filters in the process can be removed and tested after use.

Moisture death

The objective of wetting is to ensure that the pore structure of the filter membrane is fully wetted to prevent gas flow through dry areas that may adversely affect the integrity test result. Gas passes easily through dry pores.

You can wet the filter with water, a buffer solution or the product itself. Each method has its pros and cons, with cost, design complexity and product waste being some factors you need to consider. In addition, you will need to validate the integrity test parameters when not using water for wetting - this service is usually offered by the filter supplier.

The PUPSIT environment

The PUPSIT system should be placed as close as possible to the filling operation. For a single-use system, this adds complexity when the filling operation takes place inside an isolator or a restricted access barrier system also called RABS.

Factors to consider when implementing PUPSIT are:

• PUPSIT requires handling of connections, movement of valves, handling of flush and waste packages and possible rotation of the sterile filter capsule. When the operator has to perform these manual operations with isolation gloves, the difficulty of the work increases.
• PUPSIT requires you to increase the system pressure on the non-sterile side of the sterile filter. You also need to consider the risk of liquid or gas leakage as a possible source of contamination.
• The physical size of the PUPSIT system may limit the design/operation with the available space.
• There will be an impact on productivity through the installation and execution of PUPSIT.

Use Colly Flowtech support

PUPSIT requires a high degree of planning to ensure that the system design and operation are safe, repeatable and reliable, do not compromise the sterility of the product and do not pose a burden on operators.

Colly Flowtech, together with Parker, can provide technical support to biopharmaceutical manufacturers. We can help with filter selection, effective filter wetting and integrity testing methods, sterile filter validation, system design, operation and much more!

This text is written by Viktor Fredriksson, Product Manager at Colly Flowtech using Parker bioscience filtration. The original text “PUPSIT - What do you Need to Consider?” is written by Paul Hymus, filtration product manager, Parker bioscience filtration, United Kingdom.