One of the challenges faced in any biopharmaceutical process is bioburden control and containment — or how do you keep what is out, "out" and what is in "in".
For a stainless steel-based manufacturing system, the process is well understood. The lines are set up, the CIP and SIP cycles are run, the appropriate valves are closed and the system is pressurized and then left for a period of time, perhaps overnight, while it is monitored for pressure decay. If the pressure decay is minimal, you have an integral system.
If you tried this method with a single-use system, assuming the bag could take the pressure, at a minimum you would see losses from the tubing as it is a porous material which has a diffusion rate. Identifying a fail in a single-use system based on pressure decay, therefore, becomes difficult. The question is, is the decay due to a leak and therefore a faulty assembly or is it diffusion across the tubing material on an assembly that is intact and fit for use? Commercially available systems are now available which will provide the answers.
Integrity testers or leak detection systems?
A key point for discussion is: should the biopharma industry be talking about integrity testers or should we be talking about leak detection systems? This is an important difference due to the weight this industry places on the word integrity, especially if we talk about integrity tests.
If we use the language of integrity testing, it implies a level of security backed up by validation and a clear binary result. The meaning in this context is well defined and if a system fails an integrity test, a batch ultimately could be rejected, pending any rework or investigation.
At the post integrity testing stage, you can report that a sterilizing grade filter is integral or is not by using recognized and validated methods. However, it may be more difficult to make the same statement for a single-use assembly.
As an industry, we should be sure what integrity means in this context and how it should be described.
Leak detection on a system requires and allows for the interpretation of the results. Of course, if the interpretation is backed up by the manufacturer’s validation package then so much the better. The questions that are open are:
- What size of leak/hole in the system, can be detected and is there a critical limit?
- Can a collection of small holes be equal to one large hole, possibly giving a false negative?
- What is the impact of tubing on the result?
Mind your language
There is no need, however, to revert to stainless steel in bioprocessing operations. Stainless steel is not without its own challenges and potential points of weakness. The connections on a system, many of which are not used in a process — for example blanking ports on a vessel — all need to be assembled and tested. The stresses and strains, when going from ambient temperature to 121oC and back again, which are put on stainless steel systems, are avoided in single-use.
But we should be very clear about what we are testing and what those test results mean, so as not to create a false sense of security. The impact of simply assuming a single-use assembly is integral when there is no knowledge of how testing has been carried out can have serious consequences for a biopharmaceutical manufacturer.
We should also be challenging the vendors of single-use systems to ensure that the facilities and processes used to build and ship assemblies minimize any risk and that those processes are validated.
The old adage "you cannot test in quality, you must build it in", certainly rings true in this case.