Are flow controllers part of bioreactor cleaning procedures?
Before a drug can be approved for patients, all possible side effects must be completely characterized. Unfortunately, things like leaks and back pressure contamination can introduce microorganisms into the cell culture. It is therefore extremely important to tightly regulate bioreactor cleaning procedures to prevent uncontrolled batch contamination and maintain product purity. Common protocol is for bioreactors and other equipment located within the sterile boundary to be cleaned and sterilized between each batch.
Cleaning for APIs vs biologics drugs
While strict cleaning procedures are certainly important for small-molecule API production, they are even more important when producing biologics. This is simply due to the means of production: APIs are chemically synthesized and therefore easier to control, whereas biologics are produced using live cells which are susceptible to contamination. Strict cleaning and sterilization minimize the possibility of contamination so that drugs will be safe and effective when they reach patients.
How are bioreactors cleaned?
In the lab, manual cleaning and dishwashing is followed by an autoclave cycle. The cleaning ensures that no impurities are present, while the autoclave uses steam to put the equipment under high temperatures and pressures, ensuring that no living organisms remain. After cleaning and sterilization, the equipment can be reused for the next experiment or batch, without worrying about contamination from previous batches.
At larger scales, clean-in-place and sterilize-in-place (CIP/SIP) skids fulfill the equivalent jobs. CIP involves chemical cleaning compounds (strong acids and bases) with several rinse cycles. SIP, also referred to as steam-in-place, follows, playing the role of the autoclave and ensuring that no microorganisms survive.
Flow controllers in bioreactors
Flow controllers are used to create an optimal environment to facilitate healthy cellular growth. They are used to control gas flow to spargers, driving oxygen content (and oxygen uptake and transfer rates), ensuring toxic carbon dioxide is removed, and influencing the overall pH of the system.
Despite their centrality, flow controllers sit outside of the sterile boundary and therefore never come into contact with the cell culture or growth media. Even in applications where back pressure contamination is a concern, check valves are often installed to prevent flow controller contamination.
Do mass flow controllers need to be cleaned?
The only fluid or material that contacts the flow controllers in a bioprocessing setup should be clean gases: the air, oxygen, nitrogen, and carbon dioxide used to feed and sweep the bioreactor. The controllers actually sit outside of the sterile boundary, and are never in contact with microorganisms. As such, they don’t need to be chemically cleaned, steamed, or sterilized. Regardless of this, some SOPs may require all equipment to be cleaned.
Mass flow controllers cannot be put through CIP/SIP
Flow controllers may not be put through CIP/SIP. There are no high-accuracy flow controllers available which are made to withstand chemical cleaning or high-pressure steaming, or as single-use components (which would circumvent cleaning entirely). Both the harsh chemicals and the steam are likely to damage sensors, which would impede the ability of the flow controller to accurately control the various gas flows.
How to clean a mass flow controller
Manufacturers will indicate if and how this can be done in the field. Alicat flow controllers, for example, may be set to flow isopropyl alcohol backwards, followed by clean, dry air. This removes any physical impediments and dries the controller, while it remains in calibration. Flow controllers may also be hosed down as part of a broader facility cleaning. Since this cleaning is not internal, the appropriately IP-rated devices suffice.
What’s the right flow controller for my bioprocess?
If you are operating in a cGMP environment, or any area subject to strict (and difficult to change) SOPs, it is first and foremost critical to choose equipment which is compliant with the regulatory environment. This may apply to materials, accuracy specifications, control and software systems, or a myriad of other factors. However, mass flow controllers will be subject to somewhat fewer regulations specifically because they sit outside the sterile boundary. This will generally mean fewer materials regulations and more overall options for equipment specifications.
Once you are certain that the flow controllers you are assessing will meet the regulatory environment in which you are operating, a simple next step to narrow down options is to ensure that the controllers can be cleaned appropriately. Using pieces of equipment outside of the sterile boundary gives the flexibility to choose equipment based on accuracy, controllable range, turndown, and other factors relevant to your specific setup.