Process Description and Challenges

Bioreactors are one of the most complex and challenging of processes.
The challenges for instrumentation, control, and automation are equally
difficult. The product may be produced directly by the cell culture, be
contained within the cells, or even be the cells themselves.

There are three primary types of bioreactor operation: batch, fed-batch,
and continuous. With a batch reactor, you add nutrients, solvents, and
seed materials, then monitor and control the reaction until it reaches its
end point. There may be an inactivation phase, then a harvest, then
cleaning, CIP, and SIP, and then the process is repeated. Bioreactors range
widely in size, from under a liter to 20,000 liters or more.

The continuous bioreactor generally starts off like a batch reactor. When it
reaches a critical point (usually determined by cell mass), it is switched to a
continuous mode of operation. Nutrients are added and product is harvested
continuously. This provides a higher yield, since the reactor is running at
full capacity for longer. But it does bring some risks for contamination, and
some added complexity to the operation and automation.

The fed-batch reactor is something of a hybrid between batch and continuous
operations. A small batch is started in a large batch reactor. Once the
critical point is reached (again, usually determined by cell mass), more
nutrients are added to the reactor, eventually filling it to its final volume.
Nutrient addition may be linear or non-linear, or done according to a control
scheme. The harvest proceeds similarly to the batch operation.

Measurement needs may be quite complex, including temperature, pressure,
air flow, nutrient flows, pH control, and a variety of on-line composition
measurements. It is a difficult challenge to obtain all of these
measurements while maintaining sterility of the reactor vessel.

It can be difficult to get visual or physical access to the vessel or the
instruments. Troubleshooting instrumentation inside a closed stainless
steel vessel will require you to use all of your engineering skills.

Small vessels may not have enough physical space for all of these measurement
devices. Large vessels may be several stories tall, and operator
access can be a challenge. Off-line bench testing is commonly used.

Furthermore, media concentrations are often critically important. If nutrients
are prepared in other vessels, you will need to ensure complete transfer
of materials to ensure proper media concentrations. This may require special
transfer methods, such as a "buffer chase" or "air blow," to ensure that
all nutrients have been transferred to the bioreactor.