6.1 Introduction: "To Batch or Not to Batch"

The automation of processes had its theoretical and practical application
origins in the continuous petrochemical industries, starting in the mid-
twentieth century. Subsequently undergraduate level process control
courses, taught in universities, were developed, which primarily focused
on continuous linear processes running under steady-state conditions.
The content of such courses has changed little in recent years, even
though commercial batch and discrete manufacturing applications have
dramatically increased in importance.

The same can be said for commercially available vendor process control
software. The original product offerings were especially well-suited for
continuous processes. Many vendors have recently been upgrading their
products or are developing new products that offer more functionality for
non-continuous types of applications, but some gaps still exist.

Most bioprocesses are batch or "pseudo" batch in nature, rather than pure
continuous processes. The word pseudo here means a hybrid situation
where the overall process is "batch" but within which significant finite
periods of time may exist in which the process is running in an approximate
steady-state mode.

While batch processes are typically more labor intensive and operate at
lower overall productivities than continuous processes, there are several
reasons behind the batch nature of most bioprocesses (note that some reasons
apply to only certain kinds of bioprocesses):

1. Criteria for forward processing
   
   Most, if not all, commercial bioprocesses include a category of attributes
   known as "criteria for forward processing." These are typically
   "product quality" related attributes and often require the completion
   of laboratory assays, which may take hours or days to complete.
   Therefore, it is often appropriate to halt a process at such
   points and then resume processing when it is determined that the
   required "criteria for forward processing" have been satisfied.
   
   For example, it is typical in many bioprocesses, following the fermentation
   step, to put the fermentation broth (or filtered broth) in
   a holding tank, perhaps even chilling it, until it is determined that
   the fermentation was not contaminated and that the fermentation
   product yield is in a satisfactory range.
   


2. Cells' finite life
   
   Bioprocesses, by definition, include living cells/microorganisms
   that make the desired product-and living organisms have a finite
   life. Cell cultures can usually survive for a great many generations
   (i.e., cell divisions) in the favorable environment of a well-
   controlled bioreactor, but cells ultimately will slow down, die and
   lyse (break apart). In some cases, this is due to a process known as
   apoptosis. Apoptosis is not entirely understood, but is related to
   cell aging and is thought, in many cases, to be a function of the
   oxidants in the environment.
   
   These aspects of cell life are suggestive of batch, rather than continuous
   processes.
   


3. Product accumulation within cells
   
   Some bioprocesses make product that is retained within the cell
   walls, rather than being secreted. Such cells can only "hold" a
   finite amount of product. Therefore, an upper limit exists on the
   amount of product that some individual fermentations can produce.
   When the limit is approached, it is time to stop the fermentation,
   execute a "harvest" operation, and then cycle the
   bioreactor back to begin another batch.
   


4. Product degradation
   
   Some products slowly degrade in the bioreactor. If, for example,
   the degradation exhibits first order kinetics, then the degradation
   will be proportional to product concentration. So, some
   fermentations need to be stopped when product degradation
   becomes significant compared to the rate of product synthesis.
   


5. Cell mutation
   
   When cells divide, there is a small but finite chance that a mutation
   will occur, such that the daughter cells are not identical to the
   parent cell.
   
   The longer a bioprocess is allowed to continue (i.e., the greater the
   number of cell divisions), the greater will be the number of cells
   that are mutants (different from the original pure culture). While a
   tiny probability exists that some mutant cells may be superior to
   the normal cells, it is more likely that mutant cells will produce
   less, or no, product. The mutant cells may even grow/divide faster
   than the normal cells and eventually dominate the culture. As a
   result, both manufacturing companies and the FDA have an interest
   that processes be used in which the probability of accumulated
   significant mutation is relatively low.
   


6. Scheduling
   
   Some bioprocesses contain up to 20 sequential operations. Trying
   to operate them as an overall continuous operation can be a very
   complex logistical problem and would probably require additional
   redundant equipment, since many unit operations need to be shut
   down frequently for cleaning, maintenance, electrochemical sensor
   replacement, resin regeneration (for chromatography columns),
   etc. Manufacturing a product such that there are several
   batch related "stopping and hold" points, in which the processing
   material can be temporarily stored, adds much flexibility in scheduling
   operations.
   


7. Lot tracking
   
   Producing product as finite batches allows each batch to be
   assigned a lot number. Therefore, if a major processing problem
   occurs, affecting a "critical process parameter," the worst outcome
   would be that the finite batch, in which the problem occurred,
   would need to be thrown away. If a process were run continuously
   and certain major problems, such as viral contamination,
   occurred, then a much larger volume of product could conceivably
   be affected and have to be thrown away.
   
   From another perspective, if a faulty batch of product somehow
   ends up in the market place and needs to be recalled, the magnitude
   of the recall is likely to be less if the problem can be traced to
   a single relatively small batch rather than a large volume of product
   produced via a continuous process.
   
   Note that "intermediates" (i.e., precursor compounds to the final
   product compound) must also retain lot identity, which then
   becomes part of the "lot history" of the final product batch.

However, there are a few examples of portions of some bioprocesses that
are run pseudo-continuously.

For example, a few commercial mammalian cell bioprocesses are run in "perfusion"
bioreactors. This means that a nutrient mix is continuously fed to
the bioreactor-and broth in the bioreactor (cell-free to the extent possible)
is continuously withdrawn and sent to downstream processing, such that
the broth level in the bioreactor stays constant. This allows the bioreactor, in
which the desired product is secreted by the cells into the broth, to operate
for a month or more. However, the cycle time is still limited by the length of
time that cells can remain viable. The existence of apoptosis and the increasing
probability of mutant cells, etc. eventually become significant.

Challenges in using "continuous" perfusion processes include:

• Keeping the process sterile for long periods of time
• Continuous processing of the withdrawal stream (versus a short
  harvest operation for a batch process)
• The additional pumps, tanks, etc., operating in a sterile environment,
  necessary to maintain continuous feed and withdrawal operations
  (i.e., continuous fermentation is typically more capital
  intensive)

One part of some bioprocesses that comes close to operating in a continuous
mode is centrifugation operations. In this step, for example, a large
volume of solution, containing both solids (e.g., cellular debris) and
soluble components (e.g., desired product) is continuously fed to a centrifuge.
Start-up and shut-down aspects of this step are relatively short and
the large majority of the time is spent operating in near-steady-state conditions
with no major load changes.

There is also some use of a continuous form of commercial chromatography
separation, sometimes known as "simulated moving bed (SMB)"
chromatography. This form of chromatography (more commonly seen in
food and beverage operations than in pharmaceutical plants) involves
several identical chromatography columns, physically arranged in a ring.
Two inlet streams (feed and eluent) and two outlet streams (extract and
raffinate) are directed in alternating order to and from the column ring. A
complex valve and pump arrangement allows each column to be connected
to the appropriate streams for a short time, after which automated
valves cause the connections to change to a new configuration. While
there can be significant yield, purity, and solvent-use advantages of an
SMB operation, it is a more complicated equipment arrangement than a
single batch chromatography column.