Rationale for continuous processing
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Additional factors need to be considered in evaluating potential economic gains. "Given the fact that many companies find
themselves with excess capacity, the economic justification for a switch from batch to continuous is not straightforward,"
says Maddaluna. "It involves consideration of the operational benefits, write-off costs for excess capacity as well as strategic
issues. The justification for investment in continuous operations is easier for new products or specialized processes where
an investment is required anyway. For example, in the case of processes involving very active APIs or highly hazardous material,
where a containment investment might be required, a fully contained continuous process is likely to be more economical than
a batch process."
Others are more cautious on the benefits of continuous processing. "Until we are able to develop the science and technology
to design reliable systems for continuous processing, it will be very difficult to say with certainty that continuous processing
will improve manufacturing efficiency or cost," says Prabir K. Basu, executive director of the National Institute for Pharmaceutical
Technology and Education (NIPTE). "Today, continuous processes look attractive compared with batch processes because the batch
process is not well understood and optimized. There may be a misconception that just by changing to a continuous process all
problems will be resolved. But, before one thinks of changing to a continuous process, the question must be asked whether
the current batch process is fully understood."
Maddaluna, however, points to potentially achieving better process understanding in a continuous environment. "Process conditions
can be more stable through achieving a steady state," he says. "Feedback and feed-forward controls can respond to variations
in raw materials. More time and effort is required to design and develop a continuous process, therefore, the process and
upset conditions are better understood."
Others agree. "Continuous processing allows quality to be built in the process, to measure in-line, and to adjust parameters
to drive the critical quality attributes to the requested target levels," says Wim Van der Goten, sales director for GEA Pharma
Systems Collette (Wommelgem, Belgium), a solid-dosage equipment manufacturer. "Current batch production techniques are very
often inefficient and cannot manage variability of input material characteristics in a proper way. Therefore, batch processes
often have reduced reliability and poor yields. A statistically disputable sampling system after every batch process step
decides whether the product can be released for the next production step."
Testing and product release throughout the various steps in a batch manufacturing offer certain advantages. "In a batch process,
since the batch is tested and validated, the amount of material at risk is only one blender full of material," says Maddaluna.
"For a continuous process, the amount of material potentially at risk is the amount used during the length of time the processes
run (i.e., hours, days, or weeks). This concern will likely be alleviated with the advent of PAT and process controllers."
Continuous processing also presents challenges in product homogeneity because of start-ups and shutdowns caused by equipment
failures or other operational issues. "It is hard to establish criteria for when to start accepting the product and when to
start rejecting. It is very hard to validate such processes," says Basu. "One of the NIPTE members has specific experience
in a commercial pharmaceutical process where a semicontinuous filling process was shut down by FDA because of too many starts
and stops. The process, equipment, and process-control systems should be very well designed, extremely reliable, and should
produce consistent product to avoid frequent shutdowns for continuous processes to be successful."
Basu outlines other limitations of continuous processing for raw materials variation. "While a continuous process is designed
to take care of small variations in the raw materials, it is difficult to design ahead of time and predict and control all
types of variations and wide swings in the variation of raw materials," he says. "In such instances, a continuous process
is more vulnerable than a batch process, where, for example, a PAT tool could be used and variables such as time of mixing
can be adjusted to accommodate these types of variations. The raw materials need to be well characterized and variability
understood, so that a robust continuous process can be designed."
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