Technical hurdles. Coating as a unit operation already has been successfully implemented as a continuous process for neutraceutical products,
but there are still some glitches that need to be worked out before it can be used for ethical pharmaceuticals. In particular,
the product diversion during start-up and shut-down of the process needs to be defined clearly.
The key difference between a batch process and a continuous process is that in the batch mode, the process is in a dynamic
state from the beginning to the end. Depending on the process, the endpoint is predetermined so that when that point is reached,
the process is stopped, and the unit operation is done. A continuous process must undergo an initial start-up phase before
reaching a steady state. Only after this point can material be collected for further processing and finishing into the final
product. The same scenario occurs during the shut-down phase. Determining what to do with the material during these phases
and engineering a process that will take into account these scenarios have become primary objectives for those seeking continuous
How to handle material that does not meet specifications is another issue. "In commercial processes such as foods, detergents,
and fertilizers, manufacturers typically recycle the material back into a continuous process. In fact, some applications require
significant recycle loops for process stability. In pharmaceutical manufacturing, companies will have to decide whether to
scrap this material or reintroduce it in a controlled way," says Mort.
Recycle loops in pharmaceutical production may complicate abilities to trace the product back to its raw materials.
"A batch of material can be traced as it goes through the process steps," says Mort. "But with a recycle stream going in a
continuous granulation process, some materials are recycled one or more times through the process. The recycle history can
vary depending on whether the recycle is classified as fine or oversize. Oversize material is sent back through a grinder
where it is subject to additional work; or if the material is too fine or dusty it may be collected in a dust-handling system,
and now you are faced with the issue of handling fine, cohesive material. In either case, the recycle is separated from its
initial cohort of raw materials. Depending on the breadth of the distribution, the recycle streams may constitute a significant
amount of material that is spread out though time in the process."
Moreover, in a well-mixed batch system, all of the material in the batch has the same residence time. In a continuous system,
the material has a residence-time distribution and the effect of the process-time distribution on the product properties must
be controlled. "The need for dose precision is high in pharmaceutical production, so you have to take extra care and go to
lengths to make sure your in-process distributions are narrow and in control," says Mort.
Nontechnical challenges. The initial cost of equipment, process development, and quality systems is definately a hindrance.
"Because there is not a requirement to use continuous manufacturing or process analytical technology, the business case needs
to be developed to justify the investment of these technologies, which I would argue if they are used correctly and appropriately
it may result in considerable savings and enhance the efficiency of pharmaceutical manufacturing," says Nasr.
Perceived regulatory issues and current financial constraints of some manufacturers also are delaying the introduction of
Some believe it may take competitive pressure from generics to make pharma pay greater attention to manufacturing efficiencies.
"In my opinion, it is not conducive for them to make things continuous because there is no economic incentive," says John
Kossik, technical manager, Steadfast Equipment (Mill Creek, WA). "The processes for pharmaceuticals and biopharmaceuticals
are in many cases not any more complicated than those used in the chemical-process industry. The essential problem with getting
continuous processing into prescription drugs is that the laws of supply and demand don't work anymore, especially in high-value
drugs, so there is no motivation to be efficient."
For a process that already has been developed, there is capital required to change it to a continuous mode. "If a company
has a high-value drug they already have approval for, there is no reason for them to switch over to continuous processing
until the economic conditions change. When drugs go off patent even in large pharma companies, they make process changes because
they have to compete with generic-drug manufacturers, especially now that insurance companies are 'encouraging' people to
buy generics," says Kossik