Progress
Still, there are signs of progress, most notably within FDA's continuing CMC pilot program. Begun in the fall of 2005, the
program provides pharmaceutical manufacturers with an opportunity to submit applications that demonstrate modern approaches
of pharmaceutical development or quality by design (QbD). As part of this pilot, the agency works with inspection teams, reviewers,
and compliance officers from CDER to facilitate the review and the implementation of QbD principles for companies that submit
an application. So far, the program has received more than 12 submissions and has accepted 11 into the pilot and as of last
month approved at least three applications. These applications demonstrate the concepts of PAT such as immediate-release and
some elements of continuous processing.
Although implementation issues still need to be addressed, Nasr says he has witnessed "tremendous progress on the industry's
part as far as its appreciation and some very serious attempts to implement some of the new approaches in manufacturing and
quality systems."
Advancements in clinical production also are notable. "We are just starting to work with innovator pharmaceutical researchers
on the clinical manufacturing side to introduce continuous processing into their pilot-lab sequences," says Chirkot.
Lodaya admits the industry is still in the "evolutionary phase" of continuous processing for the pharmaceutical industry,
but that it is an area under active development and analysis. "To my knowledge, all major pharmaceutical companies have programs
working in this area. Over the next five to seven years, I think all the major pharmaceutical companies, those that have the
technical power and the ability to put people into these projects, will have their own way of using continuous processing,"
he says.
Applications
Companies already have taken steps in applying continuous or semicontinuous strategies to some unit operations.
Blending. Patterson-Kelley developed its "Zig-Zag" continuous blender, an adaptation of the common V-type mixer, a rotating vessel
that may or may not contain an agitator bar. The unit combines V shapes to enable continuous mixing. After the initial mix,
a lube step can be added, if required, directly into the blender. At this point the product can exit the mixer directly onto
a PAT device which senses for content uniformity in real time. At this point, the blended product can be dispensed directly
into a tablet press. The blender is fed continuously and runs at a set rate for a set period of time, both determined by the
process.
Microencapsulation. Brookwood Pharmaceuticals (Birmingham, AL) has developed both batch and continuous processes for producing microparticles
and drug-polymer implants. Its microencapsulation process is conducted two ways, depending on the scale. For laboratory scale
during feasibility studies, individual unit operations are segregated with planned stops within the overall process. Larger
scales use a semi-batch process with continuous homogenization and mixing.
Figure 1
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The patented continuous process begins with an emulsification step, followed by extraction and collection in a sequential
manner.The resulting microparticles are then dried and prepared for the filling operation (see Figure 1). Process run time
depends on the batch size and water exposure time. "From the time emulsification begins or at the initiation of microdroplet
preparation that contain API, polymer, and solvent until we're in the drying portion of the process, we keep water exposure
to the product to under 24 hours," explains Bruce Hudson, senior engineer at Brookwood.
Taking ownership
FDA has made it clear that it wants manufacturers to take the lead in moving continuous processing forward.
"What we really need to know and I ask our colleagues in industry is, What can we do in addition in order to facilitate the
implementation of these innovative technologies that are currently being used in other industries, continuous manufacturing
being one of them? We need to find a way to eliminate any perceived regulatory hurdles and find a way to encourage industry
to take ownership and to implement new technologies as they see appropriate," says Nasr.
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