individual ingredients toward a more useful end is as old as humankind. Witness
the magnificent cave paintings of our ancestors as an expression of their daily
lives that became possible by mixing common ingredients to manufacture
pigments. Of course, manufacturing efficiency has very little influence when
much of your day is given to collecting nutrients and avoiding predators, so
providing a pigment batch at irregular intervals is sufficient to the purpose.
Fast forward to
our current century where substantial process manufacturing is still being
accomplished one batch at a time. Pharmaceutical manufacturing in particular is
biased toward batch operations for a variety of reasons. Some of the reasons
are due to prior regulatory environments that favored batch validation and
general stasis of the manufacturing situation. One may argue that the unique
relationship pharmaceutical manufacturing has to human health abets the batch
inertia. However, the regulatory environment has significantly changed in the
prior decade with renewed emphasis on understanding the process very deeply
(1,2). In addition, other industries have been involved with continuous
manufacturing and they enjoy high success rates.
industries, there are examples of formulation analogues to solid oral dosage
formulations that utilize continuous techniques to manufacture their products. One
application involves cross-linking polyethylene (PE) pellets with organic
peroxides. The organic peroxide may be thought of as the active ingredient in
liquid form and thereby requires fine control of its addition to maintain the
functionality of the extruded wire coating. The PE pellets are of a similar
size to a pharmaceutical unit dosage and each pellet must have the proper amount
of peroxide applied. The components exit as effluent, in a real time release
scenario to an extruder. Inconsistencies in content uniformity may be reflected
in poor extruder performance or more importantly in a coating failure in the
field. Considering that some of these wire coatings are undersea applications,
one can see the impact of such a failure.
application with analogies to pharmaceutical manufacturing, particularly with
regard to formulation constituents, is processing detergents. These
formulations contain builders that are analogous to pharmaceutical diluents,
cleaning agents analogous to the active pharmaceutical ingredient (API) and
flow aids analogous to silicon dioxide. They also contain a striking analogue
to the lubrication step. The formulation contains a chlorinated component that
will degrade under the aggressive agitation necessary to mix the main
formulation constituents and thus requires a secondary, gentle tumble mixing
step. This, of course, mimics the requirements of lubrication addition in solid
oral dosage formulations.
Each of the
above operations is processed at several thousand kilograms per hour (kg/hr)
with good content uniformity and high yields.
manufacturing applications are transferable from batch to continuous
processing. The continuous processes often maintain similar abilities on the
ultimate result because the basic unit operation remains the same. An
influential criterion for choosing between batch and continuous processing is
the throughput requirement. Continuous operations generate substantial amounts
of product and several tons per hour are common rates. These high rates are
inappropriate for solid oral dosage manufacturing but vendors now offer pharmaceutical-ready,
low throughput devices that have much lower throughputs; often at 5 kg/hr and
low throughput continuous mixer.
list of operations that transfer well to continuous may include tumble powder
blending, high intensity powder mixing, wet granulation of various varieties,
drying and hot melt extrusion. Because of its ubiquity in general process
schemes, the continuous mixing application will be dealt with in some detail in
the succeeding paragraphs that detail the positive and negative aspects of
continuous processing. To make the contrast more effective, we will assume a
continuous operation delivering 100 kg/hr (figure 1 above) versus a singular batch
operation utilizing a 1500 liter vessel (figure 2 below). In both examples, an 8 hour
production run will yield about 800 kg of drug product.
1500 liter batch
of Continuous Processing
It is difficult
to overstate the extensive advantages of continuous processing.
are built to operate on a 24 hour per day and 7 day per week work cycle
resulting in impressive utilization efficiencies. By contrast, the batch unit
operation encompasses only a small portion of the production day. A typical
mixing time for a 1500 liter vessel would be on the order of about 30 minutes. Substantial
additional time would be encountered in ancillary duties including staging the
raw materials, loading the materials, sampling the completed batch, discharging
the batch and cleaning the vessel in preparation for a subsequent process run.
downtime may be minimized with continuous processing as these systems are
offered with the ability for a quick changeover of the vessel and agitator bar.
A single drive station is capable of accepting several sizes of the continuous
vessels, allowing wide process ranges that are typically between 5 and 200
kg/hr. The attachment point to the drive station is similar to the familiar
multi-vessel processing stations seen with batch offerings. Consequently, the
vessel and agitator bar may be quickly removed (< 15 minutes) and replaced by
a fresh system as the previous system is sent off for cleaning.
processing is simplified within continuous applications. When assessing batch
uniformity, a small group of samples is collected to represent the entire
batch. This sampling, often done with a sampling thief, has its own inherent
drawbacks that include drawing down surface material to the sample site as the
thief enters the powder bed, preferential filling of the thief cavity by
better-flowing formulation constituents and entrapment of smaller particles in
the annular space of the thief’s tube within a tube design. The analysis
requires high value employees for evaluation and the samples themselves may
languish for several weeks in the analytical queue. Continuous applications are
ideal for on-line analysis with technologies like near infrared spectroscopy
(NIR) that provide the analytical assessment very quickly, do not require
sample preparation and are suitable to remote sampling via fiber optic probes. There
is an initial method development phase where NIR, a secondary technique, must
be established versus a primary method, but once this is accomplished the
continuous analysis may be monitored within software-developed, standard
operating procedures that are quite easily adapted to the operator level.
advantage of this type of analysis is the reduction of in-process inventory, as
immediate release is now feasible. Perhaps even more important is the
pervasiveness of sampling available. A large portion of the effluent stream is
monitored continuously and a much broader profile of the system is available. Consequently
any uniformity issues can be reconciled quickly. The actual at-risk mass is
very small and is generally a kilogram or less as represented in the hold-up
volume of the mixer. Novel statistical techniques have been proposed to deal
with the larger sample size (3).
There are a few
other more esoteric advantages within continuous applications. Scale-up becomes
much less complex. With batch applications, similarity criteria (generally
geometric, kinematic and dynamic) are established in the pilot scale vessel.
These criteria are promoted to the larger vessel, with varying degrees of
success, as the scale-up factor. Continuous scale-up is time related and based
on a common period of residence among the vessel sizes. A retention time of 180
seconds in a 5 kilogram per hour operation can easily be replicated to a 100
kilogram per hour operation by increasing the hold-up volume, which, in effect,
is merely placing a larger vessel on the common drive station.
advantage, often not readily apparent, is the simplicity within which
continuous fits into efficient experimental design, especially when real time
analysis with NIR has already been established versus a primary method. A
factorial sequence with replicates that evaluates machine factors such as
agitator bar tip speed, vessel tip speed and vessel slope with respect to a
critical quality attribute such as mix uniformity, thereby proving a proven acceptable
range, may be accomplished in one day of testing. Contrast that with the time
that would be necessary to a complete a similar factorial sequence in a small
batch vessel as thief samples are drawn for analysis by the laboratory.
Finally, the space
utilization difference of batch versus continuous is another profound
advantage. A general arrangement for the continuous scenario of delivering 100
kg/hr will fit on a table top while the batch scenario of utilizing a single
1500 liter batch requires a large processing suite.
disadvantages to continuous processing but many of them may be reconciled
through judicious planning. For example, if the continuous process is not
well-characterized and controlled in the experimental stage, it is possible to
have substantial material manufactured before one is aware of any problem. The
batch unit may also contain significant material but the only at-risk portion
is what is contained in the blender and the possibility exists to re-work this
complex formulations with multiple ingredients may also be a limiting factor
for continuous processing. It is fairly easy to stage 2 or 3 feeders at the
input end of the continuous process but if the formulation contains 6 or more
ingredients, staging this many feeders may be impossible or economically
prohibitive considering the cost of additional feeders. A second issue related
to the complexity of the formulation is the addition of the lubricant. The main
formulation components with a low dosage API require a high speed mixing
environment to achieve uniformity. However, the functionality of the lubricant
would degrade under such an environment and the lubricant must be blended in a
gentle tumble mixing situation. In a batch process, it is simple to utilize the
agitator bar for the high energy step, then add the lubricant and continue the
process without the agitator and achieve a simple tumble blend. In a continuous
process, this may involve two mixers in sequence; one for the high speed
portion and the second for lubricant addition. There are continuous mixing
technologies that overcome the problem by dividing a single continuous mixer
into sections that are capable of high speed mixing followed by a gentle tumble
A final issue is
related to environmental control. In the batch unit, dust-free transfer of the
raw materials and subsequent dust-free transfer of the finished formulation to
a receiving container are well-established. The continuous may also achieve an
environmentally clean transfer but with the multiplicity of feeders and the
outflow transfer to a tablet press, environmental control becomes more
problematic and sophisticated.
First Principles and the Grand Algorithm
advantage of continuous processing is the potential to build into a grand
algorithm for efficient process control. Experimental design can readily
establish proven acceptable ranges for critical process inputs like agitator
bar tip speed, vessel tip speed and agitator bar design as these inputs relate
to critical quality attributes like blend uniformity and particle size. Available
technology can constantly monitor the critical quality attributes in near real
time and then engender adjustments of the critical process inputs according to
the process algorithm developed in the experimental phase. Sophisticated
feedback loops are possible within many common Process Analytical Technology
software packages. (4,5)
cGMPs for the 21st Century-A Risk-Based Approach: Second Progress Report and
Implementation Plan, Department of Health and Human Services, US Food and Drug
Administration, September, 2004.
2. Guidance for
Industry PAT- A Framework for Innovative Pharmaceutical Development,
Manufacturing and Quality Assurance. US Department of Health and Human
Services, US Food and Drug Administration, Center for Drug Evaluation and
Research, Center for Veterinary Medicine, Office of Regulatory Affairs, Pharmaceutical
cGMPs, September, 2004.
Verification-Providing an Alternative Approach to Process Validation,” R.
Kettlewell et al. Pharmaceutical Engineering, Jan/Feb 2011.
Analytical Technology(PAT)-PAT and Batch Recipe Execution,” Emerson Process
Management White Paper, Life Sciences, May 2010.
5. “SIPAT The
Software Heart of PAT,” Siemens Product Brochure, Siemens NV, Belgium, November, 2007.