Control
PharmTech: How can the weight of individual layers be monitored and controlled accurately?
Behrens (IMA Kilian): When producing bilayer tablets, the in-line control of production, combining compression force measurement and statistical
weight check are challenging for several reasons. If the compaction force for layer one is extremely low, it could be very
difficult to obtain a clear signal from the strain gauges. Low force compression rollers are available to help deal with this.
The reduced mass ensures more accurate and reliable measurements. Another critical point is statistical sampling of the layers
for weight checking. For sampling, the first layer has to be compressed at a higher force to achieve enough hardness to make
sampling and weighing possible. Some systems can achieve this by using specialized systems. For example, to avoid the production
of second-layer-only tablets during layer one sampling, lower punches can remain in the up position while the fill-shoe for
layer two is stopped.
Calvin (Elizabeth Companies): Usually, two different process control methods are employed to achieve this. The first, standard method is to utilize force
control, which monitors the layer tamping pressure by means of a strain gauge transducer that, in turn, provides feedback
to the press controller. This information is used to automatically adjust the metering cam to keep the set pressure constant
to maintain the correct weight and tamping pressure. The strain gauge should be sized so that it will be sensitive enough
to 'sense' the lighter tamping pressures required for producing a tablet layer compared to the strain gauge that would be
required for final tablet compression.
The secondary method is to select a multilayer tablet press that automatically collects sample tablets from each layer at
regular intervals and then sends them to a weight testing unit, which would be included in the press control feedback loop,
to provide in-process checks along with weight control.
Kirsch (Natoli): Tablet press manufacturers will be responsible for this through improved technology and engineering. By utilizing quality
by design, the science of the formulation is understood and the design space can be exploited to deliver a controllable process.
Controlled processes deliver a product with the required critical quality attributes that define what is to be delivered to
the patient.
Aesthetics
PharmTech: Aesthetically, what consideration should be given to color?
Kirsch (Natoli): Aesthetics are always important to the consumer. However, as a manufacturer, the first concern would be, what the cost is
and how well does it compress? Colors as well as flavors can affect tablet compression. Some may be more heat sensitive than
others, resulting in picking or sticking issues. Others may have excessive fines resulting in punch and die binding, which
increases tool and press wear.
A common error is developing a new product in R&D on a slow, partially tooled press and then submitting a New Drug Application
before testing it on a production machine. The R&D press may not even have the same type tooling. If the product was developed
on a 'D' tooling press and the production press was a 'B', dwell time would be reduced, resulting in poor layer cohesion or
soft tablets. Partial sets of tooling will result in more time under pressure, therefore increasing tablet hardness. Again,
poor layer cohesion and soft tablets could be an issue on a high-speed press. Production presses run at higher speeds and
temperatures, increasing possible sticking, picking, laminating, and capping issues.
The criteria for color or flavor choice should be what is least costly and runs best on a production press and not just what
'looks pretty.' There is a middle ground somewhere for marketing and production. Marketing will not have to deal with the
production headaches. It may cost thousands or hundreds of thousands to do a trial on a production press, but would be more
cost effective than wasting millions fighting it in full-scale production.
Ethirajan (Tedor Pharma): Colors play an important role in multilayered tablets. Firstly, it is a method of visual process control during compression.
The extent of cross contamination, if any, can be easily seen when granulations of different colors are mixed during compression.
When a color coating is not present, colored tablets also give a visual description to the drug product. In the case of over-the-counter
products, color and aesthetics play a major role in consumer choice.
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