March 23, 2021
Reducing “time to market” is the ultimate goal
for every pharmaceutical lab. Being the first on
the market brings a competitive advantage for
prescription, over-the-counter, or generic-drug
manufacturers. Applying quality-by-design
(QbD) principles at the formulation phase can
prevent tablet defects at an early stage and
thereby drastically reduce time during the
complex and troublesome phase of “scale-up”.
Reducing “Time to market” is the ultimate goal for every pharmaceutical lab. Being the first on the market brings a competitive advantage for prescription drugs manufacturer, Over-the-counter (OTC) or generic drug manufacturers.
Applying the Quality by Design (QbD) principles at the formulation phase can prevent tablet defects at early stages and hereby drastically reduce time during the complex and troublesome phase of “scale-up”.
The determination of the right material and quality attributes (lubrication, elasticity, cohesiveness, weight variation etc.) can help developing a robust formulation. An extensive characterization of a formulated blend can also prevent capping, sticking or even die binding on a commercial-size rotary tablet press.
Instead of waiting until the “production size phase” later in development which then forces the scientists to solve formulation issues at pilot level or even worse in the actual production only, a QbD approach secures the scale-up to production with maximum safety right from the beginning.
New tools available make these investigations steps much less painful than in the past. Major Contrat Development and Manufacturing Organisation (CDMOs) are using the QbD approach in combination with tableting instruments to secure their formulation by in-depth material characterization, by direct scale-up thanks to high speed press mimicking.
Lamination and capping are common tablet defects occurring in tablet manufacturing. Both terms are used to describe cracks on the side of the tablet. Lamination is a defect exhibiting cracks on the cylindrical part of the tablets (the “belly band”. See figure #1). Capping is a defect occurring at the junction between the cylindrical part and the convex part of the tablet (see figure #2). Even though lamination and capping look more or less the same, some of their causes can be different.
Lamination is due to air entrapment, as shown in
work from the University of Bordeaux (1). An entrapped bubble
of air begins to appear on the tablet surface at a pressure just
below the pressure where lamination (cracks) can be observed.
Applying pre-compression is then a effi cient remedy. This deaeration step will help remove the excess air. The ratio of precompression and main-compression can be studied. A pre-compression ratio of 10–30% is typically used in commercial-scale
This air-entrapment can also come from a tight clearance of the compression tooling. Every manufacturer has its own mechanical tolerance between the punch tip and the die bore. However, a very tight tolerance is not recommended as the air will have a hard time to escape from the powder bed, and will thus create air bubbles. Reversely a too large tolerance creates powder loss mainly on the lower punch.
A tableting instrument can be used to troubleshoot or predict
lamination issues. In a study performed with one of MEDELPHARMs clients, a blend was compacted on a high-speed single
punch tableting instrument using compression tooling from two
different suppliers. Mimicking a Kikusui rotary tablet press at
high speed, the tablets made with the first punch set had no lamination. The tablets made with the second punch set revealed
lamination, although all the process parameters were identical
with both punch sets. The cause of lamination was attributed to
the difference of mechanical tolerances between the punch tip
and the die bore. In this case, the tableting instrument was used
to troubleshoot manufacturing issues and pin-point the parameter to be adjusted (i.e., change punch supplier).
The effect of mechanical tolerances at the formulation phase
is something formulation scientists could take into account. This
example demonstrates that such process parameters should be
considered in the first steps of QbD.
Capping is ingloriously famous because it generally occurs during scale-up, on a commercial-size rotary press. Reformulation is most likely not an option anymore.
Capping has its origin in the chemical nature of the excipients and APIs, the tablet shape, and process parameters, such as the turret speed, compression/edge thickness (and the resulting compression force), or insertion depth (i.e., penetration depth). Capping is ingloriously famous because it generally occurs during scale-up, either at the clinical manufacturing stage or during scale-up on a commercial-size rotary press. If tablet capping is discovered at a late stage, reformulation is most likely not an option anymore.
The first process parameter that can be adjusted is the convexity of the tablet by modifying the radius of the punch tip to
reduce capping tendency. Computer simulation (2) using finite
element modeling has shown that a radial (i.e. shear) stress appears on the tablet cap when the upper punch tip is moving away
from the tablet surface. The upper punch first loses contact at the
land (i.e., the little flat portion surrounding the punch tip), which
creates stress in the radial direction, explaining why capping occurs in the land region. Some experienced tableting experts
know that the higher the curvature (i.e., the lower the radius),
the higher the risk of capping tendency. Thus curvature becomes
another process parameter to be evaluated in a QbD approach.
“Flattening” the tablet has its limits, however, especially
when the tablets have to be film coated. Trying to coat flat-face
tablets generally result in a defect known as “tablet twinning”,
where two tablets are glued together.
The second process parameter that can be adjusted after the
tooling shape is the pre-compression. This will remove excessive
air inside the powder bed and most likely enhance the cohesion
of the tablets. This additional cohesion should most likely counterbalance the shear stress inherent to the tablet shape and avoid
The third process parameter is the insertion depth, also called
upper punch penetration. By compacting deeper into the die, the
applied pressure becomes symmetrical, thus densifying and creating cohesion equally on both sides of the tablet. Similar to adjusting pre-compression, the additional cohesion on the upper
part of the tablet might be enough to prevent capping.
A fourth process parameter is the compression/edge thickness (i.e., distance between the punch). By increasing the compression thickness, the compression force will be mechanically
decreased and capping should disappear rapidly. The tablet
breaking force (cohesion) will also drop, however, and it will
most likely change the disintegration time and dissolution profiles as well. This process parameter needs to be assessed carefully
Adjusting all these parameters using a commercial-size press is
time-consuming and requires large quantities of blend, but it is
possible to evaluate capping by using single punch presses with
high strain rate capabilities. The experiments described previously can be performed on such compaction simulators to troubleshoot tablet defects with small quantities of blend in a timely
Formulators can use QbD to optimize a formulation in the early
development stage, before scaleup. Based on the quality target
product profiles (QTPP) and the process flow chart (wet/dry
granulation, tableting, coating), formulation scientists will have
to list the material attributes (MA), quality attributes (QA), and
process parameters (PP) that are required to achieve the QTTP.
This risk assessment, based on the scientist’s process understanding and experience, shall then pinpoint the critical attributes and
parameters and assess them with the compaction simulator.
As described earlier on capping and lamination, the process
parameters studied to troubleshoot the defects can be evaluated
during formulation to determine the process space to produce
good tablets without capping or lamination.
Material attributes of the API and excipients generally include physico-chemical attributes, such as assay, impurities, particle size distribution, fl ow indexes, water content, and
others. The compactibility of the ingredients, however, is not
always taken into account for a simple reason: excipients have
to comply with the monographs listed in the pharmacopeias,
and these monographs do not contain any functionally-related
specifications. Surprisingly, an excipient designed for direct
compression does not have any specifi cations on its ability to
form bonds, which is what should be expected from a binder. A
scientist getting an United States Pharmacopeia (USP)/European
Pharmacopoeia (Ph. Eur.) compendial excipient shall only rely
on the supplier’s brochure on its performance in tableting. This
is the same for an API for which it could be possible to test its
ability to form bonds under pressure.
A generic-drug manufacturer, for example, that intends to
source an API from different drug substances suppliers should
consider various properties. In addition to the chemical purity
criteria and other common physical characteristics, such as particle size distribution or specific surface area, it is wise to make
a tabletability profile on an instrumented tablet press. Due to the
poor flowability of APIs and small quantity of available API at
this stage, the loading of the die would most likely be carried out
manually. (Note that external lubrication with a dry lubricant
on the die bore and punches is often necessary to avoid sticking
and die binding). If the API is able to form bonds, it’s then possible to plot the tensile strength vs. axial pressure, as defined by
USP Chapter <1062>, which was introduced in June 2017 (3).
This tabletability profile can be used to compare the different
grades of API, and can help choosing the right grade for the drug
product. This approach can be performed the same way on neat
Evaluation of lubrication and the determination of criticality of certain material attributes should also be performed. It is widely thought that a quantity of 0.5–1% of lubricant is necessary in the tablet formulation.
But is this correct? The obvious
quality attribute to look at is the ejection force. However, there
are other QAs that can be studied. First, the ejection force is only
the peak of the complete ejection force signal. By taking a close
look at the signal, it is possible to see oscillations on the signal
just after the peak (see Figure 3). Even if the peak of the ejection
force is still fairly low, this is a sign that die binding (also known
as die tightness) is occurring. A less common approach is to consider also the transmission coefficient (4), defined as the ratio of
the upper and lower punch force. To measure those forces, an
R&D press will have to be equipped with force sensors on both
punches and be able to operate the punch in a non-symmetrical
Tableting instruments that simulate high-speed presses can be used in a QbD approach to perform in depth material characterization and direct scale-up.
Older, common technologies, such as eccentric R&D presses,
can do the trick if they are well instrumented. The compression
force recorded by the lower punch will be systematically lower
than the force recorded by the upper punch. The powder densification occurs first at the upper side of the powder bed. The energy provided to the system will be partially lost due to friction
between particles and between particles and the die bore.
This energy loss will result in a measurement of a lower punch
force. The target of the transmission coefficient should be between 90% and 100%. A low transmission ratio, such as 70%,
might be linked to ineffective lubrication. By looking at the peak
of the ejection signal, the oscillations of the ejection signal, and
the transmission ratio, the quantity of lubricant and its associated blending process can now be optimized. Different grades of
magnesium stearate, a well known lubricant, featuring different
specific surface areas, can give very different lubrication.
The full QbD approach has been implemented for complex oral solid dosage forms, such as multi-layer tablets or tablet-in-tablet, at several CDMOs.
Elastic recovery is another parameter seldom
assessed. Acquiring these data requires the tablet press to be instrumented with position sensors. The elastic recovery is the difference between the tablet thickness measured out-of-die, with a
caliper for instance, and the in-die tablet thickness measured by
the sensors at the peak of compression. Elastic recovery is often
linked to lamination as it can create micro-fractures within the
tablets. Interparticular cohesion is therefore reduced and lamination can occur. As an example, calcium phosphate excipient exhibits an elastic recovery around 4%. But some sustained release
polymers can be as high as 20%. Generally speaking, it is recommended to associate ingredients having similar mechanical
properties, especially when formulating bi-layer tablets where
an elastic layer could induce a layer separation.
The compression force is quite often considered as a process parameter. Actually, it is first a quality attribute. On a basic rotary tablet press, an operator can adjust the dosage height (and its corresponding quality attribute “tablet weight”) and the compression/edge thickness. The compression force is then measured by strain gauges located on the pressure rolls.
Decreasing the compression thickness will result in increasing the compression force and vice versa. That is the main reason why many people think that this compression thickness knob is controlling the compression force. Now, when the operator increases the dosage height, the compression force will also increase. In this case, compression force cannot be a process parameter and is in fact a quality attribute.
On the other hand, modern rotary tablet presses are equipped with a “weight control loop”. This control loop will basically rely on the relation that exists between the tablet weight and the compression force. (One exception is GEA, formerly Courtoy, which uses the relation between tablet weight and tablet thickness.) The strain gauges measuring the compression force are the indicators to monitor the tablet weight. Any variation of the compression force will be an indication of a variation of tablet weight, most likely due to a non-uniform blend density and fl owability between the beginning and end of the batch. A control loop will then electronically change the dosage height to maintain the compression force within the target value (i.e. set point). A production press is mechanically designed to compress the powder bed to a given volume, ensuring that similar force indicates similar weight. In this case, the particular set point for compression force is a process parameter. Depending on the context, compression force is both a QA and a PP.
Considering compression force as a QA can help a formulator speed up tablet development, by plotting the relation between the compression force and the tablet weight. To do that,
the PP “dosage height” has to be modified to mimic a change in
powder density during the process. For example, if the nominal
tablet weight is 850 mg, the dosage height can be adjusted to
reach 850 mg + 5% and 850 mg – 5%. Tablet weights within this
range are compliant with the uniformity of mass test as set forth
by the Ph. Eur. (5). The scientist can now plot the compression
force versus tablet weights (see Figure 4). This graph will be
crucial to help set up the ejection and tolerance set points on the
commercial-size rotary tablet press during scale-up, thus saving
time and material. In addition, other QAs, such a tablet breaking
force (also known as “hardness”), disintegration time, or even
some key dissolution times can be plotted versus tablet weight.
All these graphs will guide the formulator in the determination
of the design space.
This full QbD approach has been implemented for complex oral
solid dosage forms, such a multi-layer tablets or tablet-in-tablet,
at several contract development and manufacturing organizations. Using a tableting instrument with high speed rotary press
mimicking features, the so-called compaction simulator, allows
design of robust formulations, smooth scale-up, and reduced
risks and costs, ultimately accelerating the time to market.
1. V. Mazel et al., Int. J. Pharmaceutics 478 (2) 702–4 (2015).
2. V. Mazel et al., Int. J. Pharmaceutics 532 (1) 421–26 (2017).
3. USP, USP General Chapter <1062> Tablet Compression Characterization (US Pharmacopeial Convention, Rockville, MD, 2017).
4. T. Ménard and L. Pisarik, STP Pharma Pratiques 25 (6) (Nov-Dec 2016).
5. EDQM, EurPh, General Chapter 2.9.5, Uniformity of Mass of SingleDose Preparations (EDQM, Strasbourg, France, 2016).
Author : Regis Cazes, 2018