This article describes how measuring material properties that relate directly to the final tablet product, including the inherent ability of materials to form tablets (compressibility) reduces the overall risk in tablet development and manufacture. A case study illustrates the benefits of rapid compressibility assessment.

1. As appeared in Tablets & Capsules September 2011, Copyright CSC Publishing www.tabletscapsules.com
tabletting
Reducing risk in the development Dipankar Dey and
and manufacture of tablets using Michael Gamlen
Gamlen Tableting
rapid compressibility assessments
This article describes how measuring material properties that
relate directly to the final tablet product, including the inherent
ability of materials to form tablets (compressibility) reduces the
overall risk in tablet development and manufacture. A case
study illustrates the benefits of rapid compressibility assessment.
T ablets remain the most widely used dosage form for
drug products, but relatively little is known about how
the properties of active pharmaceutical ingredients (APIs)
or other raw materials (excipients) relate to the process-
ing parameters used to make the final product. As a
result, manufacturers encounter problems in developing

2. an ideal tablet, one that satisfies both the intended thera- (considered world-class at 3.4 defects, or incidents of
peutic use and the need to manufacture it efficiently and non-conformance, per million opportunities). Figure 2
economically. puts these figures into context.
In short, the risk entailed in developing and manufac-
turing tablets is unacceptably high, particularly as more Figure 2
drug products lose patent protection and competition
The quality of tablet manufacturing compared with the quality of
from the generics industry grows. This article discusses tablets provided to patients
how rapid compressibility testing can help formulate
tablets that minimize cost and increase efficiency.
1000000 Restaurant bills
Quality in tablet manufacturing 100000 Airline checked baggage
For more than 50 years, the manufacture of tablets has 10000 urrent g
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followed a quality-by-testing (QbT) approach whereby ufac
man
assurance of final product quality is controlled by a fixed 100 Egypt Air (5, 8␴)
set of specifications for the raw materials and API and Air India (5, 8␴)
10
Lufthansa (6, 6␴)
fixed processing parameters. This approach does not 1 vide
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pro
always have a happy ending, as Figure 1 shows. lity tients Best in class
0.1 Quato pa Quantas, SAS
0.01
Figure 1 2␴ 3␴ 4␴ 5␴ 6␴ 7␴
The quality-by-testing approach to product control
But change is afoot, as regulatory authorities now
encourage manufacturers to use a Quality-by-Design
API and (QbD) approach to pharmaceutical development and
excipient Product
specs specs manufacture. This is certainly a progressive approach,
and it requires a mechanistic understanding of the mater-
In-process ial-process relationships by which the drug product is
specs
made. Using such an approach, one could argue, elimi-
nates the need for end-product testing because process
Unit Product Product
operations In-process acceptance understanding and/or process control would provide suf-
testing testing
based on
Fixed Rejected small ficient evidence that the batches met the specification
process material number were they to be tested. See Figure 3.
parameters of initial
batches
Figure 3
The Quality-by-Design approach to product control
The material specifications and process parameters are
set tightly in an attempt to ensure consistency in manu- Qualified
facture, but they are also fixed because the FDA and API and Product
excipient specs
other regulatory bodies require it. With this arrangement, specs
if the finished drug product passes the tight specifica-
tions, the batch can be released to market. If not, the
batch must usually be discarded.
The problem with this approach is that the fundamen- Process control systems
Unit
tal properties of the formulation are not understood. Feed forward Product
operations acceptance
Thus, in the event of failure, a root cause cannot be based on
Flexible In-process
measurements process
process
determined, likely creating on-going losses of product parameters compliance
until either the root cause(s) of failure are understood and
addressed or the regulatory authorities approve supple-
ments to revise the acceptance criteria or allow you to
modify the process. However, prediction of how process and material
Indeed, the use of such tight specifications has made parameters may influence the final product is still not pos-
tablet manufacturing among the world’s most inefficient sible, particularly for solid dosage forms. That’s why
processes. Many are characterized as three-sigma extensive work, early in the development process, is
processes, meaning 66,807 defects per million opportuni- needed to reap the advantages of the QbD approach. The
ties can be expected. Therefore, most products must rely amount of upfront work, coupled with a lack of invest-
totally on end-product testing to provide patients with ment in scientific understanding and an entrenched orga-
quality products, products that reach a six-sigma level nizational culture/mindset, make it difficult for QbD—an

3. apparently radical approach—to gain a following. There pressibility leads to poor-quality tablets, which exhibit such
is no question that adoption of the QbD approach has defects as capping, picking, sticking, and lamination. Even
been much slower than expected. That doesn’t mean that worse is when the dissolution behavior of a tablet batch
companies are unaware of the benefits of QbD, but faced does not conform to specification, and no cause can be
with the level of knowledge it requires, many companies found to explain it.
prefer to retain the inefficient but familiar QbT approach Such problems illustrate the importance of measuring
to develop their products. How long this reluctance can compressibility of the granulation or blend early in the
last is debatable, but with greater commercial competition manufacturing process. That way you can understand the
driven by patent expirations and tighter healthcare bud- impact of material and process changes, and adapt to
gets, reliance on outmoded strategies such as QbT will them—within the registered design space—to avoid
ultimately result in more product failures. wasted batches. While this does not provide a mechanis-
tic solution, it does at least measure a critical material
Measuring critical quality attributes of compacted materials quality of in-process materials. That, in turn, allows you
to reduce risk to develop more flexible unit operations, giving you a
Although a mechanistic understanding of tablets as a proactive way to address how the material is processed,
drug delivery vehicle is still impossible using most systems, i.e., to granulate material until the material is actually
there are steps that can be taken to reduce risk, which pri- granulated and suitable for compression; to blend mater-
marily entail measuring the many critical quality attributes ial until the material is blended; to lubricate material until
relevant to final tablet dosage. This should be done during it is lubricated; and so on, rather than reacting based on
the product development stage and manufacturing R&D. end-product testing and relying on fixed process parame-
A key attribute of a material to be compressed is, no ters, as is done currently.
surprise, its ability to be compressed, known as its com- Several devices are available to test compressibility,
pressibility. Because compressibility determines how including a lightweight bench-top tablet press and mater-
much compression force is needed to make a tablet of a ial tester that our company offers, shown below [1].
particular physical strength, assessing it at key points When evaluating equipment to test compressibility, seek
throughout the tablet manufacturing process will ensure units that allow computer control and that provide real-
the quality of the final product. In fact, behavior of the time force and displacement readings and that monitor
compacted material is key to the tablet’s properties, ejection force. It is also beneficial if the machine can test
including its hardness, friability, and dissolution profile. the compressibility of very small amounts of material so
A typical tabletting process requires that raw materials that you can evaluate a variety of formulations and
and the API undergo a number of processing steps, called process parameters early in the development process
unit operations, before they come together in the final without fear of using up your samples. (Our tablet press
dosage form. The relationship between the physicochem- accepts as little as 2 milligrams of material.)
ical properties of the materials, the dynamics of each pro- Using such equipment allows you to test the tensile
cessing step (granulation, drying, compression, etc.) is strength of compacts and to rapidly assess the compress-
not yet predictable. Nor do we know how the more com- ibility of any particular material or blend. By making and
plex operating parameters of each process step affect the testing such compacts at different stages of the manufac-
material properties arising from the following step. This turing process, you can determine how a unit operation
is the so-called “matrix window.” affects dissolution properties, content uniformity, and
Because compressibility is a critical quality attribute of potency. It also enables you to test the tablet’s physical
the final granulation or blend that goes to the tablet press, it properties to see if problems, capping for instance, could
should be measured directly and routinely during tablet become a problem.
development and manufacturing, as shown in Figure 4. At Other uses have included evaluating an API (amoxi-
present, compressibility is only tested near the final stage of cillin) to help identify the differences in the compressibil-
manufacturing, when it is too late to modify. Poor com- ity of products offered by different suppliers; to assess
Figure 4
Risk reduction using compressibility assessments
Compressibility
Compressibility
Compressibility
Compressibility
Drug substance Lubricant
Blending Granulation Tabletting
& excipients blending
A computer-controlled tablet press and material tester [1].

4. how an API’s form changes on compaction; to measure lactose) exhibited greater tensile strength than the exist-
the effect of lubrication level and type on tablet ejection ing formulation. The results of the dissolution studies,
force and compressibility; to predict tablet capping; and shown in Figure 6, revealed that two of the direct-com-
to optimize a formulation. The case study presented pression formulations (those containing agglomerated
below illustrates how compressibility testing was used to lactose and spray-dried lactose) had dissolution profiles
investigate the feasibility of replacing a wet-granulated comparable to the existing wet-granulated formulation.
formulation with a direct-compression formulation. We The two formulations also produced tablets with tensile
conducted this study as part of a strategic product review strengths superior to those made with the existing formu-
for a major pharmaceutical manufacturer. lation. Those two formulations were also more compress-
ible than the existing one and resulted in tablets with the
Case study: Feasibility of replacing wet granulation process desired dissolution profile at lower compression forces, a
with direct compression blending major advantage over the existing process.
We investigated—using rapid compressibility assess- The replacement of the wet granulation process and
ment—the effects of changing a wet-granulated formula- the production of tablets at lower compression forces
tion of a blood pressure medicine to a direct-compression have provided the manufacturer with considerable cost,
formulation. If it were possible, the cost reduction and effi- material, time efficiencies for this drug product. In addi-
ciency improvement for our client, the manufacturer, would tion, since the formulation did not change qualitatively
be considerable. In addition, regulatory changes would be (the only change being the use of agglomerated or spray-
minimal because the qualitative formula would remain con- dried lactose instead of the existing lactose), the manu-
sistent within the terms facturer need only fol-
of the license and the low a simple route to
change would be fairly
Rapid compressibility assessment allows you to gain regulatory ap -
simple to enact. make a product decision quickly and accurately proval of the change.
We compared six and consumes very little material. The impressive point
different direct-com- of the rapid compress-
pression formulations to the existing wet-granulated for- ibility assessment is that it provided evidence to the man-
mulation by compressing 100 milligrams of each formula- ufacturer to make a strategic product decision quickly
tion at forces ranging from 100 to 400 kilograms. The and accurately while using minimal quantities of material.
resulting compacts were then fractured to determine It provided valuable information about the options avail-
strength details, and we calculated—based on the tablets’ able for developing and manufacturing this particular
dimensions and the force applied—the tensile strength of product. The manufacturer is now in a position to manu-
each tablet. facture pilot-scale quantities of the material to confirm
The compressibility assessments shown in Figure 5 the results of the rapid compressibility assessment. Done
illustrate the differences between the formulations. Some otherwise, the evaluation of the seven different formula-
direct-compression formulations (those with agglomer- tions would have entailed more time, material, and effort
ated lactose, microcrystalline cellulose, and spray-dried to reach the same conclusions.
Figure 5 Figure 6
Compressibility assessment of the wet-granulated formulation Dissolution profile of the wet-granulated formulation and the
and the different direct-compression formulations direct-compression formulations
2
Extra MCC
1.8 100.00
Agglomerated
1.6 lactose 80
% spironolactone dissolved
Spray-dried 0.00
Tensile strength (MPa)
Wet granulate (400 kg)
.4 Wet granulate (200 kg)
lactose Spray-dried lactose (400 kg)
1.2 Wet Spray-dried lactose (200 kg)
granulate 60.00 Extra MCC (400 kg)
1 Extra MCC (200 kg)
Sieved Agglomerated lactose 80 (400 kg)
0.8 lactose 80
Agglomerated lactose 80 (200 kg)
40.00 Partial pregelatinized starch (400 kg)
Partial pregelatinized starch (200 kg)
0.6 Lactose powder 200 Lactose powder 200 (400 kg)
Lactose powder 200 (200 kg)
0.4 Partially Sieved lactose 80 (400 kg)
pregelatinized 20.00 Sieved lactose 80 (200 kg)
0.2 starch
0 0
0 20 40 60 80 100 120 140 160 0 5 10 15 20 25 30 35 40 45
Compaction pressure (MPa) Time (min)

5. Conclusion
Tablets will remain, for the foreseeable future, the
dominant drug delivery vehicle for the majority of
patients worldwide. As economic and commercial pres-
sures demand more efficiency and regulatory authorities
demand further scientific insight into their development
and manufacture, the risks of tablet development and
manufacture can be controlled by applying relatively sim-
ple measurements of material compressibility. The ratio-
nale behind this is simple: Tablet properties, including
hardness and dissolution profile, are strongly related to
the ability of the mixture to form tablets. By measuring
material compressibility at routine critical control points
in the development and manufacturing process, you can
better anticipate risk and thus better control it. T&C
References
1. GTP1 bench-top tablet press and material tester
from Gamlen Tableting, Nottingham, UK.
Dipankar Dey. Ph.D., is technical manager and Michael
Gamlen, Ph.D., is managing director of Gamlen Tableting,
Biocity Nottingham, Pennyfoot Street, Nottingham NG1 1GF
UK. Tel. +44 20 8676 6032. Website: www.compressibility.com.
Dey has more than 20 years’ experience in the pharmaceutical
industry and until recently led the process and validation section
of a major tablet press manufacturer. Gamlen has more than 30
years’ experience in tablet development and led tablet develop-
ment at The Wellcome Foundation for 15 years. He specializes
in managing product development, formulation, and tablet and
process development studies.