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As appeared in Tablets & Capsules September 2011, Copyright CSC Publishing www.tabletscapsules.com

tabletting

Reducing risk in the development

and manufacture of tablets using

rapid compressibility assessments

Dipankar Dey and

Michael Gamlen

Gamlen Tableting

This article describes how measuring material properties thatrelate directly to the final tablet product, including the inherentability of materials to form tablets (compressibility) reduces theoverall risk in tablet development and manufacture. A casestudy illustrates the benefits of rapid compressibility assessment.

ablets remain the most widely used dosage form fordrug products, but relatively little is known about howthe properties of active pharmaceutical ingredients (APIs)or other raw materials (excipients) relate to the process-ing parameters used to make the final product. As aresult, manufacturers encounter problems in developing

an ideal tablet, one that satisfies both the intended thera-peutic use and the need to manufacture it efficiently andeconomically.

In short, the risk entailed in developing and manufac-turing tablets is unacceptably high, particularly as moredrug products lose patent protection and competitionfrom the generics industry grows. This article discusseshow rapid compressibility testing can help formulatetablets that minimize cost and increase efficiency.

Quality in tablet manufacturing

For more than 50 years, the manufacture of tablets hasfollowed a quality-by-testing (QbT) approach wherebyassurance of final product quality is controlled by a fixedset of specifications for the raw materials and API andfixed processing parameters. This approach does notalways have a happy ending, as Figure 1 shows.

The material specifications and process parameters areset tightly in an attempt to ensure consistency in manu-facture, but they are also fixed because the FDA andother regulatory bodies require it. With this arrangement,if the finished drug product passes the tight specifica-tions, the batch can be released to market. If not, thebatch must usually be discarded.

The problem with this approach is that the fundamen-tal properties of the formulation are not understood.Thus, in the event of failure, a root cause cannot bedetermined, likely creating on-going losses of productuntil either the root cause(s) of failure are understood andaddressed or the regulatory authorities approve supple-ments to revise the acceptance criteria or allow you tomodify the process.

Indeed, the use of such tight specifications has madetablet manufacturing among the world’s most inefficientprocesses. Many are characterized as three-sigmaprocesses, meaning 66,807 defects per million opportuni-ties can be expected. Therefore, most products must relytotally on end-product testing to provide patients withquality products, products that reach a six-sigma level

Figure 1

The quality-by-testing approach to product control

API and excipient

specs

Unit operations

Fixedprocess

parameters

Productacceptancebased on

small numberof initialbatches

Productspecs

Producttesting

In-processtesting

Rejected material

In-processspecs

(considered world-class at 3.4 defects, or incidents ofnon-conformance, per million opportunities). Figure 2puts these figures into context.

But change is afoot, as regulatory authorities nowencourage manufacturers to use a Quality-by-Design(QbD) approach to pharmaceutical development andmanufacture. This is certainly a progressive approach,and it requires a mechanistic understanding of the mater-ial-process relationships by which the drug product ismade. Using such an approach, one could argue, elimi-nates the need for end-product testing because processunderstanding and/or process control would provide suf-ficient evidence that the batches met the specificationwere they to be tested. See Figure 3.

However, prediction of how process and materialparameters may influence the final product is still not pos-sible, particularly for solid dosage forms. That’s whyextensive work, early in the development process, isneeded to reap the advantages of the QbD approach. Theamount of upfront work, coupled with a lack of invest-ment in scientific understanding and an entrenched orga-nizational culture/mindset, make it difficult for QbD—an

Figure 2

The quality of tablet manufacturing compared with the quality oftablets provided to patients

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Quality provided

to patients

Restaurant bills

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Figure 3

The Quality-by-Design approach to product control

Qualified API andexcipient

specs

Productspecs

Unit operations

Flexibleprocess

parameters

Productacceptancebased onprocess

compliance

Process control systems

Feed forward

In-processmeasurements

pressibility leads to poor-quality tablets, which exhibit suchdefects as capping, picking, sticking, and lamination. Evenworse is when the dissolution behavior of a tablet batchdoes not conform to specification, and no cause can befound to explain it.

Such problems illustrate the importance of measuringcompressibility of the granulation or blend early in themanufacturing process. That way you can understand theimpact of material and process changes, and adapt tothem—within the registered design space—to avoidwasted batches. While this does not provide a mechanis-tic solution, it does at least measure a critical materialquality of in-process materials. That, in turn, allows youto develop more flexible unit operations, giving you aproactive way to address how the material is processed,i.e., to granulate material until the material is actuallygranulated and suitable for compression; to blend mater-ial until the material is blended; to lubricate material untilit is lubricated; and so on, rather than reacting based onend-product testing and relying on fixed process parame-ters, as is done currently.

Several devices are available to test compressibility,including a lightweight bench-top tablet press and mater-ial tester that our company offers, shown below [1].When evaluating equipment to test compressibility, seekunits that allow computer control and that provide real-time force and displacement readings and that monitorejection force. It is also beneficial if the machine can testthe compressibility of very small amounts of material sothat you can evaluate a variety of formulations andprocess parameters early in the development processwithout fear of using up your samples. (Our tablet pressaccepts as little as 2 milligrams of material.)

Using such equipment allows you to test the tensilestrength of compacts and to rapidly assess the compress-ibility of any particular material or blend. By making andtesting such compacts at different stages of the manufac-turing process, you can determine how a unit operationaffects dissolution properties, content uniformity, andpotency. It also enables you to test the tablet’s physicalproperties to see if problems, capping for instance, couldbecome a problem.

Other uses have included evaluating an API (amoxi-cillin) to help identify the differences in the compressibil-ity of products offered by different suppliers; to assess

apparently radical approach—to gain a following. Thereis no question that adoption of the QbD approach hasbeen much slower than expected. That doesn’t mean thatcompanies are unaware of the benefits of QbD, but facedwith the level of knowledge it requires, many companiesprefer to retain the inefficient but familiar QbT approachto develop their products. How long this reluctance canlast is debatable, but with greater commercial competitiondriven by patent expirations and tighter healthcare bud-gets, reliance on outmoded strategies such as QbT willultimately result in more product failures.

Measuring critical quality attributes of compacted materialsto reduce risk

Although a mechanistic understanding of tablets as adrug delivery vehicle is still impossible using most systems,there are steps that can be taken to reduce risk, which pri-marily entail measuring the many critical quality attributesrelevant to final tablet dosage. This should be done duringthe product development stage and manufacturing R&D.

A key attribute of a material to be compressed is, nosurprise, its ability to be compressed, known as its com-pressibility. Because compressibility determines howmuch compression force is needed to make a tablet of aparticular physical strength, assessing it at key pointsthroughout the tablet manufacturing process will ensurethe quality of the final product. In fact, behavior of thecompacted material is key to the tablet’s properties,including its hardness, friability, and dissolution profile.

A typical tabletting process requires that raw materialsand the API undergo a number of processing steps, calledunit operations, before they come together in the finaldosage form. The relationship between the physicochem-ical properties of the materials, the dynamics of each pro-cessing step (granulation, drying, compression, etc.) isnot yet predictable. Nor do we know how the more com-plex operating parameters of each process step affect thematerial properties arising from the following step. Thisis the so-called “matrix window.”

Because compressibility is a critical quality attribute ofthe final granulation or blend that goes to the tablet press, itshould be measured directly and routinely during tabletdevelopment and manufacturing, as shown in Figure 4. Atpresent, compressibility is only tested near the final stage ofmanufacturing, when it is too late to modify. Poor com-

Figure 4

Risk reduction using compressibility assessments

TablettingLubricant blending

GranulationBlendingDrug substance

& excipients

Com

pres

sibi

lity

Com

pres

sibi

lity

Com

pres

sibi

lity

Com

pres

sibi

lity

A computer-controlled tablet press and material tester [1].

how an API’s form changes on compaction; to measurethe effect of lubrication level and type on tablet ejectionforce and compressibility; to predict tablet capping; andto optimize a formulation. The case study presentedbelow illustrates how compressibility testing was used toinvestigate the feasibility of replacing a wet-granulatedformulation with a direct-compression formulation. Weconducted this study as part of a strategic product reviewfor a major pharmaceutical manufacturer.

Case study: Feasibility of replacing wet granulation processwith direct compression blending

We investigated—using rapid compressibility assess-ment—the effects of changing a wet-granulated formula-tion of a blood pressure medicine to a direct-compressionformulation. If it were possible, the cost reduction and effi-ciency improvement for our client, the manufacturer, wouldbe considerable. In addition, regulatory changes would beminimal because the qualitative formula would remain con-sistent with in the termsof the license and thechange would be fairlysimple to enact.

We compared sixdifferent direct-com-pression formulations to the existing wet-granulated for-mulation by compressing 100 milligrams of each formula-tion at forces ranging from 100 to 400 kilograms. Theresulting compacts were then fractured to determinestrength details, and we calculated—based on the tablets’dimensions and the force applied—the tensile strength ofeach tablet.

The compressibility assessments shown in Figure 5illustrate the differences between the formulations. Somedirect-compression formulations (those with agglomer-ated lactose, microcrystalline cellulose, and spray-dried

lactose) exhibited greater tensile strength than the exist-ing formulation. The results of the dissolution studies,shown in Figure 6, revealed that two of the direct-com-pression formulations (those containing agglomeratedlactose and spray-dried lactose) had dissolution profilescomparable to the existing wet-granulated formulation.The two formulations also produced tablets with tensilestrengths superior to those made with the existing formu-lation. Those two formulations were also more compress-ible than the existing one and resulted in tablets with thedesired dissolution profile at lower compression forces, amajor advantage over the existing process.

The replacement of the wet granulation process andthe production of tablets at lower compression forceshave provided the manufacturer with considerable cost,material, time efficiencies for this drug product. In addi-tion, since the formulation did not change qualitatively(the only change being the use of agglomerated or spray-dried lactose instead of the existing lactose), the manu-

facturer need only fol-low a simple route togain regulatory ap -proval of the change.

The impressive pointof the rapid compress-

ibility assessment is that it provided evidence to the man-ufacturer to make a strategic product decision quicklyand accurately while using minimal quantities of material.It provided valuable information about the options avail-able for developing and manufacturing this particularproduct. The manufacturer is now in a position to manu-facture pilot-scale quantities of the material to confirmthe results of the rapid compressibility assessment. Doneotherwise, the evaluation of the seven different formula-tions would have entailed more time, material, and effortto reach the same conclusions.

Figure 5

Compressibility assessment of the wet-granulated formulationand the different direct-compression formulations

0 20 40 60 80 100 120 140 160

2

1.8

1.6

.4

1.2

1

0.8

0.6

0.4

0.2

0

Extra MCC

Agglomeratedlactose 80

Sievedlactose 80

Lactose powder 200

Spray-driedlactose

Wet granulate

Compaction pressure (MPa)

Tens

ile s

tren

gth

(MP

a)

Figure 6

Dissolution profile of the wet-granulated formulation and thedirect-compression formulations

Wet granulate (400 kg)

Wet granulate (200 kg)

Spray-dried lactose (400 kg)

Spray-dried lactose (200 kg)

Extra MCC (400 kg)

Extra MCC (200 kg)

Agglomerated lactose 80 (400 kg)

Agglomerated lactose 80 (200 kg)

Partial pregelatinized starch (400 kg)

Partial pregelatinized starch (200 kg)

Lactose powder 200 (400 kg)

Lactose powder 200 (200 kg)

Sieved lactose 80 (400 kg)

Sieved lactose 80 (200 kg)

Time (min)

% s

piro

nola

cton

e di

ssol

ved

100.00

0.00

60.00

40.00

20.00

00 5 10 15 20 25 30 35 40 45

Rapid compressibility assessment allows you tomake a product decision quickly and accurately

and consumes very little material.

Partially pregelatinizedstarch

Conclusion

Tablets will remain, for the foreseeable future, thedominant drug delivery vehicle for the majority ofpatients worldwide. As economic and commercial pres-sures demand more efficiency and regulatory authoritiesdemand further scientific insight into their developmentand manufacture, the risks of tablet development andmanufacture can be controlled by applying relatively sim-ple measurements of material compressibility. The ratio-nale behind this is simple: Tablet properties, includinghardness and dissolution profile, are strongly related tothe ability of the mixture to form tablets. By measuringmaterial compressibility at routine critical control pointsin the development and manufacturing process, you canbetter anticipate risk and thus better control it. T&C

References

1. GTP1 bench-top tablet press and material testerfrom Gamlen Tableting, Nottingham, UK.

Dipankar Dey. Ph.D., is technical manager and MichaelGamlen, Ph.D., is managing director of Gamlen Tableting,Biocity Nottingham, Pennyfoot Street, Nottingham NG1 1GFUK. Tel. +44 20 8676 6032. Website: www.compressibility.com.Dey has more than 20 years’ experience in the pharmaceuticalindustry and until recently led the process and validation sectionof a major tablet press manufacturer. Gamlen has more than 30years’ experience in tablet development and led tablet develop-ment at The Wellcome Foundation for 15 years. He specializesin managing product development, formulation, and tablet andprocess development studies.