Two-Piece Hard Capsules for Pharmaceutical Formulations

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Summer 2010 Volume 14 Number 3 31

PHARMACEUTICAL PRO CESSES

G

L O W I M A G E S / G E T T Y I M A G E S

Two-Piece Hard Capsules

for PharmaceuticalFormulations

“Pharmaceutical Processes” discusses scientific and technical principles associated

with pharmaceutical unit operations useful to practitioners in compliance and valida-

tion. We intend this column to be a useful resource for daily work applications. The

primary objective for this feature: Useful information.Reader comments, questions, and suggestions are needed to help us fulfill our

objectives. Case studies submitted by readers are most welcome. Please send your

comments and suggestions to column coordinator Armin Gerhardt at arminhg@com-

cast.net or to journal coordinating editor Susan Haigney at [email protected].

KEY POINTS

The following key points are discussed:Two-piece hard capsules are a well-established, widely used dosageform with a long history in the pharmaceutical industryTwo-piece capsules offer speed of development versus tablets as well as

flexibility of fill materialsThe filling process for two-piece capsules is a robust process and can bewell controlled through the use of proper process monitoringTwo-piece capsules are an excellent tool for the blinding ofclinical suppliesColorants and printing can create a globally accepted dosage form thatcan also improve product identification and patient complianceCapsule design features include an inward tapered rim, side air vents,a cap with dimples, and a cap and body with reinforced domes andmatching lock rings

A wide range of capsule sizes and types for different applications

are availableCapsule fill materials must be uniformly filled into capsules, have goodbioavailability, and be compatible with the capsule. Fill materials maybe powders, granules, pellets, tablets, and other types of materialsTwo-piece capsules have traditionally been made of gelatin. Hypro-mellose capsules are now available and may be used in place ofgelatin for improved product stability

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Dennis Murachanian



32 Journa l of GX P Compliance

PHARMACEUTICAL PROCESSES

Compliance personnel must be aware of thepotential problem areas that present high risksto manufacturing processes, drug properties,and product quality attributes such as stabil-ity, solubility, and dissolution. These include

formulation changes, capsule changes, storage,handling, processing conditions, product pack-aging, and other considerations.

INTRODUCTION

Two-piece hard capsules are a well-established dos-age form that provides solutions to many of today’sdrug delivery requirements and challenges. Widelyused in the pharmaceutical and nutritional supple-ment industries for more than a century, they are afrequently used dosage form for administering both

solid and liquid drugs. As drug discovery produces ever more complex

drug molecules, the pharmaceutical formulatoris increasingly challenged to develop an orallyavailable dosage form while meeting demandingdevelopment timelines. Hard capsules typicallyoffer a quicker and simpler formulation approachthan tablets, making them increasingly relevant intoday’s cost-constrained pharmaceutical environ-ment. While most hard capsule shells are made ofgelatin, alternative shell materials such as hyprom-

ellose have emerged in recent years offering furtheroptions to formulation scientists. Additionally,hard capsules offer flexibility for various fill materi-als including powders, pellets, granules, mini-tab-lets, liquids, and semisolid formulations. Specialhard capsules are even available for the blinding ofclinical supplies and rodent administration.

Hard capsules are available in a wide range ofsizes for dosing f lexibility and to accommodatespecial requirements. Colorants and printing op-tions can further improve product identificationand patient compliance. Hard capsules are often apreferred dosage form for their visual appeal, easeof swallowing, and taste and odor masking.

HISTORY OF TWO-PIECE CAPSULES

Capsules are one of the oldest dosage forms inpharmaceutical history, dating back to the ancient

• Egyptians. In 1730, de Pauli, a pharmacist from Vienna, produced oval-shaped capsules to coverthe unpleasant taste of turpentine he prescribedfor people with gout. A century later, patents weregranted to François Achille Barnabé Mothès in Paris

for his invention and the manufacture of gelatincapsules. By the following year, capsules were be-ing produced in many different parts of the world.

Around the same time, Jules Cèsar Lehuby wascredited for the invention of the two-piece gela-tin capsule and granted a French patent for his“medicine coverings.” Although his principlesfor manufacturing two-piece capsules establishedthe method still used today, technical difficul-ties stopped further development of this form foranother century. In 1931, Arthur Colton, on behalf

of Parke, Davis & Co., designed a machine thatsimultaneously manufactured both capsule bodiesand caps and fitted them together to form a hardgelatin capsule. His machine still represents thebasic design of machinery used today.

With advances made in hard capsule technology,the use and importance of capsules as a deliverydevice has steadily increased, and the market hasseen continuous growth. In the past, capsules werefilled either manually in a labor-intensive process orby slower machine types. Modern automatic filling

machines can fill as many as 200,000 capsules perhour. These capsule filling machines are fully auto-mated and instrumented to monitor fill weights andcontinuously adjust to maintain target fill weightsmaking the filling process highly efficient.

HARD-GELATIN CAPSULE MANUFACTURE

While two-piece capsules may be comprised ofvarious materials, the vast majority are still madeusing high-quality gelatin prepared from colla-gen. Collagen is a fibrillary protein that contains18 different amino acids. The collagen of bonesand hides is subject to a maceration and purifica-tion process with acids and alkalis that split ithydrolytically into an almost unbranched amino-acid chain of variable length. This end product isknown as gelatin. After physical, chemical, andmicrobiological testing, the gelatin is released for




A rm in H . Ge rha rd t , Coo rd i na t o r

capsule production. Gelatin used in hard capsulemanufacturing must meet the requirements of allmajor pharmacopeias.

Capsules are manufactured under strict environ-mental conditions by a dipping process on high ca-

pacity machines. The gelatin is melted with demin-eralized, filtered, and sterilized water. Entrappedair is removed by vacuum. The gelatin solution isthen mixed with colorants and transferred to thecapsule manufacturing line.

Standardized steel pins are arranged in rows onthe capsule manufacturing machine. Pins are thendipped into a temperature-controlled solution to aprecise regulated depth. After dipping, the bars arerotated to evenly distribute the gelatin around thepins. Correct gelatin distribution is critical to en-

sure a homogenous and precise wall thickness. Thepins are then passed through several drying stagesto achieve the optimal water content. After drying,the capsule halves are stripped from the pins, cut tothe correct length, and the cap and body are joined.

CAPSULE COLORANTS AND PRINTING

Capsule Colorants

Capsule colorants must satisfy the following threekey requirements:

Regulatory approval in the countries intendedfor distributionProduct protection and marketingPatient acceptance.

Regulatory approval considerations. Thecapsule colorant must meet the regulatory require-ments of all countries designated for distribution.Because color regulations vary from country tocountry, this is an important consideration prior tocapsule approval. Each country or region has a listof acceptable colorants along with allowable levelsfor certain colorants. The term “globally acceptable”generally refers to the regions of the US, EuropeanUnion (EU), and Japan. For a global presentation,the available palette of colorants is vastly reduced,consisting mainly of the iron oxides, titanium diox-ide, and blue #2.

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Iron oxides present a special challenge as theycontain elemental iron that can be toxic at elevatedlevels. For patient safety, each country or regionindicates an allowable daily intake of elementaliron. Guidelines have been established for the daily

intake of iron oxides and elemental iron to assurepatient safety. For example, the World Health Or-ganization has established a limit of 0.5mg/day/kgof iron oxide, while the US Code of Federal Regula-tions has an established limit of 5mg/day of elemen-tal iron. It is therefore incumbent on the formula-tions, quality assurance, and regulatory teams tobe aware of the levels of iron oxide in their capsulecolor formulation and calculate the total daily ironintake based on the daily capsule intake. A repu-table capsule supplier can provide assistance and

reformulate to lower iron oxide levels if necessary.Blue #2 presents another important considerationas this colorant is known to be light sensitive andprone to fading. Light protective packaging shouldbe used to avoid capsule discoloration in capsulescontaining blue #2.

A single globally acceptable capsule color can beapplied to both commercial and clinical suppliesand will eliminate the need for multiple capsulepresentations. This strategy will thus reduce stabil-ity, testing, and inventory requirements. In the

case of clinical supplies, this approach allows formaintenance of a readily available inventory of cap-sules when clinical materials are needed on shortnotice regardless of the clinical site. Further, thisapproach reduces possible confusion and productmix-ups at the clinical site and acts as an additionalmeans of reassurance to the clinician. To avoidintroducing bias into a clinical trial where blindingby over-encapsulation is required, it is important tochoose a colorant that is sufficiently opaque to fullyhide the contents of the capsule.

Product protection and marketing. Capsulecolorants are an important means of creating astrong brand identity and enhancing brand image.They can also play an important role in productidentification and can help avoid product confusion,especially for elderly patients taking multiple medica-tions. Capsule suppliers can even produce customized





color combinations and may offer exclusivity. Capsuleprinting is an additional means of product identifica-tion and is even required by the US Food and Drug Administration for pharmaceutical capsules.

Patient acceptance. Finally, patient acceptance

is the third key consideration in color choice. Withdistinct colors, patients can more easily identify theirmedications, which may lead to improved patientcompliance and safety. In various studies it has beenconsistently demonstrated that the color of the dos-age form is the attribute most readily recognizable bypatients followed by other attributes such as productname, dosage form, shape, and size. Patients are oftenimmediately aware when their medication or brand isswitched based on a new color. Broadly defined rulesexist for associating colors with certain indications,

studies have also demonstrated the psychologicalinfluence of capsule colors on the therapeutic effect ofa drug. An experienced capsule supplier can help de-sign and select the capsule appearance that maximizespatient acceptance and utilization.

Capsule Printing

Printing on the dosage form is required for phar-maceutical products to comply with FDA product iden-tification requirements. This is not a requirement fornutritional supplements. The print must contain some

form of product identification such as the productname, strength, or code number and is often a means

of improving capsule appearance when a global pre-sentation results in an otherwise dull-looking capsule.The wide array of printing options provides greaterpossibilities in brand protection and identification,while novel colors and printing also help deter coun-

terfeiting by making drugs harder to copy. Colorantsfor printing inks follow the same regulatory approachas for capsule colorants.

CAPSULE DESIGN

Hard capsules are designed to not only containpharmaceutical and nutritional formulations but alsoto withstand the rigors of packaging, shipping, andhandling on high-speed filling machines. The fill-ing machine process involves feeding, rectification,separation of cap and body, filling, closing of cap and

body, and ejection (Figure 1). For high-speed fillingmachines, these steps may occur at rates up to 200,000capsules per hour making the design and integrity ofthe capsule of paramount importance.

The typical capsule design involves a body with aninward tapered rim and side air vents, a cap with dim-ples, and both a cap and body with reinforced domesand matching lock rings (Figure 2). Let’s examine eachof these features to fully understand their function.

Lock-Rings And Side Air Vents

Capsules were originally produced as a simplestraight cap and body with no additional features.

Figure 1:The capsule filling process.





With the advent of high-speed filling machines, itquickly became apparent that this design was inad-equate to meet the needs of the industry. One of thefirst problems observed was the ease with which thecap and body would separate after filling and during

shipping. This was often due to air entrapment in thecapsule during the high-speed filling process thus cre-ating sufficient internal pressure to cause separation ofthe two parts. To remedy this problem, matching lock-rings were introduced onto the cap and body to assurea tight closure. As capsule filling became ever moreefficient and faster, the lock-rings alone were oftennot sufficient to withstand internal forces. To furtherimprove the capsule design, air vents were introducedonto the body that allow air to escape during the fillingprocess and thus eliminate the most common cause of

cap-body separation.

Inward-Tapered Rim

Another important capsule design feature is an inwardtapered rim on the body. As with the side air vents,the tapered body was introduced in response to thedemands of high-speed filling machines. Prior tothe introduction of the tapered body, even very slightvariances in lateral cap-body alignment would causeimproper closing and result in split and deformedcapsules. The introduction of the tapered body allows

for additional machine tolerance to assure that capsulerejoining occurs without damage. Of course it is stillcritical that the filling machine be properly set-upby an experienced mechanic prior to a filling run toensure a smooth filling operation.

Reinforced Domes

Reinforced domes on the cap and body were anotherimprovement made to assure that capsules maintaintheir integrity during the closing process on the fillingmachine. This is achieved by distributing sufficient

gelatin along the dome and transition shoulders duringthe dipping and molding process.

Dimples

Dimples are molded into the cap during manu-facturing and provide a level of pre-lock force thatprevents the cap and body from separating during

shipping and handling. The placement and depth

of the dimples also assure that the cap and body arenot difficult to separate during the filling process.

CAPSULE SIZES AND TYPES

Capsule sizes are designated numerically from sizes000 to 5. Size 000 are the largest size and size 5 is thesmallest. The Table lists the most commonly availablecapsule sizes and their respective fill capacities.

Determining the optimal capsule size for a givenproduct is done by first determining the density ofthe formulation using tapped density for powders

and bulk density for pellets and granules. A capsulevolume chart (see Table), generally available from thecapsule supplier, is then referenced. The appropri-ate capsule size may then be calculated using themeasured density of the formulation, the target fillweight, and the capsule volume.

There are a variety of capsule types that have beendesigned for specific applications such as DBcap de-signed specifically for double blind clinical studies.There are two important requirements for blindedclinical trial materials. The patient should not be able

to see the contents of the capsule, and it should bedifficult for the patient to open the capsule and thusbreak the blind. DBcaps meet these requirementswith a cap that covers most of the capsule bodycreating a double layer of shell so only the roundedends are visible. This dual layer not only ensuresthe opacity of capsule contents, but also makes it

Figure 2:Coni-Snap capsules.





virtually impossible to open, thereby maintainingthe integrity of the blind. As the size and cost ofclinical studies increases, the need to maintain studyintegrity becomes ever more critical. The two-piece

capsule can be an invaluable tool in preventingpatient bias by making it difficult for the patient tobreak the blind.

Other capsule types include the Licaps DrugDelivery System. This capsule is designed specifi-cally to contain liquids through a special designand locking feature. The miniscule size 9 capsule isuseful for rodent and small animal dosing. This isespecially valuable for obtaining early phase phar-macokinetic data.

CAPSULE FILL MATERIALS

Two-piece capsules are an excellent option for con-taining many different types of fill materials includ-ing those that are difficult to compress. Importantly,capsule formulations typically require less excipientthan tablet formulations and are, therefore, easier toformulate. Capsule formulations are by far the mostcommon dosage form for early phase clinical stud-ies where speed to clinic and early proof of safety andefficacy studies are desired. Cases exist where it waspossible to formulate a new product as a tablet but a

capsule was chosen as the commerical dosage form forspeed to market, usually for competitive reasons.

Regardless of the fill material type, the capsuleformulation must meet the following three importantrequirements:

Capsule filling. The formulation should runefficiently on the desired filling machine and

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should maintain content uniformity during thecourse of the filling runBioavailability. The contents of the capsulemust release in its entirety in-vivo to guarantee

good bioavailabilityCompatibility. The formulation must be com-patible with the capsule.

Capsule filling machines often operate at highspeeds and must accurately and consistently dosethe correct weight of fill material into each capsule.The following is a list of some of the more importantphysicochemical parameters to control for a smoothand efficient filling run:

Particle size and shape to assure homogeneity

and flowUniformity of particle size to assure constant fillweightsHomogeneity of the mixture to assurecontent uniformityFlow properties to assure accurate fill weights Appropriate moisture content; too high mayresult in powder caking and poor flow, andtoo low can result in a build-up of electrostaticcharge causing poor flow and a potential safetyhazard

Ability to form compacts under pressure in orderto meet the requirements of filling machine dos-ing mechanisms.

Some of the more common fill materials for cap-

sules are depicted in Figure 3 and are as follows.

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TABLE: Capsule volumes and filling capacities.

Size 000 00el 00 0el 0 1el 1 2el 2 3 4 5

Capsule volume (ml) 1.37 1.02 0.91 0.78 0.68 0.54 0.50 0.41 0.37 0.30 0.21 0.13

Powder tapped density Capsule capacity (mg)

0.6g/ml 822 612 546 468 408 324 300 246 222 180 126 78

0.8g/ml 1096 816 728 624 544 432 400 308 296 240 168 104

1.0g/ml 1370 1020 910 780 680 540 500 410 370 300 210 130

1.2g/ml 1644 1224 1092 936 816 648 600 492 444 360 252 156





Powders

The most common fill materials for two-piece capsulesare immediate release powders. Powders require fewerprocessing steps, reduced excipient requirement, andoverall time savings as compared to tabletting. It is

often possible to go directly from a dry powder blendto the filling machine with no intermediate steps.

Granules

Granules are useful when a powder formulationexhibits poor flow or inadequate content uniformity.Granules may be coated with gastric resistant polymersin cases where the drug is destroyed by stomach acids.Other polymer applications can be used to create adelayed release profile and to improve drug stability.Granules are often denser than comparable powder

formulations. This usually enables higher fill weightsand thus a smaller capsule size.

Pellets

Pellets are an excellent tool for numerous applications.Pellets can be coated with sustained release and entericfilm coatings to achieve unique release profiles ormultiple release rates in a single dosage unit by mixingpellets with different film coatings. Pellets also offerthe ability to mix multiple active ingredients or incom-patible active ingredients in a single capsule.

Tablets

A common application is the filling of tablets intocapsules for blinding in clinical trials or filling of mini-tablets coated to achieve multiple release profiles.

Liquid And Semisolids

As drug discovery continues to yield poorly watersoluble molecules, there is an increasing need for

formulation techniques that can improve drug solu-bility. One such approach is the use of lipid-basedformulations using either liquid-based systems orsemisolids to improve drug solubility and bioavail-ability. Two-piece hard capsules are an excellent

container for such formulations.

Dosing Of Pure Active Pharmaceutical Ingredient

Capsules may be filled directly with pure activeingredient as a means of achieving speed to clinicwithout the time requirement of preformulation,formulation, or stability studies. This approach isbecoming increasingly popular as developers faceescalating demands to reduce costs and determineproof of concept more quickly. Filling machinesdesigned specifically for this application are avail-

able and in some cases can accurately dose weightsas low as 100 mcg.

Dry Powder Inhalers

Two-piece hard capsules, especially those com-prised of hypromellose, are used in conjunctionwith specially designed inhalation devices forpulmonary delivery of medication. The benefit ofthis approach includes an inexpensive and portabledelivery system that does not require propellants,as well as the bypassing of hurdles for oral delivery

of peptides such as insulin.

ISSUES RELATED TO FILLING

It is important to establish filling limits and moni-tor and control each filling run. The basic steps todo so effectively are as follows:

Sample 10 capsules at regular intervals of15-30 minutes. Calculate average weight andweight range. The results may be plottedagainst target valuesIf the values are within specification but trend-

ing towards the upper or lower limit for sixconsecutive measurements, then the weight set-ting should be adjustedIf the mean or the range fall outside of thetarget values, then the run must be stoppedimmediately and an investigation performed toidentify the cause followed by corrective action

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Figure 3:

Capsule fill materials.



38 Journa l of GXP Compliance


Isolate all product collected from the previoussatisfactory weight check and either discard orweight-sort the capsules.

Quality Of Filled Capsules

It is important to perform periodic visual checks ofcapsules, usually at the same time as weight checks,to ensure that filled capsules meet acceptable qual-ity limits. Acceptable quality levels (AQLs) shouldbe established for visual appearance, and charts areusually available from the capsule supplier. Thefollowing are examples of quality problems, some ofwhich are related to filling machine set-up:

Punched ends—closing force is too highTelescoped or split capsules—misalignment ofupper and lower capsule segments, incorrect

setting in the joining stationPinholes and cracks that will lead to powderleakage from capsule—usually due to excessivevacuum during separation or incorrect setup ofthe joining pinGrease, which affects visual appearance.

A good operator training program and a detailedmachine set-up checklist are invaluable in reduc-ing the amount of waste from a capsule filling run.Problems such as content uniformity and weight

variation can often be traced back to issues thatbegan during capsule filling.

Stability And Storage

Two-piece hard gelatin capsuleshave a water content of 12%-15%. When moisture levels are below12%, capsule brittleness becomesa problem. When moisture levelsare above this range, deformationbecomes apparent. Empty hard

gelatin capsules should be storedin closed containers at 15°-25°Cand 35%-55% relative humidity(RH). Capsule filling should alsobe conducted under controlledtemperature and humidity condi-tions. Filled capsules should be

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stored in a controlled environment based on theproduct stability profile, and the storage area shouldhave a monitoring system. Figure 4 demonstratesthe effect of moisture content on capsule shell brit-tleness for both gelatin and hypromellose capsules

(discussed in a later section).It is always a good practice to ensure that all

fill materials are compatible with the hard gelatincapsule. For example, moisture sensitive drugsmay degrade in the presence of capsule moisture. Also, some excipients may be hygroscopic caus-ing the capsule shell to lose moisture and becomebrittle or discolored.

Packaging for hard gelatin capsules should pro-tect the capsules from both mechanical effects andhigh atmospheric humidity. High-density polyeth-

ylene bottles are usually an acceptable container forbulk capsules, though a desiccant may be requiredfor water sensitive drugs. For blister packaging,PVC alone may be acceptable but is known to havea high moisture vapor transmission rate. A combi-nation blister film of PVC/PVDC may be necessaryto minimize brittleness problems. Aluminum films,while expensive, provide an excellent moisturebarrier and may be the advisable choice for capsulescontaining water-sensitive drugs.

Gelatin crosslinking is a phenomenon wherein

amino acids from adjacent protein strands or withina protein strand bind together. Crosslinking causesthe formation of a swollen, rubbery, water-insolublemembrane (pellicle) during dissolution testing in

Figure 4:Mechanical properties.





distilled water. Figures 5 and 6demonstrate a dissolution me-dia of distilled water containingacceptable dissolving gelatincapsules and cross-linked cap-

sules. The insoluble film actsas a barrier to drug release andusually causes out-of-specifica-tion dissolution results. Com-mon causes of gelatin crosslink-ing include aldehydes (in theactive ingredient or excipients),high heat and humidity, andrayon coilers. FDA recognizesthe limitations of distilled waterdissolution media and has ap-

proved an enzyme test methodto remedy the problem of cross-linked gelatin capsules. Theenzyme dissolution test methodis official in the United StatesPharmacopeia, National Formu-lary (USP33-NF28).

CAPSULE MATERIALS

Gelatin and hypromellose arematerials used to make two-

piece hard capsules.

Gelatin

Gelatin is by far the most com-mon and well-known mate-rial used to produce two-piecehard capsules. Its origin hasalready been described in thisarticle. Gelatin has a long his-tory of safety and outstandingperformance characteristics

making it an excellent polymerfor producing capsules. It isnontoxic, widely used in foods,acceptable for use worldwide,and recognized in all pharma-ceutical pharmacopeia.

Figure 5:Passing capsules.

Figure 6:Cross-linked capsules.





Hypromellose

In recent years gelatin alternatives have been inves-tigated for reasons of stability and also because ofobjections to animal-derived materials. Hypromellosehas been extensively and successfully developed into

two-piece capsules for use in the pharmaceutical andnutritional industries and is available from numeroussuppliers. Hypromellose is a plant-derived materialand, therefore, answers the need for certain religious,cultural, and dietary restrictions.

Important benefits of hypromellose include a mois-ture content of approximately 4%-6% making it anexcellent container for moisture-sensitive drugs. Hy-promellose capsules are also less prone to brittleness. Additionally, hypromellose does not bind to itself;therefore, dissolution delays due to crosslinking are not

an issue. However, capsules made with hypromellosehave a higher oxygen transmission rate than thosemade from gelatin, which may be a consideration foroxygen-sensitive compounds.

Hypromellose capsules are manufactured by a dip-ping and curing process somewhat similar to that ofgelatin capsules. Though numerous manufacturersnow produce such capsules, it is important to be awarethat unlike gelatin capsules, there may be importantdifferences in the composition of hypromellose cap-sules. Depending on the capsule manufacturing pro-

cess, a gelling agent may be necessary. These gellingagents vary by supplier. For example, some capsulesmay be produced using gellan gum while others areproduced with various types of carrageenan. Eachof these gelling agents imparts different performancecharacteristics to the capsules. For certain manufac-turing processes a gelling agent may not be requiredand these are reported to have dissolution benefits overthose made with gelling agents. It is important to beaware of the complete composition of the hypromellosecapsules being used when developing a new product.

IMPLICATIONS FOR COMPLIANCE

The information discussed previously is fun-damental to the use and handling of two-piececapsules in pharmaceutical manufacturing.Compliance personnel should have a generalunderstanding of the properties of the active

drugs, products, and processes for which theyare responsible. This includes knowledge aboutthe inactive ingredients including the two-piececapsules used in product formulations. Qualitypersonnel should be aware of the potential prob-

lem areas that present high risk to manufactur-ing processes. This includes situations that maypotentially impact drug properties and productquality attributes such as stability, solubility, anddissolution. These risks should be appropriatelyevaluated and addressed with proactive responses.

The following are hard capsule considerationson which compliance personnel should be espe-cially vigilant:

Formulation changes. When changing cap-sule formulations, a stability study should be

conducted to assure that drug stability and dos-age forms visual appearance remains intact. Aparticular consideration for gelatin capsules is astability study to ensure that dissolution perfor-mance potentially affecting bioavailability is notadversely impacted by the formulation change. A formulation change might also cause capsulesto become brittle or deformed due to a hydro-dynamic effect. A filling machine trial shouldbe conducted on equipment representative ofa commercial filling machine to verify that the

formulation continues to meet specifications forcontent uniformity and uniformity of fill weightCapsule changes. When changing suppliersfor gelatin capsules it is necessary to performstability and dissolution testing to verify thatthe product meets established product perfor-mance criteria. In most cases an abbreviatedstability study will be acceptable, though a fullstability protocol may be required as a matterof company policy or for products with knownstability challenges. The need for a bioequiva-lence study when changing capsule suppliersis a question that often arises. In most cases,especially for immediate release powder for-mulations, bioequivalence studies are notconducted when changing gelatin capsule sup-pliers. However, this issue is usually taken ona case-by-case basis and needs to be addressed

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by the formulations, quality control, and regu-latory affairs teams. Due to potential variations in compositionamongst suppliers of hypromellose capsulesa supplier change will usually prompt a full

stability study and potentially a bioequivalencestudy. A change in capsule polymers (e.g., from gelatinto hypromellose) will most likely be viewed asa significant change requiring full stability andbioequivalence studiesCapsule storage and handling. To maintaincapsule integrity, empty capsules should bestored in closed containers under controlledconditions of 15°-25°C and 35%-55% RH.Capsule processing conditions. It is best to

avoid temperature extremes and maintain a rela-tive humidity of 40-60% when handling emptycapsules and storing filled capsules. If possible,finished product should be stored in an environ-ment monitored for temperature and humidityCapsule manufacturing. Capsule fillingmachines may vary in operating principle,machine set-up, and operation depending onthe machine supplier. Thorough and ongo-ing training of filling machine technicians isimperative to ensure efficient capsule filling

that meets product specifications with a mini-mum of rejected productCapsule product packaging. Because mois-ture is critical to the physical property of thecapsule shell, product packaging should besufficiently moisture resistant. Bulk high-den-sity polyethylene bottles are usually acceptablewith or without a desiccant. Blister materialscan be designed to provide adequate resistanceto moisture vapor transmission. Changes toblister films for cost reduction purposes shouldalso be carefully evaluated to avoid stabilityproblems with the final dosage form.

SUMMARY

This article has addressed the basics of two-piecehard capsule preparation as it relates to formula-tion development, stability, manufacturing, and

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patient compliance. Hard capsules are one of themost widely used dosage forms. Their formula-tion and processing have been well documentedfor many years. Over time, the expanded selectionof polymers has made the capsule dosage form

advantageous for a broad range of uses. Continu-ous technological innovations have considerablyincreased the speed of production with continuousmonitoring and adjustment capabilities.

Compliance personnel should be aware of thefactors affecting two-piece capsules and capsule fill-ing to ensure that finished product meets all speci-fications. Changes to the capsule supplier, poly-mer, fill formulation, or even capsule colorant canimpact product performance and must, therefore,be thoroughly evaluated before implementation.

Capsule moisture content is especially impor-tant to capsule performance. Capsule storage andhandling should be conducted under controlledconditions. Product packaging and stability musttake capsule moisture into consideration.

Capsule colorants and printing are useful meansof product identification. When evaluating a cap-sule color formulation and print ink, the compli-ance professional should confirm that all dyes andcolorants meet the regulatory requirements for theintended countries of distr ibution. Iron content

and daily iron intake limits must also be consideredwhen using capsules containing iron oxides.

Monitoring and continuous checks of the capsulefilling operation are important to ensure that thefinished product is in compliance. High rejectrates, frequent stoppages to the filling operation,and difficulty maintaining target fill weights are allindicators of a problematic process requiring inves-tigation and corrective action.

Two-piece hard capsules are a well-known andcharacterized dosage form and are recognized inall of the major pharmacopeia. Two-piece capsuleswill perform reliably when used in conjunctionwith a well understood formulation and validatedmanufacturing process. The use of colorants makesthe capsule an appealing and acceptable dosageform to the final user, the patient.



42 Journal of GXP Compliance


GENERAL REFERENCES

Augsburger, L.L ., “Hard and Soft Shell Capsules,” Modern Phar-

maceutics, Third Edition, Gilbert S. Banker, Christopher T.

Rhodes, Editors, Marcel Dekker, 1996.

Capsugel Division of Pfizer, Technical Reference File, February 2009.

Capsugel Library, “All About The Hard Gelatin Capsule,” 1997.Cole, G.C., “Capsule Types, Filling Tests, And Formulation,”

Hard Capsules, K.Ridgway Editor, The Pharmaceutical

Press, 1987.

Digenis, G.A., Gold, T.B., Shah,V.P., “Crosslinking Of Gelatin

Capsules And Its Relevance To Their In Vitro-In Vivo Perfor-

mance,” J.Pharm.Sci. 83, 7, 1994.

Lightfoot, D.K., “Capsule Filling, Answers to 10 Common Questions

About Capsule Filling,”Tablets and Capsules, January 2007.

Overgaard, A.B.A., Højsted, J., Hansen, R., Møleer-Sonner-

gaard, J., Christrup, L.L., “Patients Evaluation Of Shape,

Size And Colour Of Solid Dosage Forms,” Pharmacy World

& Science, Volume 23, Number 5, 2001.

Stegemann,S., “Colored Capsules-A Contribution to Drug

Safety,” Pharm.Ind. 67, No.5, pp 1088-1095, 2005. G X P

ABOUT THE AUTHOR

Dennis Murachanian, R.Ph., M.S. is Senior Manager of Business

Development at Capsugel Division of Pfizer. Dennis has been in

the pharmaceutical industry for over 20 years with experience

in formulations and technical operations. Dennis has been a

course instructor at numerous short courses and holds a patent

for novel drug delivery. He may be reached by e-mail at [email protected].

ABOUT THE COLUMN COORDINATOR

Armin H. Gerhardt, Ph.D., is an industry consultant who spent

more than 16 years at Abbott split between formulation services in

R&D and project management for new drug product development

teams. Armin retired from Abbott in 2007. He has taught various

courses in pharmaceutical processing for many years. Armin has

also authored book chapters on pharmaceutical unit operations.

He can be reached by e-mail at [email protected].



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Two-Piece Hard Capsules for Pharmaceutical Formulations

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