Pharmaceutical Blister Packaging

68 Pharmaceutical Technology NOVEMBER 2000 www.pharmaporta l .com

ackaging is one of the largest in-dustry sectors in the world, worth$280 billion. Consumer healthcarepackaging represents 4% ($11.2 bil-

lion) of the packaging industry. As drugmanufacturers approach the 21st century,they face a number of challenges thatpackaging can help them meet.

A decade ago packaging often was anafterthought for many pharmaceuticalcompanies, viewed as merely the final stepin manufacturing. But now firms mustconsider packaging earlier during the de-velopment process. Pharmaceutical pack-aging is quickly becoming an essentialpart of the drug delivery system as wellas a core element of the marketing mix,through which manufacturers can dif-ferentiate their products from those oftheir competitors. The demand for phar-maceutical packaging is increasing andwill continue to increase as companiesrely more on packaging and labeling as

media to protect and promote their prod-ucts, increase patient compliance, andmeet new regulations.

Basic configuration ofblister packagingBackground. Two basic types of pharma-ceutical blister packages exist. In one va-riety the cavity is constructed of clear,thermoformed plastic, and the lid isformed of clear plastic or a combinationof plastic, paper, and/or foil. The othertype of package contains foil as an es-sential component of both webs, and itscavity is created by cold stretching. Fig-ure 1 shows the basic configuration of ablister pack.

In the early 1960s, Karl Klein designedthe first machinery for producing push-through blister packaging. He did not ob-tain a patent for the design because theEuropean pharmaceutical industry wasnot very interested in it — that is, until

Ron Pilchik is a principal atThe Techmark Group, 1040North Kings Highway, Suite 707,Cherry Hill, NJ 08034-1921, tel. 609.482.8871, fax 609.482.9263, e-mail [email protected],www.techmarkgroup.com.

Pharmaceutical Blister Packaging, Part IRationale and MaterialsRon Pilchik

Eighty-five percent ofsolid drugs in Europe arepacked in blisters,compared with less than20% of those in theUnited States. However,blister packaging isbecoming more acceptedin the United States asboth manufacturers andconsumers recognize itsbenefits. This articlediscusses the materialsused for blister packagesand typical blisterconstructions.

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the birth control pill was formulated a fewyears later. For this revolutionary productSchering (Berlin, Germany) chose blisterpackaging because it seemed to be themost appropriate way to package the pillfor effective administration.

Thus the most important reason forintroducing blister packaging technologywas to offer patients a clearly marked in-dividual dose, enabling them to checkwhether they had taken the prescribeddrugs on a given day. Moreover, the drugsthat were not taken remained in the ori-ginal package and were fully protectedagainst adverse external conditions. Thepatient could handle the blister packagemore easily and could store it more con-veniently than conventional packages.

Very soon, manufacturers and pack-agers recognized other advantages of blis-ter packaging such as the prevention ofbroken glass bottles and reduced costs andhigher packaging speeds relative to otherpackaging materials. Another importantbenefit became apparent later: It is easierto prove misuse with blister packagingthan with conventional packaging. Thus,blister packages effectively meet the de-mand for tamper-evident packaging. Allthese advantages explain why blister pack-aging is used for approximately 85% ofsolid drugs in Europe.

Use in Europe versus use in the UnitedStates. The situation is just the oppositein the United States, where virtually allover-the-counter and prescription drugsare packaged in bottles. For example, lessthan 20% of nonliquid pharmaceuticalproducts in the United States currently aresold in blister packs.

There has been a great deal of specula-tion about the causes for the difference inthe use of blister packaging in the UnitedStates and Europe. First, following WorldWar II, European packaging machinery(like almost everything else) lay in ruins.Drug packagers in Europe started overfrom scratch, and when they did theychose blister machinery over bottle equip-ment. Second, European regulations onchild-resistant closures are far less strin-gent than rules in the United States.

A third reason lies in the differencesamong health plans in the two areas. InEurope, most health plans limit the num-ber of units that can be prescribed at onetime to a 10- to 14-day supply. In the

United States, however, insurers allow alonger supply period, typically 30 to 60days. The smaller European purchasequantity favors blister packaging becauseit costs less to package small numbers ofitems in blisters than in bottles. Finally,the European community has strongerenvironmental incentives to use blisterpackaging. For example, manufacturersare penalized for introducing excessivematerial into the system. The use of blis-ter packaging allows manufacturers to re-duce packages to a minimal size.

Increased use in the United States. Blisterpackaging is becoming more accepted inthe United States as pharmaceutical manu-facturers and consumers recognize itsbenefits. Blister packs can help patientsfollow drug regimens, protect drugs overa long shelf life, and are portable. Advo-cates of blister packaging in the UnitedStates cite five aspects in which blisterpackaging is better than conventionalpackaging.● product integrity● product protection● tamper evidence● reduced possibility of accidental misuse ● patient compliance.

Product integrity. The retail-level prepara-tion of prescription drugs in the UnitedStates is troubling. Pharmacists or phar-maceutical technicians count pills in theuncontrolled atmosphere of the super-market and drug store, where many fac-tors can negatively affect sensitive drugsas they are transferred from container tocontainer.

Blister packaging helps retain productintegrity because drugs that are pre-packaged in blisters are shielded from adverse conditions. Furthermore, oppor-tunities for product contamination areminimal, and each dose is identified byproduct name, lot number, and expira-tion date. Therefore, blister packaging ensures product integrity from the pro-ducer directly through distribution to theconsumer.

Product protection. Blister packaging pro-tects pharmaceuticals in the home betterthan bottles do. For example, most con-sumers store their medicines within themedicine cabinet in the bathroom. But thebathroom environment periodically isfilled with clouds of steam. As a result, itmay be no exaggeration to say that once

an opened bottle of pills has been storedunder these conditions, the unused pillswill never be the same.

Blister packaging, however, keeps eachtablet or capsule hermetically sealed inits own bubble. Drugs that are not takenremain in the original package and arefully protected against external condi-tions. A blister protects a moisture-sensitive tablet right up to administra-tion. In contrast, the moisture in theheadspace of a multiple-unit bottle is re-placed each time the bottle is opened.

Tamper evidence. Tamper evidence is an-other strength of blister packaging. Thedosage units are individually sealed inconstructions of plastic, foil, and/orpaper. The package must be designed sothat one must tear the compartment toget at the product, and it must not bepossible to separate the backing materi-als from the blister without leaving evi-dence. Once a bottle has been opened,whatever tamper-evident mechanism ithad is gone. With blister packaging, how-ever, each tablet or capsule is individu-ally protected from tampering until use,so any form of tampering with a blisterpackage is immediately visible.

Possibility of accidental misuse. Blister pack-aging also can be made child resistant,and several such designs currently are inuse. Most child-resistant blister packagescontain a paper/film layer with a peelableadhesive. Patients must peel the adhesiveaway from the foil backing before the pillcan be pushed through. Specifying 15-milpolyvinyl chloride (PVC) blister stockprovides extra security because it is lesslikely that children could puncture thepackage by biting through it. Companiesalso are experimenting with bitter coat-ings to deter children from putting pack-ages in their mouths.

Patient compliance. Finally, an additional

Plastic blister

Product

Lid

Figure 1: The basic configuration of blisterpackaging.


benefit is the role of blister packaging incompliance. As many as 30% of all pre-scriptions are not taken properly initially,and as many as 50% are not continuedafter one year. Such misuse can cause arange of adverse drug reactions, includ-ing death.

The Healthcare Compliance PackagingCouncil (HCPC, Washington, DC) wasformed in 1990 as a nonprofit corpora-tion to educate consumers, professionals,and policymakers in the healthcare fieldabout the role of blister packaging inpharmaceutical compliance. Following aresome of the relevant data that HCPC hasuncovered in recent studies in the UnitedStates:● A total of 1.8 billion prescriptions are

given each year, and half are taken in-correctly.

● Ten percent of all hospital admissions re-sult from pharmaceutical noncompliance.

● The cost of such noncompliance is esti-mated at $13–15 billion annually.

● Twenty-three percent of the people ad-mitted to nursing homes are aged andcannot manage their medications intheir own homes.

● An estimated 125,000 people in theUnited States die each year because theydo not take medications as prescribed.

● The elderly population, which consumesroughly 50% of all prescription drugs,is growing, making abuse problems evenmore critical.Furthermore, blister packs can be bar

coded for use in hospitals and nursinghomes to prevent errors in distributingmedication. One final important benefitof blister packaging in patient complianceis that pharmacists have a greater oppor-tunity to communicate with and advisetheir patients because less time is neces-sary to fill the prescription.

The use of blister packaging in theUnited States is on the rise. For example,several years ago the states of New Yorkand New Jersey adopted regulations re-quiring hospitals to implement unit-doseblister-packaging distribution systems.The New Jersey Society of HospitalPharmacists cited reports showing thatfewer medication errors occur in suchunit-dose blister package systems. Logicwould seem to dictate that more stateswill adopt similar regulations.

Blister packaging componentsThe four basic components of pharma-ceutical blister packages are the formingfilm, the lidding material, the heat-sealcoating, and the printing ink (see Figure2). The most common blister package inthe United States is made of a foil, film,paper, or multimaterial backing that isadhered to a sheet of thermoformed plas-tic bubbles. Forming films account for ap-proximately 80–85% of the blister pack-age, and lidding materials make up15–20% of the total weight of the pack-age. Because the forming film and the lid-ding material form an integrated pack-age, they must match precisely.

Forming filmThe forming film is the packaging com-ponent that receives the product in deep-drawn pockets. One key to package suc-cess is selecting the right plastic film forthe blisters in terms of its property type,grade, and thickness. Consideration mustbe given to the height and weight of theproduct, sharp or pointed edges of thefinal package, and the impact resistance,aging, migration, and cost of the film.The plastic also must be compatible withthe product. Factors influencing packageproduction and speed of assembly mustbe taken into account, including heat-sealing properties and the ease of cuttingand trimming formed blisters.

Characteristics. Plastic forming filmssuch as PVC, polypropylene (PP), andpolyester (PET) can be thermoformed,but support materials containing alu-minum are cold-formed. The formingfilm usually is colorless and transparent,but it can be obscured for use in child-resistant packages or to protect light-sensitive drugs. The forming web for blis-ter packs nearly always is PVC, sometimes

Table I: Comparison of forming films.Type and Thickness WVTR Price perof Forming Film (mil) (g/m2/day)* Unit Area**

PVC (10) 1.1 1PVC/PVDC (10/1.2) 0.17 2.1PVC/CTFE (8/0.76) 0.07 2.1PP (12) 0.20 1.3PET (10) 2.6 1.4PS (12) 6 1.2OPA/aluminum/PVC (1/1.8/2.4) 0 2.9

*As measured on the unformed film at an ambient temperature of 20 8C and 85% RH.**Where 1 represents the price per unit area of 10-mil PVC.

Lidding material

Lidding

Forming film

Forming film

Basic material

Basic material

Print primerInks

Coating

Sealing agent

Figure 2: Basic components of blister packaging.


coated or laminated with additional com-ponents that enhance the oxygen andwater-vapor barrier. Table I compares thewater-vapor transmission rate (WVTR)and the price per unit area of variousforming films.

Types of forming films. PVC forming filmis called rigid PVC because it is almost freeof softening agents. Rigid PVC is a veryclear, stiff material with a low WVTR. Itexhibits excellent thermoformability; ahigh flexural strength; good chemical re-sistance; low permeability to oils, fats, andflavoring ingredients; easy tintability; andlow cost. These properties make rigid PVCthe material of choice for blister packag-ing, and it essentially has 100% of the mar-ket for the plastic component. PVC filmsthat are thermoformed have a thicknessof about 10 mil.

The use of PVC has attracted muchcriticism because its combustion produceshydrochloride emissions and, under un-favorable conditions, highly toxic dioxins.Legislation in Germany and Switzerlandprohibits the incineration of PVC, theprincipal method of disposal used in thosecountries. This has created a bias towardthe use of PP for blister packaging in Eu-rope, where many pharmaceutical com-panies now stipulate that any new blistermachines must be capable of handlingboth PVC and PP.

Polyvinylidene chloride (PVDC)–coated PVC. Al-though its volume in drug packaging issmall, PVDC plays a critical role in blis-ter packaging as laminations or coatingson PVC. PVDC is the most common coat-ing in blister packaging because it can re-duce the gas and moisture permeabilityof PVC blister packages by a factor of5–10. Coated PVC films have a thicknessof 8–10 mil; the thickness of the PVDCcoat amounts to 1–2 mil. The coating isapplied on one side and usually faces theproduct and the lidding material.

PVC/chlorotrifluoroethylene (CTFE). Films madefrom PVC and CTFE have the lowestwater-vapor permeability of all films usedfor blister packaging. When compared withthe water-vapor permeability of 10-milPVC, the permeability of 8-mil PVC/0.76-mil CTFE is lower by a factor of 15. How-ever, the environmental concerns regard-ing PVC also apply to PVC/CTFE films.

PP. There is an increasing trend towardusing PP as a support material for blister

packages. The water-vapor permeabilityof uncoated PP is lower than that of PVCand is comparable to that of PVDC-coatedPVC. The thickness of PP films used in thethermoforming process ranges from 10 to12 mil.

Advantages of PP include easy recycla-bility, no release of toxins during inciner-ation, and good moisture-barrier proper-ties. PP is a possible replacement for PVC,especially in Europe.

However, the use of PP has its draw-backs. One problem is thermoforming.The temperatures required for thermo-forming PP and for the subsequent cool-ing process must be controlled precisely.Warping also can occur, in which case thepackages must be straightened before car-toning. Other difficulties associated withthe use of PP include its thermal insta-bility, higher rigidity than PVC, and sus-ceptibility to postprocessing shrinkage.

In addition, PP is difficult to run on astandard blister machine and cannot beprocessed as fast as PVC. If a companyruns PP and needs new equipment, itmust go through a precise validationprocess, performing various tests on PPto satisfy FDA requirements. As a result,PP is virtually nonexistent in pharma-ceutical blister packaging in the UnitedStates, and it still appears to be used mini-mally for that purpose in Europe.

PET is another material that may replacePVC, but its relatively high water-vaporpermeability compared with that of PVCwill prevent its universal use. PVDC-coated PET could have the same water-vapor barrier effect as PVC, but this doesnot appear to be promising in view of thelarger goal to replace chlorous plastics withPET.

Polystyrene (PS) is perfectly compatiblewith thermoforming, but its high water-vapor permeability makes it unsuitableas a blister material for pharmaceuticalpurposes.

Oriented polyamide (OPA)/aluminum/PVC ornylon/aluminum/PVC. OPA/aluminum/PVClaminates are intriguing. With a laminatestructure consisting of 1-mil OPA, 1.8-mil aluminum, and 2.4-mil PVC it is pos-sible to eliminate water-vapor permea-bility almost entirely. Moreover, becauseof the large proportion of aluminum inthe laminate, recycling this material hasbecome feasible (particularly becausemost lidding materials also contain alu-minum). Enormous efforts are beingmade to replace PVC with PP in suchlaminates to comply with environmentalstandards.

Like other laminates containing alu-minum, the OPA/aluminum/PVC lami-nate is cold-formed. Its cost per squaremeter can stand any critical comparisonwith PVDC-coated PVC. Cold-forming,however, requires more packaging mate-rial than does thermoforming to packagethe same number of the same size oftablets or capsules.

CTFE homopolymer. Honeywell (Morris-town, NJ) recently introduced a 3-milCTFE homopolymer barrier film (AclarUltRx 3000) that can be thermoformedeasily and that exhibits the highest mois-ture barrier of clear films. This reflects thetrend toward the use of higher-barriermaterials. Various Aclar products have al-lowed wider use of blister packaging be-cause they can be thermoformed intoclear or tinted blister cavities and exhibitbarrier properties close to those of thenear-perfect barrier offered by foil.

Paper (45–50 g/m2)

Heat-seal coating (6–9 g/m2)

PET (12 mm)Adhesive

Inks

Foil (15–25 mm)

Adhesive

Figure 3: Cross section of a peel off–push through lidding material.


Lidding materialsThe lidding material provides the base ormain structural component upon whichthe final blister package is built. It mustbe selected according to the size, shape,and weight of the product as well as thestyle of the package to be produced. Lid-ding materials range in caliper or thick-ness from 0.36 to 0.76 mm, but 0.46–0.61mm is the most popular range. The sur-face of the lidding material must be com-patible with the heat-seal coating process.Clay coatings are added to the lidding ma-terial to enhance printing. Heat-sealingand printability are both important con-siderations in blister packaging, and thelidding material must offer the best work-able compromise.

Characteristics. The lidding material canbe clear plastic, but in pharmaceuticalpackaging it is either plain or printed 1-mil foil (for push-through blister types)or paper/foil or paper/PET/foil lamina-tions (for child-resistant peel–push types).The lidding material must guarantee aWVTR that is at least as low as that of theforming films, and it must be suitable forthe type of opening appropriate to thepackage (e.g., push-through or peel-off).Figure 3 shows a cross-section of a peeloff–push through lidding material. TableII shows the comparative cost per unitarea of various lidding materials.

Types of lidding materials. Hard aluminum isthe most widely used push-through liddingmaterial in Europe. The foil usually has athickness of 0.8 mil. There are endeavors,however, to reduce the thickness of this foilto 0.6 mil. The hardness of the aluminumfacilitates push-through opening.

Usually, only the print primer side fea-tures a printed design, but occasionally theside with the heat-sealing coating also can

be printed. A double coat of heat-sealingcoating (a heat-sealing primer and the ac-tual heat-sealing coating) has become thestandard for lidding materials.

The heat-sealing primer ensures opti-mum adhesion of the heat-sealing coatingto the aluminum foil. The heat-sealingcoating can then be matched to the formedfilms. If the heat-sealing primers are col-ored, applying the heat-sealing coating overthe primer can protect the packaged prod-uct from coming in contact with the pig-ments. If additional printing is requiredon the side of the heat-sealing coating, theonly alternative is to apply two coats of thecoating. This technique is necessary be-cause the printing inks must be located be-tween the heat-sealing primer and the ac-tual heat-sealing coating.

Soft aluminum (1 mil) frequently is usedfor child-resistant push-through foils. Withthe exception of the type of aluminumused, the structure of this lidding mater-ial corresponds to that of hard aluminum(0.8 mil). The softness and thickness ofthis type of aluminum help prevent chil-dren from pushing tablets through it. Thismaterial also is supplied with a perfora-tion along the sealed seams so that it can-not be peeled off the formed film in onepiece.

Paper/aluminum. In combinations of paperand aluminum, the weight of the paperamounts to 40–50 g/m2. In Europe, thethickness of the aluminum typically is0.28–0.48 pm, but in the United States ithas a thickness of 0.6–1 mil. The reasonfor this difference lies in the fact that thislidding material is used in Europe forchild-resistant push-through packages, sothe aluminum foil must be relatively thin.In the United States, this type of materialis used as a peel-off foil, so the foil must

be relatively thick for effective peeling. Be-cause printing is applied to the side withthe paper, no print primer is required. Vir-tually all of the previous comments re-garding heat-sealing coating apply to com-binations of paper and aluminum.

Paper/PET/aluminum. Lidding materialmade of a paper/PET/aluminum laminateis often called peel off–push through foil.This kind of material is used predomi-nately in the United States. The conceptis to first peel off the paper/PET laminatefrom the aluminum and then to push thetablet through the aluminum.

Heat-seal coatingsFor blister packages, heat-seal coatings areperhaps the most critical component inthe entire system. The appearance andphysical integrity of the package dependsupon the quality of the heat-seal coating.

Heat-seal coatings provide a bond be-tween the plastic blister and the printedlidding material. These solvent- or water-based coatings can be applied to rolls orsheets of printed paperboard using rollcoaters, gravure or flexographic methods,knives, silk-screening, or sprays. Whateverthe system, it is essential that the propercoating weight be applied to the liddingmaterial for optimum heat-sealing results.

Characteristics. A successful heat-sealcoating for blister packages must exhibitgood gloss, clarity, abrasion resistance, andhot tack and must seal to various blisterfilms. Hot tack is particularly importantbecause the product usually is loaded intothe blister and the lidding material heat-sealed in place (face down) onto the blis-ter. When the package is ejected from theheat-seal jig, the still-warm bond line mustsupport its entire weight. A relatively lowheat-seal temperature is desirable for rapidsealing and to prevent heat distortion ofthe blister film.

Although heat-seal coatings used forblister packaging still are predominantlysolvent-based vinyls (because of their su-perior gloss), water-based products aremaking some inroads. However, they mustbe evaluated carefully for hot-tack prop-erties, gloss retention, adhesion to specificinks, and sealability to selected blister films.

In addition, the heat-seal coating mustprecisely match the lidding material andthe plastic material of the forming films.Precisely match means that with pre-

Table II: Comparison of lidding materials.Price per Unit Area

Lidding Material (g/m2) Weight*

0.8-mil Aluminum, hard, push-through 60 10.8-mil Aluminum, hard, heat seal–coated,

side-printed, push-through 61 1.251-mil Aluminum, soft, child resistant 76 1.1545 g(m22)/1-mil Paper/aluminum, peel-off 121 1.5545 g(m22)/0.48-mil Paper/PET/aluminum,peel off–push through 142 2.00

*Where 1 represents the price per unit area of 0.8-mil, hard, push-through aluminum.

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determined sealing parameters, a per-manent sealing effect between the liddingmaterial and the forming film must beguaranteed under any climatic condi-tions. The heat-seal coating must also en-sure constant sealing for any given seal-ing parameter. With the proper heat-sealcoating, strong fiber-tearing bonds canbe obtained. Specifically, the sealingstrength must fall within predeterminedtolerance limits and must be suitable forpush-through or peel-off opening. Theheat-seal coating also protects the printedarea and provides a glossy finish. Mostimportantly, the heat-seal coating mustcomply with FDA recommendations.

Printing inksPrinting inks provide graphics and aes-thetic appeal. They can be applied to thelidding material by letterpress, gravure, off-set, flexographic, or silk-screen printingprocesses. Printing inks must resist heat-sealing temperatures as high as 300 8Cwithout showing any discoloration ortackiness (blocking). In addition, they mustsufficiently resist abrasion, bending, andfading and must be safe for use with theintended product. Printing inks should notcontain excessive amounts of hydrocarbonlubricants, greases, oils, or release agents.Qualification tests should always precedeproduction runs. Finally, printing inksmust comply with FDA recommendations.

Cold-formed foil/foilBest known to Americans is the blisterpackage made of a foil, film, paper, ormultimaterial backing that is adhered toa sheet of thermoformed plastic blisters.

However, a less common type of blis-ter is the foil/foil lamination used for prod-ucts that are particularly susceptible tomoisture and/or light. Unlike all-plasticblisters, these are not thermoformed butinstead are cold-pressed into shape.

Products that require the highest de-gree of protection are packed in an all-foilpackage. The use of cold-formable foils isgrowing because more moisture-sensitivedrugs are on the market. Cold-formablefoil is finding favor because it is the onlymaterial that provides a 100% barrier tomoisture, oxygen, and light. This hashelped expand the applications in whichblisters can be used, allowing the blisterpackaging of sensitive products.

Characteristics. One element of thefoil/foil blister pack comprises a lamina-tion of plastic film (PVC or PE), adhesive,foil, adhesive, and an outer plastic film.The outer film, which can be PET or PVC,supports the thin aluminum layer and actsas the heat-seal layer. The aluminum layerusually consists of several very thin layersrather than a single thick one. The mul-tiple layers help ensure that pinholes donot go all the way through the foil. Theyalso increase the stretchability of the metaland facilitate the cold-stretching process.

Even so, the brittleness of cold-formedaluminum means that foil/foil blisters can-not be made as formfitting as plastic ones.These multilayer webs are formed, filled,and sealed on a machine that performsthese functions in sequence much as thethermoform–fill–seal machine does ex-cept that neither web is heated before theforming step.

Process. During the cold-forming pro-cess, the foil is shaped and molded arounda plug to form a cavity. As such, it is amarginally more expensive process thanthermoforming, and its tooling is a bitmore expensive than that of thermo-formers. Upgrading is an option for manycompanies — most new machines can beconverted to cold-form aluminum. Onedisadvantage is that the cavities must bemade larger in the cold-forming processthan during thermoforming, thus in-creasing the overall area of the packageand often allowing the product to shiftinside the blister.

Part II will discuss the technology ofblister package processing and the futureoutlook for this packaging methodology.

AcknowledgmentThis information was presented in partat FilmPack ’99 in Philadelphia, Pennsyl-vania (3 December 1999). PT

Circle 49 or eINFO 49

56 Pharmaceutical Technology DECEMBER 2000 www.pharmaporta l .com

lister packs are portable, can helppatients follow drug regimens, andcan protect drugs over a long shelflife. Advocates cite several aspects

in which blister packaging is better thanconventional packaging, including prod-uct integrity, product production, tamperevidence, reduced possibility of acciden-tal misuse, and patient compliance. Part Iof this article discussed the materials usedfor blister packages and typical blister con-structions (1). Part II reviews the ma-chinery, assembly, and costs of blisterpackaging and discusses future trends.

Blister packaging machineryModern thermoform–fill–seal machinescan operate at speeds <800 packages/min.Today, much of the emphasis in improv-ing production is placed on applyingmicroprocessor controls that electroni-cally connect the filling and formingequipment with other downstream ma-chinery for cartoning and wrapping.These controls also feed tablets or liquidsinto the unit-dose blisters, ensuring thatan exact volume is put into each. Modernmachinery also uses integrated vision sys-tems to help ensure the accuracy of thefill and the integrity of the product in theblister. These machines have become quiteversatile and can readily accommodateseveral types of lidstocks and basestocks,allowing the manufacturer to obtain bet-ter compatibility between the medicineand its packaging material as well as bet-ter patient compliance.

Blister packaging offers many advan-tages to the industry and to the public,and the machinery will continue to sup-port this proven form of pharmaceuticalpackaging. Improvements in the form,materials, and machinery for blister pack-

aging will continue to increase the ap-plicability of this method for containingand distributing pharmaceutical products.Figure 1 shows an example of a blisterpackaging machine.

General assembly. The sequence involvesheating the plastic, thermoforming it intoblister cavities, loading the blister with theproduct, placing lidding material over theblister, and heat-sealing the package. Thiscan be a simple manual process, or it canbe partially or fully automated. Althoughpurchasing empty, preformed blisters andlidding material and then filling the prod-uct in a separate step is possible, this israrely done. Instead, the package is cre-ated and filled on the same machine (seeFigure 2).

Detailed assembly. Blister packaging ma-chines typically operate with intermittentmotion. The seal is made during the dwelltime required for thermoforming. The es-sential parts and functions of an inter-mittently operating packaging machineinclude the following.

The unwinding station. The unwinding sta-tion supplies the forming films and thelidding material at a rate correspondingto the speed of the packaging machine (seeFigure 1, part A).

The heating station. The heating stationraises the temperature of the plastic form-ing films to a level suitable for deep draw-ing. Forming films containing thepolyvinyl chloride (PVC) support mater-ial are heated to 120–140 8C. Polypropy-lene (PP) forming films are heated to140–150 8C. Forming films containingaluminum are not heated before the form-ing process (see Figure 1, part B).

The forming station. The forming stationforms the plastic blister cavities via com-pressed air or die plates. Films containing

Ron Pilchik is a businessmanager at Mocon (Cherry Hill,NJ), tel. 856.482.8871 or888.MEDIPKG, fax 856.482.9263, e-mail [email protected], www.mocon.com.

PharmaceuticalBlister Packaging, Part IIMachinery and AssemblyRon Pilchik

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Blister packaging and labeling is quickly being recognized as a beneficial tool in helpingmanufacturers protect andpromote their products andmeet new regulations. Part II of this article reviews themachinery, assembly, and costs of blister packaging anddiscusses how clinical trials andrecent regulatory developmentswill grow the blister packagingindustry in the United States.

B


aluminum are formed with mechanicalforming tools only (see Figure 1, part B).

The cooling station. The cooling stationcools PP films after the forming process.Laminates containing PVC or aluminumdo not need to be cooled.

The feeding machine. The loading area fillsthe blister cavities with product. The feed-ing machine can be linked, or the prod-uct to be packaged can simply be sweptinto the blisters (see Figure 1, part C).

The sealing station. The sealing station heat-seals the lidding material to the formingfilm that contains the product (see Figure1, part D). All heat-sealing methods matethe blister and lid under constant pressure

for a specified time, during which heat issupplied. The mating surfaces fuse andbond, setting almost instantaneously whenheat input stops. Depending on the typeof machine, the sealing temperature typi-cally ranges between 140 and 340 8C.

The cooling station. The cooling station isnecessary with all forming films (see Fig-ure 1, part D). PP forming films must becooled longer than other types of film.

Labeling through packaging. Packages are la-beled, notched, and then marked with abatch number at the coding station. Theperforating device makes a cross-shapedperforation along the sealing seams. At thepunching station, the packages are then

separated into sheets that typically con-tain from 10 to 20 individual blisters.

The vision system checks the filledpackages for defects. Finally, a multi-packing machine packs the individualpackages into bigger cartons.

Blister packaging costsThe package can significantly affect theprofitability of drug products. Packagingcosts are ;10% of the total product costfor ethicals and as high as 50% of the totalcost for over-the-counter (OTC) products.Therefore, sales can be positively or neg-atively influenced by the package, espe-cially in the case of OTC products.

Cost comparisons. The costs of variousdrug packages rarely are published. How-ever, one cost study reported that blisterpackaging for unit-dose oral medicationsis cost-competitive with bulk packagingin bottles (3). The study compared 60- and125-cm3 bottles with five sizes of blisters,dosage counts from 7 to 100, and six blis-ter structures (PVC, PVDC-coated PVC,and PVC/Aclar [Honeywell, Morristown,NJ] in child-resistant and non-child-resistant versions). The researchers alsoconsidered expenses incurred for eachcomponent, including● packaging-line operation (e.g., ma-

chinery, line speed, efficiency, andstaffing)

● shipping● freight● distribution● pharmacy inventory and dispensing.

The study found that when total sys-tem costs (including repackaging suppliesand pharmacists’ time) are considered,blister packaging can represent a signifi-cant savings over conventional bottles. Forexample, a child-resistant, PVC blisterpackage can save as much as $4.58 per 100doses when compared with a bottle. Froma manufacturing perspective, however,bottles tend to be more economical thanblister packages except for the most com-pact blister formats and the simplest struc-tures. Table I lists cost comparisons fromthe study.

In this example, even if material costswere doubled, a blister design would stillbe favorable because the blister compo-nent accounts for only part of the mate-rial cost, with the rest being the liddingstructure, and the total cost would be just

A. Film strip unwinderB. Heating and thermoforming areaC. Loading areaD. Heat sealing, die-cutting, ejection and leaving cut area

A B C D

Figure 1: A blister packaging machine.

Blisterpackscut off

Liddingheat-sealed

Productinserted

Blistersthermoformed

Lidding material

Forming web

Figure 2: A typical procedure for blister packaging assembly.

Table I: Representative cost comparisons for packages containing 30 tablets.Packaging Material Material Costs ($) Labor Costs ($) Total Costs ($)

Glass bottle 0.51 0.70 1.21Plastic bottle 0.125 0.70 0.825Blister pack 0.07 0.25 0.32


$0.32 per package. The fact that labor sav-ings account for most of the advantage inthe cost of blisters over plastic or glassbottles is typical of flexible packaging be-cause of its higher degree of automation.In addition, economies of production arebetter in blister packaging because it isfully automatic and requires minimumhuman support.

Break-even point. At some product-quantity point, the blister packaging losesits advantage, and bottles become morecost-effective than blister packs. Gener-ally speaking, that break-even point is the100-count unit. Tablets distributed inquantities of ,100 can be packaged mosteconomically in blisters — say, 10 cardsof 10 tablets each. Pharmaceutical prod-ucts distributed in quantities higher thanthat can be packaged most economicallyin bottles. Therefore, this study indicatedthat blister packaging is cheaper for smallpackage counts in the 50–100 range andmore expensive for package counts .100.

Future trends in blister packagingUnit-dose packaging is a major trend witha strong influence on blister packaging. Inaddition, two major forces will have anenormous effect on the growth of blisterpackaging in the United States: clinical tri-als and regulatory developments.

Clinical trials. With the increasing inci-dence of clinical trials, many of which re-quire complex regimens, more pharma-ceutical companies are using blisterpackaging. From a convenience and pa-tient compliance standpoint, the use ofblister packaging in clinical trials can bebeneficial. For example, for a dose-rangestudy in which patients should take fourtablets (or placebo) per day, the easiestpackaging method is a blister pack. It is lessconvenient for a patient to take a tabletfrom one bottle, then a tablet from anotherbottle, etc. With a blister pack, all the med-ication is in one place and is easily marked.

New regulations. Two regulatory devel-opments relating to iron supplements andmethamphetamine manufacturing alsowill affect the future growth of blisterpackaging.

Iron supplements. FDA’s final rule titled“Iron-Containing Supplements andDrugs: Label Warning Statements andUnit-Dose Packaging Requirements” tookeffect on 15 July 1997 (2). One provision

of the ruling calls for unit-dose packag-ing for iron-containing products con-taining at least 30 mg of iron per dosageunit. Some companies have had to takeiron products off the market because theywere not in unit-dose packaging. Thus, tobe in compliance, these companies willhave to use blister packaging.

Methamphetamine manufacturing. On 3 Oc-tober 1996, President Clinton signed intolaw the comprehensive MethamphetamineControl Act of 1996. The law broadenscontrol over certain chemicals used in theproduction of methamphetamines, in-creases penalties for the trafficking andmanufacture of methamphetamines andlisted chemicals, and expands regulatorycontrols to include the distribution of cer-tain lawfully marketed products that in-corporate ephedrine, pseudoephedrine(PSE), and phenylpropanolamine (PPA).The law subjects transactions involvingPSE and PPA to the registration, record-keeping, and reporting requirements ofthe Controlled Substances Act.

However, the law creates a safe-harborexemption for the retail sale of ordinaryOTC products that contain PSE andPPA. To be included in the safe harbor,the product must meet the following two requirements:● The package must contain not more

than 3 g of the base ingredient.● The product must be in blister packs of

not more than two tablets per blister(unless use of a blister pack is techni-cally impossible, such as for liquids).For products not packaged in accor-

dance with the safe-harbor exemption asof 3 October 1997, pharmaceutical retail-ers are required to register with the DrugEnforcement Administration if they sellmore than 24 g in a single transaction andto keep records of such transactions. Inother words, to avoid the paperwork in-volved in registering, a retailer should sellcertain OTC products containing PSE andPPA in blister packaging. The law is de-signed to stop the unscrupulous manu-facture of illegal drugs from these sub-stances by making it more difficult to openeach blister package to acquire the re-quired amount of drug.

ConclusionDemand for pharmaceutical packaging isincreasing and will continue to do so as

companies in the highly competitive andrapidly changing pharmaceutical marketcome to rely more on packaging to pro-tect and promote their products. Althoughhealthcare practitioners usually select thepharmaceutical product, drug manu-facturers must design their packaging withusers in mind. Just as appearance and easeof use are important for consumer prod-ucts, they are key to a drug’s success. Fur-thermore, for those OTC drugs and nu-tritional supplements, consumer appealis paramount.

Companies that use blister packagingwill definitely have to face both challengesand opportunities. Packaging engineershave been called upon to develop creativesolutions for meeting the Consumer Prod-uct Safety Commission’s child-resistantand senior-friendly requirements. Withadditional regulatory developments suchas the International Conference of Har-monization’s testing guidelines and FDA’srule on iron supplements, a large increasein blister packaging use, along with theuse of innovative materials and designs,is expected. PT

Reference1. R. Pilchik, “Pharmaceutical Blister Packag-

ing, Part I: Rationale and Materials,” Pharm.Technol. 24 (11), 68–78 (2000).

2. Code of Federal Regulations, Title 21, Food andDrugs, Parts 101, 111, and 310 (January1997).

3. Michigan State University School of Pack-aging (East Lansing, MI, 1994).

Pharmaceutical Blister Packaging

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