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Pharmaceutical Blister Packaging,Part I Rationale and Materials

Ron Pilchik

Eighty-five percent of solid drugs in Europe are packed in blisters, compared with less than 20% of those in the

United States. However, PHOTODISC, INC. blister packaging is becoming more accepted ackaging is one of the largest in- media to protect and promote their prod- in the United States as dustry sectors in the world, worth ucts, increase patient compliance, and both manufacturers and $280 billion. Consumer healthcare meet new regulations. consumers recognize its packaging represents 4% ($11.2 bil- Plion) of the packaging industry. As drug Basic configuration of benefits.This article manufacturers approach the 21st century, blister packaging discusses the materials they face a number of challenges that Background. Two basic types of pharma- used for blister packages packaging can help them meet. ceutical blister packages exist. In one va- and typical blister A decade ago packaging often was an riety the cavity is constructed of clear, constructions. afterthought for many pharmaceutical thermoformed , and the is companies, viewed as merely the final step formed of clear plastic or a combination in manufacturing. But now firms must of plastic, , and/or foil. The other consider packaging earlier during the de- type of package contains foil as an es- velopment process. Pharmaceutical pack- sential component of both webs, and its aging is quickly becoming an essential cavity is created by cold stretching. Fig- part of the drug delivery system as well ure 1 shows the basic configuration of a as a core element of the marketing mix, blister pack. Ron Pilchik is a principal at through which manufacturers can dif- In the early 1960s, Karl Klein designed The Techmark Group, 1040 North Kings Highway, Suite 707, ferentiate their products from those of the first machinery for producing push- Cherry Hill, NJ 08034-1921, their competitors. The demand for phar- through blister packaging. He did not ob- tel. 609.482.8871, fax 609.482. maceutical packaging is increasing and tain a patent for the design because the 9263, e-mail ronp@netreach. will continue to increase as companies European pharmaceutical industry was net,www.techmarkgroup.com. rely more on as not very interested in it — that is, until

68 Pharmaceutical Technology NOVEMBER 2000 www.pharmaportal.com the birth control pill was formulated a few United States, however, insurers allow a years later. For this revolutionary product longer supply period, typically 30 to 60 Plastic blister Schering (Berlin, Germany) chose blister days. The smaller European purchase packaging because it seemed to be the quantity favors blister packaging because most appropriate way to package the pill it costs less to package small numbers of Product for effective administration. items in blisters than in . Finally, Thus the most important reason for the European community has stronger introducing blister packaging technology environmental incentives to use blister Lid was to offer patients a clearly marked in- packaging. For example, manufacturers dividual dose, enabling them to check are penalized for introducing excessive Figure 1: The basic configuration of blister whether they had taken the prescribed material into the system. The use of blis- packaging. drugs on a given day. Moreover, the drugs ter packaging allows manufacturers to re- that were not taken remained in the ori- duce packages to a minimal size. an opened of pills has been stored ginal package and were fully protected Increased use in the United States. Blister under these conditions, the unused pills against adverse external conditions. The packaging is becoming more accepted in will never be the same. patient could handle the blister package the United States as pharmaceutical manu- Blister packaging, however, keeps each more easily and could store it more con- facturers and consumers recognize its tablet or capsule hermetically sealed in veniently than conventional packages. benefits. Blister packs can help patients its own bubble. Drugs that are not taken Very soon, manufacturers and pack- follow drug regimens, protect drugs over remain in the original package and are agers recognized other advantages of blis- a long , and are portable. Advo- fully protected against external condi- ter packaging such as the prevention of cates of blister packaging in the United tions. A blister protects a moisture- broken bottles and reduced costs and States cite five aspects in which blister sensitive tablet right up to administra- higher packaging speeds relative to other packaging is better than conventional tion. In contrast, the moisture in the packaging materials. Another important packaging. headspace of a multiple-unit bottle is re- benefit became apparent later: It is easier ● product integrity placed each time the bottle is opened. to prove misuse with blister packaging ● product protection Tamper evidence. Tamper evidence is an- than with conventional packaging. Thus, ● tamper evidence other strength of blister packaging. The blister packages effectively meet the de- ● reduced possibility of accidental misuse dosage units are individually sealed in mand for tamper-evident packaging. All ● patient compliance. constructions of plastic, foil, and/or these advantages explain why blister pack- Product integrity. The retail-level prepara- paper. The package must be designed so aging is used for approximately 85% of tion of prescription drugs in the United that one must tear the compartment to solid drugs in Europe. States is troubling. Pharmacists or phar- get at the product, and it must not be Use in Europe versus use in the United maceutical technicians count pills in the possible to separate the backing materi- States. The situation is just the opposite uncontrolled atmosphere of the super- als from the blister without leaving evi- in the United States, where virtually all market and drug store, where many fac- dence. Once a bottle has been opened, over-the-counter and prescription drugs tors can negatively affect sensitive drugs whatever tamper-evident mechanism it are packaged in bottles. For example, less as they are transferred from to had is gone. With blister packaging, how- than 20% of nonliquid pharmaceutical container. ever, each tablet or capsule is individu- products in the United States currently are Blister packaging helps retain product ally protected from tampering until use, sold in blister packs. integrity because drugs that are pre- so any form of tampering with a blister There has been a great deal of specula- packaged in blisters are shielded from package is immediately visible. tion about the causes for the difference in adverse conditions. Furthermore, oppor- Possibility of accidental misuse. Blister pack- the use of blister packaging in the United tunities for product contamination are aging also can be made child resistant, States and Europe. First, following World minimal, and each dose is identified by and several such designs currently are in War II, European product name, lot number, and expira- use. Most child-resistant blister packages (like almost everything else) lay in ruins. tion date. Therefore, blister packaging contain a paper/film layer with a peelable Drug packagers in Europe started over ensures product integrity from the pro- . Patients must peel the adhesive from scratch, and when they did they ducer directly through distribution to the away from the foil backing before the pill chose blister machinery over bottle equip- consumer. can be pushed through. Specifying 15-mil ment. Second, European regulations on Product protection. Blister packaging pro- (PVC) blister stock child-resistant closures are far less strin- tects pharmaceuticals in the home better provides extra security because it is less gent than rules in the United States. than bottles do. For example, most con- likely that children could puncture the A third reason lies in the differences sumers store their medicines within the package by biting through it. Companies among health plans in the two areas. In medicine cabinet in the bathroom. But the also are experimenting with bitter coat- Europe, most health plans limit the num- bathroom environment periodically is ings to deter children from putting pack- ber of units that can be prescribed at one filled with clouds of steam. As a result, it ages in their mouths. time to a 10- to 14-day supply. In the may be no exaggeration to say that once Patient compliance. Finally, an additional

70 Pharmaceutical Technology NOVEMBER 2000 www.pharmaportal.com The use of blister packaging in the Lidding material United States is on the rise. For example, several years ago the states of New York and New Jersey adopted regulations re- quiring hospitals to implement unit-dose blister-packaging distribution systems. The New Jersey Society of Hospital Pharmacists cited reports showing that fewer medication errors occur in such Forming film unit-dose blister package systems. Logic would seem to dictate that more states Lidding Inks Print primer will adopt similar regulations. Basic material Sealing agent Blister packaging components The four basic components of pharma- ceutical blister packages are the forming Basic material Forming film film, the lidding material, the heat-seal coating, and the ink (see Figure Figure 2: Basic components of blister packaging. 2). The most common blister package in the United States is made of a foil, film, paper, or multimaterial backing that is Table I: Comparison of forming films. adhered to a sheet of thermoformed plas- tic bubbles. Forming films account for ap- Type and Thickness WVTR Price per proximately 80–85% of the blister pack- 2 of Forming Film (mil) (g/m /day)* Unit Area** age, and lidding materials make up PVC (10) 1.1 1 15–20% of the total weight of the pack- PVC/PVDC (10/1.2) 0.17 2.1 age. Because the forming film and the lid- PVC/CTFE (8/0.76) 0.07 2.1 ding material form an integrated pack- PP (12) 0.20 1.3 age, they must match precisely. PET (10) 2.6 1.4 PS (12) 6 1.2 Forming film OPA/aluminum/PVC (1/1.8/2.4) 0 2.9 The forming film is the packaging com- *As measured on the unformed film at an ambient temperature of 20 ЊC and 85% RH. ponent that receives the product in deep- **Where 1 represents the price per unit area of 10-mil PVC. drawn pockets. One key to package suc- cess is selecting the right for benefit is the role of blister packaging in ● The cost of such noncompliance is esti- the blisters in terms of its property type, compliance. As many as 30% of all pre- mated at $13–15 billion annually. grade, and thickness. Consideration must scriptions are not taken properly initially, ● Twenty-three percent of the people ad- be given to the height and weight of the and as many as 50% are not continued mitted to nursing homes are aged and product, sharp or pointed edges of the after one year. Such misuse can cause a cannot manage their medications in final package, and the impact resistance, range of adverse drug reactions, includ- their own homes. aging, migration, and cost of the film. ing death. ● An estimated 125,000 people in the The plastic also must be compatible with The Healthcare Compliance Packaging United States each year because they the product. Factors influencing package Council (HCPC, Washington, DC) was do not take medications as prescribed. production and speed of assembly must formed in 1990 as a nonprofit corpora- ● The elderly population, which consumes be taken into account, including heat- tion to educate consumers, professionals, roughly 50% of all prescription drugs, sealing properties and the ease of cutting and policymakers in the healthcare field is growing, making abuse problems even and trimming formed blisters. about the role of blister packaging in more critical. Characteristics. Plastic forming films pharmaceutical compliance. Following are Furthermore, blister packs can be bar such as PVC, (PP), and some of the relevant data that HCPC has coded for use in hospitals and nursing (PET) can be thermoformed, uncovered in recent studies in the United homes to prevent errors in distributing but support materials containing alu- States: medication. One final important benefit minum are cold-formed. The forming ● A total of 1.8 billion prescriptions are of blister packaging in patient compliance film usually is colorless and transparent, given each year, and half are taken in- is that pharmacists have a greater oppor- but it can be obscured for use in child- correctly. tunity to communicate with and advise resistant packages or to protect light- ● Ten percent of all hospital admissions re- their patients because less time is neces- sensitive drugs. The forming web for blis- sult from pharmaceutical noncompliance. sary to fill the prescription. ter packs nearly always is PVC, sometimes

72 Pharmaceutical Technology NOVEMBER 2000 www.pharmaportal.com coated or laminated with additional com- ponents that enhance the oxygen and Inks water-vapor barrier. Table I compares the water-vapor transmission rate (WVTR) and the price per unit area of various Paper (45Ð50 g/m2) forming films. Adhesive Types of forming films. PVC forming film PET (12 ␮m) is called rigid PVC because it is almost free Adhesive of softening agents. Rigid PVC is a very Foil (15Ð25 ␮m) clear, stiff material with a low WVTR. It exhibits excellent thermoformability; a 2 high flexural strength; good chemical re- Heat-seal coating (6Ð9 g/m ) sistance; low permeability to oils, fats, and flavoring ingredients; easy tintability; and Figure 3: Cross section of a peel off–push through lidding material. low cost. These properties make rigid PVC the material of choice for blister packag- packages. The water-vapor permeability (PS) is perfectly compatible ing, and it essentially has 100% of the mar- of uncoated PP is lower than that of PVC with , but its high water- ket for the plastic component. PVC films and is comparable to that of PVDC-coated vapor permeability makes it unsuitable that are thermoformed have a thickness PVC. The thickness of PP films used in the as a blister material for pharmaceutical of about 10 mil. thermoforming process ranges from 10 to purposes. The use of PVC has attracted much 12 mil. Oriented (OPA)/aluminum/PVC or criticism because its combustion produces Advantages of PP include easy recycla- /aluminum/PVC. OPA/aluminum/PVC hydrochloride emissions and, under un- bility, no release of toxins during inciner- laminates are intriguing. With a laminate favorable conditions, highly toxic dioxins. ation, and good moisture-barrier proper- structure consisting of 1-mil OPA, 1.8- Legislation in Germany and Switzerland ties. PP is a possible replacement for PVC, mil aluminum, and 2.4-mil PVC it is pos- prohibits the incineration of PVC, the especially in Europe. sible to eliminate water-vapor permea- principal method of disposal used in those However, the use of PP has its draw- bility almost entirely. Moreover, because countries. This has created a bias toward backs. One problem is thermoforming. of the large proportion of aluminum in the use of PP for blister packaging in Eu- The temperatures required for thermo- the laminate, this material has rope, where many pharmaceutical com- forming PP and for the subsequent cool- become feasible (particularly because panies now stipulate that any new blister ing process must be controlled precisely. most lidding materials also contain alu- machines must be capable of handling Warping also can occur, in which the minum). Enormous efforts are being both PVC and PP. packages must be straightened before car- made to replace PVC with PP in such (PVDC)–coated PVC. Al- toning. Other difficulties associated with laminates to comply with environmental though its volume in is the use of PP include its thermal insta- standards. small, PVDC plays a critical role in blis- bility, higher rigidity than PVC, and sus- Like other laminates containing alu- ter packaging as or ceptibility to postprocessing shrinkage. minum, the OPA/aluminum/PVC lami- on PVC. PVDC is the most common coat- In addition, PP is difficult to run on a nate is cold-formed. Its cost per square ing in blister packaging because it can re- standard blister machine and cannot be meter can stand any critical comparison duce the gas and moisture permeability processed as fast as PVC. If a company with PVDC-coated PVC. Cold-forming, of PVC blister packages by a factor of runs PP and needs new equipment, it however, requires more packaging mate- 5–10. Coated PVC films have a thickness must go through a precise validation rial than does thermoforming to package of 8–10 mil; the thickness of the PVDC process, performing various tests on PP the same number of the same size of coat amounts to 1–2 mil. The coating is to satisfy FDA requirements. As a result, tablets or capsules. applied on one side and usually faces the PP is virtually nonexistent in pharma- CTFE homopolymer. Honeywell (Morris- product and the lidding material. ceutical blister packaging in the United town, NJ) recently introduced a 3-mil PVC/chlorotrifluoroethylene (CTFE). Films made States, and it still appears to be used mini- CTFE homopolymer barrier film (Aclar from PVC and CTFE have the lowest mally for that purpose in Europe. UltRx 3000) that can be thermoformed water-vapor permeability of all films used PET is another material that may replace easily and that exhibits the highest mois- for blister packaging. When compared with PVC, but its relatively high water-vapor ture barrier of clear films. This reflects the the water-vapor permeability of 10-mil permeability compared with that of PVC trend toward the use of higher-barrier PVC, the permeability of 8-mil PVC/0.76- will prevent its universal use. PVDC- materials. Various Aclar products have al- mil CTFE is lower by a factor of 15. How- coated PET could have the same water- lowed wider use of blister packaging be- ever, the environmental concerns regard- vapor barrier effect as PVC, but this does cause they can be thermoformed into ing PVC also apply to PVC/CTFE films. not appear to be promising in view of the clear or tinted blister cavities and exhibit PP. There is an increasing trend toward larger goal to replace chlorous with barrier properties close to those of the using PP as a support material for blister PET. near-perfect barrier offered by foil.

74 Pharmaceutical Technology NOVEMBER 2000 www.pharmaportal.com Table II: Comparison of lidding materials. be relatively thick for effective peeling. Be- cause printing is applied to the side with Price per Unit Area the paper, no print primer is required. Vir- Lidding Material (g/m2) Weight* tually all of the previous comments re- 0.8-mil Aluminum, hard, push-through 60 1 garding heat-sealing coating apply to com- 0.8-mil Aluminum, hard, heat seal–coated, binations of paper and aluminum. side-printed, push-through 61 1.25 Paper/PET/aluminum. Lidding material 1-mil Aluminum, soft, child resistant 76 1.15 made of a paper/PET/aluminum laminate 45 g(mϪ2)/1-mil Paper/aluminum, peel-off 121 1.55 is often called peel off–push through foil. 45 g(mϪ2)/0.48-mil Paper/PET/aluminum, This kind of material is used predomi- peel off–push through 142 2.00 nately in the United States. The concept *Where 1 represents the price per unit area of 0.8-mil, hard, push-through aluminum. is to first peel off the paper/PET laminate from the aluminum and then to push the tablet through the aluminum. Lidding materials be printed. A double coat of heat-sealing The lidding material provides the base or coating (a heat-sealing primer and the ac- Heat-seal coatings main structural component upon which tual heat-sealing coating) has become the For blister packages, heat-seal coatings are the final blister package is built. It must standard for lidding materials. perhaps the most critical component in be selected according to the size, shape, The heat-sealing primer ensures opti- the entire system. The appearance and and weight of the product as well as the mum adhesion of the heat-sealing coating physical integrity of the package depends style of the package to be produced. Lid- to the aluminum foil. The heat-sealing upon the quality of the heat-seal coating. ding materials range in caliper or thick- coating can then be matched to the formed Heat-seal coatings provide a bond be- ness from 0.36 to 0.76 mm, but 0.46–0.61 films. If the heat-sealing primers are col- tween the plastic blister and the printed mm is the most popular range. The sur- ored, applying the heat-sealing coating over lidding material. These solvent- or water- face of the lidding material must be com- the primer can protect the packaged prod- based coatings can be applied to rolls or patible with the heat-seal coating process. uct from coming in contact with the pig- sheets of printed using roll Clay coatings are added to the lidding ma- ments. If additional printing is required coaters, gravure or flexographic methods, terial to enhance printing. Heat-sealing on the side of the heat-sealing coating, the knives, silk-screening, or sprays. Whatever and printability are both important con- only alternative is to apply two coats of the the system, it is essential that the proper siderations in blister packaging, and the coating. This technique is necessary be- coating weight be applied to the lidding lidding material must offer the best work- cause the printing inks must be located be- material for optimum heat-sealing results. able compromise. tween the heat-sealing primer and the ac- Characteristics. A successful heat-seal Characteristics. The lidding material can tual heat-sealing coating. coating for blister packages must exhibit be clear plastic, but in pharmaceutical Soft aluminum (1 mil) frequently is used good gloss, clarity, abrasion resistance, and packaging it is either plain or printed 1- for child-resistant push-through foils. With hot tack and must seal to various blister mil foil (for push-through blister types) the exception of the type of aluminum films. Hot tack is particularly important or paper/foil or paper/PET/foil lamina- used, the structure of this lidding mater- because the product usually is loaded into tions (for child-resistant peel–push types). ial corresponds to that of hard aluminum the blister and the lidding material heat- The lidding material must guarantee a (0.8 mil). The softness and thickness of sealed in place (face down) onto the blis- WVTR that is at least as low as that of the this type of aluminum help prevent chil- ter. When the package is ejected from the forming films, and it must be suitable for dren from pushing tablets through it. This heat-seal jig, the still-warm bond line must the type of opening appropriate to the material also is supplied with a perfora- support its entire weight. A relatively low package (e.g., push-through or peel-off). tion along the sealed seams so that it can- heat-seal temperature is desirable for rapid Figure 3 shows a cross-section of a peel not be peeled off the formed film in one sealing and to prevent heat distortion of off–push through lidding material. Table piece. the blister film. II shows the comparative cost per unit Paper/aluminum. In combinations of paper Although heat-seal coatings used for area of various lidding materials. and aluminum, the weight of the paper blister packaging still are predominantly Types of lidding materials.Hard aluminum is amounts to 40–50 g/m2. In Europe, the solvent-based vinyls (because of their su- the most widely used push-through lidding thickness of the aluminum typically is perior gloss), water-based products are material in Europe. The foil usually has a 0.28–0.48 pm, but in the United States it making some inroads. However, they must thickness of 0.8 mil. There are endeavors, has a thickness of 0.6–1 mil. The reason be evaluated carefully for hot-tack prop- however, to reduce the thickness of this foil for this difference lies in the fact that this erties, gloss retention, adhesion to specific to 0.6 mil. The hardness of the aluminum lidding material is used in Europe for inks, and sealability to selected blister films. facilitates push-through opening. child-resistant push-through packages, so In addition, the heat-seal coating must Usually, only the print primer side fea- the aluminum foil must be relatively thin. precisely match the lidding material and tures a printed design, but occasionally the In the United States, this type of material the plastic material of the forming films. side with the heat-sealing coating also can is used as a peel-off foil, so the foil must Precisely match means that with pre-

76 Pharmaceutical Technology NOVEMBER 2000 www.pharmaportal.com determined sealing parameters, a per- Characteristics. One element of the manent sealing effect between the lidding foil/foil blister pack comprises a lamina- material and the forming film must be tion of plastic film (PVC or PE), adhesive, guaranteed under any climatic condi- foil, adhesive, and an outer plastic film. tions. The heat-seal coating must also en- The outer film, which can be PET or PVC, sure constant sealing for any given seal- supports the thin aluminum layer and acts ing parameter. With the proper heat-seal as the heat-seal layer. The aluminum layer coating, strong fiber-tearing bonds can usually consists of several very thin layers be obtained. Specifically, the sealing rather than a single thick one. The mul- strength must fall within predetermined tiple layers help ensure that pinholes do tolerance limits and must be suitable for not go all the way through the foil. They push-through or peel-off opening. The also increase the stretchability of the metal heat-seal coating also protects the printed and facilitate the cold-stretching process. area and provides a glossy finish. Most Even so, the brittleness of cold-formed importantly, the heat-seal coating must aluminum means that foil/foil blisters can- comply with FDA recommendations. not be made as formfitting as plastic ones. These multilayer webs are formed, filled, Printing inks and sealed on a machine that performs Printing inks provide graphics and aes- these functions in sequence much as the thetic appeal. They can be applied to the thermoform–fill–seal machine does ex- lidding material by letterpress, gravure, off- cept that neither web is heated before the set, flexographic, or silk-screen printing forming step. processes. Printing inks must resist heat- Process. During the cold-forming pro- sealing temperatures as high as 300 ЊC cess, the foil is shaped and molded around without showing any discoloration or a plug to form a cavity. As such, it is a tackiness (blocking). In addition, they must marginally more expensive process than sufficiently resist abrasion, bending, and thermoforming, and its tooling is a bit fading and must be safe for use with the more expensive than that of thermo- intended product. Printing inks should not formers. Upgrading is an option for many contain excessive amounts of hydrocarbon companies — most new machines can be lubricants, greases, oils, or release agents. converted to cold-form aluminum. One Qualification tests should always precede disadvantage is that the cavities must be production runs. Finally, printing inks made larger in the cold-forming process must comply with FDA recommendations. than during thermoforming, thus in- creasing the overall area of the package Cold-formed foil/foil and often allowing the product to shift Best known to Americans is the blister inside the blister. package made of a foil, film, paper, or Part II will discuss the technology of multimaterial backing that is adhered to blister package processing and the future a sheet of thermoformed plastic blisters. outlook for this packaging methodology. However, a less common type of blis- ter is the foil/foil used for prod- Acknowledgment ucts that are particularly susceptible to This information was presented in part moisture and/or light. Unlike all-plastic at FilmPack ’99 in Philadelphia, Pennsyl- blisters, these are not thermoformed but vania (3 December 1999). PT instead are cold-pressed into shape. Products that require the highest de- gree of protection are packed in an all-foil package. The use of cold-formable foils is growing because more moisture-sensitive drugs are on the market. Cold-formable foil is finding favor because it is the only material that provides a 100% barrier to moisture, oxygen, and light. This has helped expand the applications in which blisters can be used, allowing the blister packaging of sensitive products. Circle 49 or eINFO 49 www.pharmaportal.com Pharmaceutical Blister Packaging,Part II Machinery and Assembly

Ron Pilchik

lister packs are portable, can help aging will continue to increase the ap- patients follow drug regimens, and plicability of this method for containing can protect drugs over a long shelf and distributing pharmaceutical products. Blife. Advocates cite several aspects Figure 1 shows an example of a blister in which blister packaging is better than packaging machine. conventional packaging, including prod- General assembly. The sequence involves uct integrity, product production, tamper heating the plastic, thermoforming it into evidence, reduced possibility of acciden- blister cavities, loading the blister with the tal misuse, and patient compliance. Part I product, placing lidding material over the of this article discussed the materials used blister, and heat-sealing the package. This for blister packages and typical blister con- can be a simple manual process, or it can structions (1). Part II reviews the ma- be partially or fully automated. Although chinery, assembly, and costs of blister purchasing empty, preformed blisters and packaging and discusses future trends. lidding material and then filling the prod-

DAVID LOVEALL DAVID uct in a separate step is possible, this is Blister packaging machinery rarely done. Instead, the package is cre- Modern thermoform–fill–seal machines ated and filled on the same machine (see Blister packaging and labeling can operate at speeds р800 packages/min. Figure 2). is quickly being recognized Today, much of the emphasis in improv- Detailed assembly. Blister packaging ma- as a beneficial tool in helping ing production is placed on applying chines typically operate with intermittent manufacturers protect and microprocessor controls that electroni- motion. The seal is made during the dwell promote their products and cally connect the filling and forming time required for thermoforming. The es- meet new regulations. Part II equipment with other downstream ma- sential parts and functions of an inter- chinery for cartoning and wrapping. mittently operating packaging machine of this article reviews the These controls also feed tablets or liquids include the following. machinery, assembly, and into the unit-dose blisters, ensuring that The unwinding station.The unwinding sta- costs of blister packaging and an exact volume is put into each. Modern tion supplies the forming films and the discusses how clinical trials and machinery also uses integrated vision sys- lidding material at a rate corresponding recent regulatory developments tems to help ensure the accuracy of the to the speed of the packaging machine (see will grow the blister packaging fill and the integrity of the product in the Figure 1, part A). blister. These machines have become quite The heating station. The heating station industry in the United States. versatile and can readily accommodate raises the temperature of the plastic form- several types of lidstocks and basestocks, ing films to a level suitable for deep draw- allowing the manufacturer to obtain bet- ing. Forming films containing the ter compatibility between the medicine polyvinyl chloride (PVC) support mater- and its packaging material as well as bet- ial are heated to 120–140 ЊC. Polypropy- ter patient compliance. lene (PP) forming films are heated to Blister packaging offers many advan- 140–150 ЊC. Forming films containing Ron Pilchik is a business tages to the industry and to the public, aluminum are not heated before the form- manager at Mocon (Cherry Hill, NJ), tel. 856.482.8871 or and the machinery will continue to sup- ing process (see Figure 1, part B). 888.MEDIPKG, fax 856.482. port this proven form of pharmaceutical The forming station. The forming station 9263, e-mail ronp@netreach. packaging. Improvements in the form, forms the plastic blister cavities via com- net, www.mocon.com. materials, and machinery for blister pack- pressed air or die plates. Films containing

56 Pharmaceutical Technology DECEMBER 2000 www.pharmaportal.com separated into sheets that typically con- tain from 10 to 20 individual blisters. The vision system checks the filled packages for defects. Finally, a multi- packing machine packs the individual packages into bigger .

AB C D Blister packaging costs The package can significantly affect the A. Film strip unwinder B. Heating and thermoforming area profitability of drug products. Packaging C. Loading area costs are ϳ10% of the total product cost D. Heat sealing, die-cutting, ejection and leaving cut area for ethicals and as high as 50% of the total cost for over-the-counter (OTC) products. Figure 1: A blister packaging machine. 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 various Lidding material drug packages rarely are published. How- ever, one cost study reported that blister packaging for unit-dose oral medications Blister Lidding packs heat- Product Blisters is cost-competitive with bulk packaging cut off sealed inserted thermoformed in bottles (3). The study compared 60- and 125-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, Forming web NJ] in child-resistant and non-child- resistant versions). The researchers also considered expenses incurred for each component, including ● packaging-line operation (e.g., ma- Figure 2: A typical procedure for blister packaging assembly. chinery, line speed, efficiency, and staffing) Table I: Representative cost comparisons for packages containing 30 tablets. ● shipping ● freight Packaging Material Material Costs ($) Labor Costs ($) Total Costs ($) ● distribution 0.51 0.70 1.21 ● pharmacy inventory and dispensing. 0.125 0.70 0.825 The study found that when total sys- Blister pack 0.07 0.25 0.32 tem costs (including repackaging supplies and pharmacists’ time) are considered, blister packaging can represent a signifi- aluminum are formed with mechanical for a specified time, during which heat is cant savings over conventional bottles. For forming tools only (see Figure 1, part B). supplied. The mating surfaces fuse and example, a child-resistant, PVC blister The cooling station. The cooling station bond, setting almost instantaneously when package can save as much as $4.58 per 100 cools PP films after the forming process. heat input stops. Depending on the type doses when compared with a bottle. From Laminates containing PVC or aluminum of machine, the sealing temperature typi- a manufacturing perspective, however, do not need to be cooled. cally ranges between 140 and 340 ЊC. bottles tend to be more economical than The feeding machine.The loading area fills The cooling station. The cooling station is blister packages except for the most com- the blister cavities with product. The feed- necessary with all forming films (see Fig- pact blister formats and the simplest struc- ing machine can be linked, or the prod- ure 1, part D). PP forming films must be tures. Table I lists cost comparisons from uct to be packaged can simply be swept cooled longer than other types of film. the study. into the blisters (see Figure 1, part C). Labeling through packaging. Packages are la- In this example, even if material costs The sealing station. The sealing station heat- beled, notched, and then marked with a were doubled, a blister design would still seals the lidding material to the forming batch number at the coding station. The be favorable because the blister compo- film that contains the product (see Figure perforating device makes a cross-shaped nent accounts for only part of the mate- 1, part D). All heat-sealing methods mate perforation along the sealing seams. At the rial cost, with the rest being the lidding the blister and lid under constant pressure punching station, the packages are then structure, and the total cost would be just

58 Pharmaceutical Technology DECEMBER 2000 www.pharmaportal.com $0.32 per package. The fact that labor sav- of the ruling calls for unit-dose packag- companies in the highly competitive and ings account for most of the advantage in ing for iron-containing products con- rapidly changing pharmaceutical market the cost of blisters over plastic or glass taining at least 30 mg of iron per dosage come to rely more on packaging to pro- bottles is typical of flexible packaging be- unit. Some companies have had to take tect and promote their products. Although cause of its higher degree of automation. iron products off the market because they healthcare practitioners usually select the In addition, economies of production are were not in unit-dose packaging. Thus, to pharmaceutical product, drug manu- better in blister packaging because it is be in compliance, these companies will facturers must design their packaging with fully automatic and requires minimum have to use blister packaging. users in mind. Just as appearance and ease human support. Methamphetamine manufacturing. On 3 Oc- of use are important for consumer prod- Break-even point. At some product- tober 1996, President Clinton signed into ucts, they are key to a drug’s success. Fur- quantity point, the blister packaging loses law the comprehensive Methamphetamine thermore, for those OTC drugs and nu- its advantage, and bottles become more Control Act of 1996. The law broadens tritional supplements, consumer appeal cost-effective than blister packs. Gener- control over certain chemicals used in the is paramount. ally speaking, that break-even point is the production of methamphetamines, in- Companies that use blister packaging 100-count unit. Tablets distributed in creases penalties for the trafficking and will definitely have to face both challenges quantities of Ͻ100 can be packaged most manufacture of methamphetamines and and opportunities. Packaging engineers economically in blisters — say, 10 cards listed chemicals, and expands regulatory have been called upon to develop creative of 10 tablets each. Pharmaceutical prod- controls to include the distribution of cer- solutions for meeting the Consumer Prod- ucts distributed in quantities higher than tain lawfully marketed products that in- uct Safety Commission’s child-resistant that can be packaged most economically corporate ephedrine, pseudoephedrine and senior-friendly requirements. With in bottles. Therefore, this study indicated (PSE), and phenylpropanolamine (PPA). additional regulatory developments such that blister packaging is cheaper for small The law subjects transactions involving as the International Conference of Har- package counts in the 50–100 range and PSE and PPA to the registration, record- monization’s testing guidelines and FDA’s more expensive for package counts Ͼ100. keeping, and reporting requirements of rule on iron supplements, a large increase the Controlled Substances Act. in blister packaging use, along with the Future trends in blister packaging However, the law creates a safe-harbor use of innovative materials and designs, Unit-dose packaging is a major trend with exemption for the retail sale of ordinary is expected. PT a strong influence on blister packaging. In OTC products that contain PSE and addition, two major forces will have an PPA. To be included in the safe harbor, Reference enormous effect on the growth of blister the product must meet the following two 1. R. Pilchik, “Pharmaceutical Blister Packag- packaging in the United States: clinical tri- requirements: ing, Part I: Rationale and Materials,” Pharm. Technol. 24 (11), 68–78 (2000). ● als and regulatory developments. The package must contain not more 2. Code of Federal Regulations, Title 21, Food and Clinical trials. With the increasing inci- than 3 g of the base ingredient. Drugs, Parts 101, 111, and 310 (January dence of clinical trials, many of which re- ● The product must be in blister packs of 1997). quire complex regimens, more pharma- not more than two tablets per blister 3. Michigan State University School of Pack- ceutical companies are using blister (unless use of a blister pack is techni- aging (East Lansing, MI, 1994). packaging. From a convenience and pa- cally impossible, such as for liquids). tient compliance standpoint, the use of For products not packaged in accor- blister packaging in clinical trials can be dance with the safe-harbor exemption as beneficial. For example, for a dose-range of 3 October 1997, pharmaceutical retail- study in which patients should take four ers are required to register with the Drug tablets (or placebo) per day, the easiest Enforcement Administration if they sell packaging method is a blister pack. It is less more than 24 g in a single transaction and convenient for a patient to take a tablet to keep records of such transactions. In from one bottle, then a tablet from another other words, to avoid the paperwork in- bottle, etc. With a blister pack, all the med- volved in registering, a retailer should sell ication is in one place and is easily marked. certain OTC products containing PSE and New regulations. Two regulatory devel- PPA in blister packaging. The law is de- opments relating to iron supplements and signed to stop the unscrupulous manu- methamphetamine manufacturing also facture of illegal drugs from these sub- will affect the future growth of blister stances by making it more difficult to open packaging. each blister package to acquire the re- Iron supplements. FDA’s final rule titled quired amount of drug. “Iron-Containing Supplements and Drugs: Warning Statements and Conclusion Unit-Dose Packaging Requirements” took Demand for pharmaceutical packaging is effect on 15 July 1997 (2). One provision increasing and will continue to do so as

60 Pharmaceutical Technology DECEMBER 2000 www.pharmaportal.com