Compliance formats have advanced with innovations in package design,materials, and machinery.
By David Vaczek, Senior Editor
Compliance packaging has made great strides in the past 20 years, as the health industry has focused attention on promoting the safe and effective use by patients of their medications.
Challenged to ensure that the package going into the home is both child-resistant and easily accessible to seniors, suppliers and drug manufacturers have delivered a progression of innovation in package interfaces and structural designs.
With compliance formats, drugs are provided in unit-dose blisters, time-marked to help in regimen management, with literature for patient understanding of the drug and disease, and often with directions for finding more assistance.
As marketing departments embraced packages’ billboarding space for branding and promotional objectives, cartoned blisters debuted in easy-to-carry shapes and sizes for discretely fitting into daily routines.
Packaging Coordinators Inc. (PCI) was an early advocate of compliance packaging, and its Slide-Pack offered to the market in the 1990s provided a package that resisted access by children yet remained senior accessible.
“Non-compliance is a national health problem. And medical researchers and packaging experts concur that compliance blister packaging can improve the prescription-taking practices of millions of Americans,” said PCI president Daniel Gerner in 1997.
A growing body of studies have pointed to the advantage of blisters over bottles in furthering patient adherence. Studies from Michigan State University and Ohio State University demonstrated the packaging’s adherence benefits, and cost advantages when the time pharmacists spend counting out pills is factored in.
By 2012, the Healthcare Compliance Packaging Council issued a white paper reviewing eight studies that highlight improved adherence with blisters, including recent separate retrospective analyses of patient refill behavior sponsored by Meadwestvaco Healthcare and Catalent Pharma Solutions that showed adherence improvement to statistically significant levels.
Milestones In Compliance Packaging
1994-The BuSpar Dividose Tablet starter kit from Bristol-Myers Squibb, featuring 21 tabs in card format with literature for patients wins HCPC Compliance Package of the Year.
1994-Michigan State University study compares blister and bottle costs showing savings with blisters of $4.59 per 100 doses.
1995-Consumer Product Safety Commission (CPSC) increases the age bracket for testing to 50-to-70 years of age, acknowledging the aging of America and that a high percentage accidental ingestion by children occurs in grandparents’ homes.
1996-Procter & Gamble’s Helidac Therapy for duodenal ulcers individually packages each day’s supply of three medicines in senior-friendly, child-resistant blister format, supplied with patient booklet and reminder devices.
1996-Romaco Inc. debuts a system for 20-minute roll stock change over on its NOACK 900 blister thermoformer.
1998-International Conference on Harmonization issues new more stringent requirements for stability testing.
2001-Dividella debuts the NeoWallet packaging system for blisters. A range of compact, compliance Wallet and BoxWallet formats for NeoWallet production are introduced in subsequent years.
2001-Constantia Hueck Foils offers blister foil line sealable to Aclar, supporting improved barrier with ‘Aclar-In’ forming web structures.
2002-The Dosepak from Westvaco, featuring a senior-friendly peel-push blister in an outer carton with a child-resistant locking mechanism, is commercialized.
2002-MWV’s Shellpak, invented as the “Slimpak,” debuts, featuring a blister in an injection-molded plastic shell.
2003-Procter & Gamble’s Actonel 35-mg Dosepak osteoporosis drug with an F=1 CPSC test rating features the format’s extra panels for instruction and leaflets.
2004-MWV announces F=1 rating for the “Slimpak” design, that would be rebranded and relaunched as the Shellpak in 2006.
2005-FDA unit-of-use and bar code rule drives unit-of-use blisters in hospitals.
2006-Medicare Part D prescription drug benefit becomes available.
2006-Dividella develops its first F=1 rated BoxWallets, with the PeelPak and LabelPak.
2007-Klöckner Pentaplast offers the Pentapharm alfoil E S03 film as a transparent film with barrier comparable to higher grades of Aclar.
2007-Perlen Converting debuts its highest barrier PVdC film with Perlalux Tristar ultra.
2007-Rohrer AG introduces High-Pressure Cold Forming Technology, enabling almost as many blisters on a cold form card as with thermoformed film.
2007-Cardinal Health earns F=1 rating for its HingePak, a simple-to-manufacture design with sliding gates set in motion by pressing on a perfed tab.
2008-Alcoa Flexible Packaging offers Safety-Pak Plus lid stock, a paper-less laminate that expands the temperature sealing window.
2008-One World Design & Manufacturing Group debuts the NextBottle, a bottle that dispenses one dose at a time, with a compliance wheel dial mechanism for keeping track of day and hour.
2008-Walmart adopts MWV Healthcare’s Shellpak for generic drugs in its $4 RX program.
2009-Carton Service-Packaging Insights develops the CRx Pack, a fold-over blister pack with a proprietary CR locking mechanism, designed for high-speed automated production.
2009-McKesson RxPak launches the Burgopak for a sample kit including its LoyaltyScript card.
2009-MGS Machine debuts the modular design Blister Card Wallet machine, handling glue-style wallets and fold-over heat seal cards at 300 per minute.
2009-Alcan Global Pharmaceutical packaging launches four CR SF blister pack designs with unique packaging and opening features.
2009-Dosepak Express eliminates the heat sealed inner card of the Dosepak for cost reduction and easier production.
2010-Klöckner Pentaplast offers the Pentapharm kpVantage blister film platform that enables lower forming temperatures and faster line speeds.
2010-The Patient Protection and Affordable Care Act (“Healthcare Reform”) is enacted.
2010-McKesson RxPak launches the Burgopak in CR version for the U.S. market, with automated production using a Bosch Sigpack cartoning line.
2011-Tekni-Films relaunches the ALU-LOOK family of blister films for creating laminates with the high quality look of cold form.
2012-The Tasigna 150/200mg Dosepak physician sample from Novartis and Anderson Packaging wins HCPC 2011 Compliance Package of the Year. The kit features an instruction card on co-pay assistance, educational materials on DVD and USB device, a medication record keeper, patient guide, and wheel for seeing intervals for dosing and food consumption.
2012-Constantia Flexibles introduces EASY-PIESY CR blister lidding foil, a paper-free laminate enabling lower sealing temps and easier peeling.
2012-Amcor adds Interior Tinted/Printed Formpack to its cold form line, providing a better background for tablet vision inspection.
2012-Almac Pharma Services installs Uhlmann UPS4 for high speed thermoform and cold form blistering.
“Study after study over the past 20 years support the use of modernized patient-prompting packaging to improve patient adherence. We’re thrilled that the nation’s healthcare system is becoming more aware of the impact poor medication adherence has on the overall health of the populace,” commented HCPC executive director Walter Berghahn in 2012.
While many think that pharmaceutical blister packaging began with contraceptives, Melabon was packaged in a peel-off blister preceding contraceptives, according to “The Blister Blog,” a history of blister technology being compiled by Montesino Associates. (montesino.squarespace.com).
In year 2000, PMP News was citing blisters as the fastest growing segment of the healthcare packaging market, as containers offering improved compliance, portability, and shelf-life protection.
Retailers and hospitals have driven blister growth in demanding unit-dose packaging for its efficiency and patient safety advantages. Bob Hartwig, director of sales and marketing for Uhlmann Packaging Systems Inc. in 1998, identified hospitals as an “untapped” growth market, some years before FDA would require bar-coded, unit-dose blisters for hospitals.
“There is an exciting future ahead for compliance packaging. I see many more applications surfacing every year,” said Michael Castaldo, director of package development for Reed-Lane in 2001, noting the trend of multiple dosage forms supplied in the same pack for hospital pharmacies and nursing homes.
Momentum for compliance packaging was cited by Ed Hancock, president of American Health Packaging in 2004. “It is accepted that there is a need, and there is a groundswell of interest out there. I think we are on the threshold of a revolution in compliance packaging.”
In 2004, PMP News was reporting predictions of blister growth of 12% a year, noting an upswing in growth for hospitals, nursing homes, and sampling.
Pharmacies entered the picture as a force driving for compliance formats when Walmart in 2008 adopted Meadwestvaco Healthcare’s Shellpak for packaging generics in its $4 prescription program. Citing the packaging’s advantages for patient safety and for efficiencies in its reconfigured pharmacies, Walmart by 2012 would add the Ecoslide-RX compliance pack from Key Stone Folding Box Co. to the program.
“Walmart giving blisters out over the pharmacy counter for its 30-day regimens is something we wouldn’t have seen 10 years ago. Walmart broke the grid . . . and now other companies are following suit,” Ben Brower, vice president of sales, Pharmaworks, observed in 2011.
“The biggest driver for compliance packaging is on the commercial side, with generics approaching 80% of scripts in the United States,” says Peter Schmitt, managing director, Montesino Associates. “This means retail is selling the drugs, not big pharma. Walmart, CVS, and Rite Aid have figured out they have the muscle, and they don’t want their pharmacists counting out pills,” Schmitt adds.
Yet blister packaging has faced persisting head winds in the U.S. market. Patient familiarity with bottles and frustration with blisters has been a barrier. Many patients with multiple medications to organize empty the packs into other containers, thereby losing all the benefits of the original packaging including shelf-life protection.
An installed capital base for bottle production is a hurdle. Doctors have favored bottles as not constraining how may pills they can prescribe. Additionally, manufacturers in adopting blisters must design formats that both pass Consumer Product Safety Commission (CPSC) protocols and are yet easily manufactured.
In 2009, a dearth of new drug approvals—and a spate of drug firm mergers—were cited by blister machinery manufacturers as a drag on sales.
“We see 15% of tabs and capsules going into blisters, with the balance into bottles. That ratio hasn’t changed much in the last 20 years,” Bernie Conlon, president of Oystar USA Pharmaceutical Packaging Division of Oystar IWK, observed that year.
When CPSC in 1995 substituted seniors ages 50–70 for young adults on testing panels, the difficulty and expense of blister packaging was compounded. Packaging had to be made friendlier to debilitated seniors even as it stymied access by children.
Industry recognized the need for more-accessible compliance designs that would meet the CPSC testing hurdles.
| Using the Burgopak Slider pack, the patient holds down buttons on each side while pulling a tab to release the tray and leaflets. When the contents are pushed back in, the CR lock reengages.
“CPSC protocol testing certainly meets the regulation, but it does not always give you all the information you need to ensure your package will be well received in the market place” commented Arthur Jaeger, director of package development for Merck & Co. in 2001.
“What we are trying to accomplish with the CR package is to make it as intuitive as possible. And it’s hard to make a blister intuitive at a higher toxicity level. When a failure means that children can access just one tablet, a blister becomes a very difficult package to present, especially to arthritic patients or the elderly,” said John Bitner, manager of package design and development, Pharmacia that year.
FDA made a move that surprised many in 1997 when it called for unit-dose packaging of products containing 30 mg or more of iron per dosage unit—the first time the agency had mandated packaging. In 2003, an appeals court ruled FDA had overstepped its authority, as the power to regulate poison prevention packaging resides with CPSC.
FDA’s ruling was based on the false assumption that blisters are inherently CR, Bitner asserted in 2001, citing the need for a universal program of national education about poisons.
“The challenge with iron tablets was education. Young mothers in general did not realize that iron tablets could be harmful or toxic. They were left exposed and accessible to children,” says Bitner, now president of Bitner Associates Inc.
CPSC testing was spotlighted in 2003, when HCPC petitioned the commission to change its definition of test failure by removing the “amount that is toxic” clause. CPSC would deny that petition in 2005, leaving failure defined as a child accessing 8 units or an amount that can cause serious illness or injury, whatever is lower.
HCPC had argued the test definition creates a stricter standard on unit-dose packing than on bottles, and hence a disincentive for packagers to use
blisters. Among HCPC’s arguments were that children can access more pills when circumventing a bottle CR closure, whereas unit-dose packaging has the advantage of limiting the number of doses the child can consume once it gains access.
Blisters and cartoning would evolve to better accommodate seniors and ensure child resistance, with designs that focused on the patients’ cognitive ability rather than on strength or dexterity for opening.
“Some CR features can be a significant barrier to patient acceptance and adherence to dosing requirements. But don’t lose the benefit of unit-dose packaging. Look for solutions,” Stephen Hess, former director of packaging, Merck, advised in 2003.
Merck that year redesigned the Fosamax package, with a patented CR SF zipper-back feature.
Pfizer’s Z-Pak for the Zithromax antibiotic was held up as an example of how a user friendly package can win over customers who took to the product as the “Z-Pak” brand.
Procter & Gamble in 2003 debuted a package meeting CPSC’s highest F=1 rating with the Actonel 35-mg osteoporosis drug, using the Dosepak format’s extra panels to carry instruction and leaflets.
The Tasigna 150/200 mg physician sample from Novartis and Anderson Packaging earned HCPC’s 2011 Compliance Package of the Year. The CR Dosepak featured a Med Guide, an instruction card on co-pay assistance, education materials on DVD and a USB device, a recordkeeper for tracking medication use, and a wheel for seeing intervals for dosing and food consumption.
Suppliers have released new formats in a steady stream since the debut of MWV’s Dosepak in 2002. In Rondo/Dividella’s TopPak Box Wallet, the CR function is provided by the outer pack to which the blister is attached. Bosch Pharma Solid, of Bosch Packaging Technology, developed the SmartWallet for assembly with blister on the Bosch CUT130SW walleter. Keystone Folding Box Co. launched the Key Pack Plus, and Nosco the Key-In compliance package.
Suppliers emphasized portable designs. Stora Enso’s Pharm DDS is a slim, light-weight package with an opening lock feature requiring minimal dexterity. McKesson Rx-Pak launched the Burgopak in the United States, providing a pocketable format with sliding panels that keep the literature with the package.
In 2009, Anderson Packaging debuted the first commercial use of its F=1-rated IntuiDose package. The format emphasizes simple dispensing as tabs are pushed from the blister side through a perforated chad and a windowed back panel.
“Smart” packaging that electronically captures patients’ dosing behavior became more favored in clinical trials, an area where compliance formats have historically gained the most traction for keeping patients on trial protocols.
“We use blisters from a convenience and compliance standpoint. For a dose range study where the patient is taking four tablets a day or a placebo, the only way to do it is in a blister. It’s hard to tell a patient to take one tablet from (multiple bottles). With a blister, all the medication is there, easily marked,” Gary Puzio, clinical supplies manager, Phase IV research group, Schering-Plough, said in 1998.
Pharmaceutical companies dove deeper into package development with a focus on packaging tailored to patient subgroups. “Customers are not viewing this issue as one size fits all anymore,” noted Daryl Madeira then marketing director, Alcan Pharmaceutical packaging, in 2009, describing drug firms analyzing patient behavior to develop custom solutions designed for subsets of patients.
Materials and machinery for making blisters have progressed in hand with package design to ensure package performance and efficient manufacturing.
Joe Lally, director of sales at Howell Packaging in 2004, then noted the production concerns as Howell launched its Howell. CR. III compliance package. “The biggest challenge to package design and process engineering is to deliver packages that are practically manufactured at high speed and at low cost,” said Lally.
HIGHER BARRIER NEEDS
Packagers evaluating blister and lidding materials have had their hands full as a stream of new films, foils, and structures have come to market. In 1998, the International Conference on Harmonization put forth new accelerated stability test requirements, spurring use of higher barrier films.
“The testing conditions are much more severe now. The same drug that passed before won’t necessarily pass in the same package under the new stability testing,” Knud Christiansen, director of pharmaceutical films, Klöckner Pentaplast of America, said in 1998.
Higher-barrier materials are driven by drug forms more sensitive to oxygen, moisture, and light, expanding markets into challenging climate zones, and for assurance that packaging is not delayed in stability testing. In 2004, Klöckner Pentaplast offered Pentapharm Aclar G03 as a cost-effective alternative to foil. That year,
Tekni-Films added cold form foil to its product line, and a new MV02 series of high barrier laminate films.
“You look at PVC for example. A 0.9-ml thickness used to be the standard. Now its 2 ml—that reflects the shift to higher barrier materials,” commented Michiel van den Berg, director of global pharmaceutical package development of Tekni-Films, in 2004.
Suppliers’ response to the accelerating trend was noted by Remco Van Weeren, then senior vice president, films and foils, US, Bilcare Inc. in 2007: “There is a rush to develop cost-effective higher performance materials . . . and derive the optimal packaging based on products’ stability characteristics, and populate a range of cost/barrier alternatives,” Van Weeren said.
Technology advanced for handling difficult materials, as Kevin Carter, then market development specialist—pharmaceutical films, Klöckner Pentaplast of America Inc., noted in 2004. “The control systems around the forming systems have improved because of servo technology. Some companies are also using servo on plug-assist and can achieve an incremental depth control of 0.001 in. Because of these new control systems, you can get more precise parameters when you are setting up,” he said.
Servos brought more consistency to material handling, Walter Berghahn, then-director of machine sales and marketing, Uhlmann Packaging Systems, also noted that year.
“How the material comes out of the extruder affects how it stretches, shrinks, and forms. New machines all have devices to put things back in order. We can use servo index to adjust for shrinkage and stretch. Experience goes further than anything, even spec sheets. Specs are static, but machines are dynamic,” Berghahn said.
Material suppliers helped secure packaging against counterfeits. Perlen Converting offered hologram strips integrated into its Perlalux PVC and PVdC blister films. For creating a package that is difficult to duplicate, Bilcare provides metallized PVdC coatings that impart different colors and shades to the forming web.
High-capacity technology has remained in demand. For example, Sharp Corp. deployed the Stealth cartoner from MGS Machine Corp. for fully automated high speed production of the Dosepak. Yet market trends have favored lower capacity blister machines that can handle as many materials and formats as possible and are quickly reconfigured for new jobs.
“Flexibility is on everyone’s agenda as batch sizes have been shrinking for quite a while. For supplying to different countries, a packager might require different sizes, languages, and art work,” said Dirk Corsten, managing director, Uhlmann Packaging Systems, in 2009.
That year Sharp Corp supplemented high-capacity Uhlmann machines with the Uhlmann Blister Express Center 300 for small batch blistering and cartoning. Start-up contractor A+ Secure Packaging launched blister production in 2011 with two TF1e blister machines from Pharmworks Inc. for their small batch flexibility.
“The long campaign runs of a weeklong with the same product really are not typical anymore. The trend is to machines with a reasonable output that are extremely flexible, quickly changed over, easy to clean, and operator friendly,” commented Darren Meister, vp of sales, IMA Safe division of IMA NA in 2011, noting steady demand for IMA Safe’s Giant 1 blister/cartoner.
And addressing the smaller lot sizes, Körber Medipak company MediSeal in 2005 launched its late-stage customizing system in which blister production, cartoning, and printing are independently performed, supported by a BIB-BOB blister transport system. MediSeal would build on the concept with the White Line system, adopted by Bristol-Myers Squibb in Italy in 2010. The White Line system improves materials and inventory logistics and production efficiency by bundling small lots into one batch. Lidding, leaflets, and cartons are supplied blank and printed with country specific information on the packaging line.
Drugs—when they are taken—are often cited as the best value in healthcare. As reform has advanced in private and government health systems, adherence is being emphasized for reducing healthcare spending and improving patient outcomes.
With the enactment of healthcare reform in 2012, health systems have accelerated change in how healthcare is delivered and paid for. New payment models such as the Centers for Medicare and Medicaid Services’ Star Ratings program have promoted adherence practices.
With the changing focus on healthcare delivery, compliance packaging is considered in the larger context of the patient-provider relationship, as a supplement to caregiver instruction and support.
Not that the limits of packaging went unrecognized early on. PCI’s Gerner would observe in 2000: “You can write all the regulations you want, but none can be enforced when the patient takes the medication home and doesn’t use the package as intended. Pharmaceutical companies, government, pharmacists, and physicians all need to educate the population.”
The Institutes of Medicine cited a patient-provider “paradigm shift” in its report “Preventing Medical Errors,” saying, “patients should understand more about their medications and take more responsibility for monitoring those medications, while providers should take steps to educate, consult with, and listen to patients.”
“For decades, healthcare research and history has emphasized patient behavior as essential to sustainable recovery. And yet for decades the approach to compliance has been based on fear—which is a poor motivator to someone in pain and discomfort. The compliance package cannot stand alone as an independent compliant tool, [rather it] must be incorporated into a total patient adherence program,” Bitner says.
In one area of advancement, packagers are stepping up to the challenge of helping seniors manage multiple medications.
AvidiaMed, a Körber Medipak company, since 2012 in Germany has tested the MediFalter system which provides patients with one blister containing tabs sorted for the week with personalized dosage instructions.
Named by HCPC as the year’s best compliance package in 2012, the Avive customized dosing system from Meadwestvaco Healthcare advances a personalized medicine approach. The pharmacy service provides a month’s supply of medication packets with regimens customized to each patient.
“One of the huge unmet needs of current oral solids packaging is there is no way to handle patients taking multiple pills in multiple regimens. There is something wrong with the packaging if seniors are repackaging pills in plastic boxes at the home level, [behavior that is] fraught with all kind of problems,” says Montesino’s Schmitt.
“We at Montesino believe we are at the beginning of a transition [where] blisters and bottles will come together in a new kind of user interface. The Shellpak is not an elegant or perfect solution, but it is an interesting combination of rigid and flexible packaging that points the way to more development work and more rigorous packaging solutions,” Schmitt adds.
Packaging convergence with “intelligence” will be another big driver for compliance, where the patient points a cell phone at package bar code to receive supporting correspondence.
“Seniors like cell phones, and younger people are texting. For some of these more expensive drugs, companies can afford to give a cell phone away as part of the regimen,” says Schmitt.
Compliance packaging has “established itself as possibly a viable tool for patient adherence,” and yet is “sadly under-utilized,” Bitner says.
“A typical compliant package today is drab and dreary without focus on vital information such as regimen and importance of adherence to a healthy and fulfilling life. Package regimens need not add to the despair and frustration associated with illness.
“Creativity is not an expensive alternative. Creativity is a result of inspiration. Inspiration is born through leadership and intimate support. And the reward is unbiased, fact-based evidence that ‘people cure people’. The skill set is out there to respond with unprecedented technology,” Bitner adds.