F.J. Quinn, Contributing Editor

Fig. 1. Savsu’s PHD shipper for small volumes.

		Upholding cold-chain integrity and regulatory compliance standards are morphing into major issues, experts say, with the explosion of temperature-sensitive pharmaceutical products, new global and regional manufacturing mandates, and supply chains extending worldwide. These are among the primary drivers affecting the development of specialized shipping boxes and containers used for transporting these drugs to market.

		The stakes are high, as an estimated $243 billion worth of cold-chain biopharmaceuticals will be in worldwide distribution by 2016, up 55% from 2010, according to the Biopharma Cold Chain Sourcebook published by Pharmaceutical Commerce. The majority of biotech products require refrigerated (2—8°C) storage and transportation, as do most vaccines, blood products and other injectables. Meanwhile, regulatory requirements for what has traditionally been called “controlled room temperature” (CRT) storage (15–25°C) and transportation are tightening—and that covers the majority of pharmaceuticals.

		Last year, Pharmaceutical Commerce listed more than 35 suppliers of temperature-sensitive packaging solutions (

), and each year, a handful of new companies show up at industry events offering novel combinations of packaging materials, insulation and refrigerants.

		Among the most significant policy changes made in the past three years are “Good Distribution Practices” (GDPs). These regulations exist in various forms and numerous countries or regulatory jurisdictions, and their principles are in place in many contractual agreements between manufacturers and service providers. Many GDPs share the same basic principles: document and verify work processes; test and monitor equipment (including temperature mapping of containers); and document actual performance of cold chain tasks.

		“Prior to the regulations, companies were not required to ship CRT drugs in temperature-controlled packages,” notes Stu Krupnick, global marketing manager, Sonoco ThermoSafe (Arlington Heights, IL), a provider of assurance packaging products. “With this change, temperature-controlled shippers are needed, which can significantly add to a company’s cost.” To address this requirement, Sonoco ThermoSafe launched a number of parcel- and pallet-sized CRT shippers in 2013, with more in development to address specific logistics needs in Europe.

		The latest jurisdiction to implement a regulatory change, the European Union (EU), has already created a stir, industry members say. Implemented last July, the GDP places an emphasis on taking temperature-controlled distribution management from a prescriptive process of selecting appropriate packaging. As a result, shippers are re-examining their current practices and packaging and often finding problems with their current solutions.

		Many are finding that their packaging is non-compliant or there are more cost-effective solutions available, experts say. “Products that formerly were shipped in the ambient environment now must have further proof that the shipping environment does fall within their stability,” says Karl Kussow, manager of quality and validation for FedEx Custom Critical (Uniontown, OH), which specializes in expedited freight shipping and solutions for transporting sensitive shipments. “If not, then appropriate packaging or containers must be used.” FedEx Custom Critical recently launched a service called Temp-Assure Shipping Studies which enables customers to improve the quality of their temperature-control supply chain through a combination of research, evaluation and recommendations related to specific shipping methods and lanes.

		The EU GDP specifies that for temperature-sensitive products, qualified equipment—such as thermal packaging, temperature-controlled containers or vehicles&mdash;be used to ensure correct conditions are maintained between the manufacturer, intermediate points and ultimately the customer. It calls for staff to be properly trained and written procedures for assembly and handling. “The extent to which this affects package selection cannot be determined,” Krupnick says. “It does imply, however, that users understand how their packaging performs, that they can document that it performs as expected, and that the implementing parties within the supply chain can be held accountable if they do not.”

		Observers say the requirements emphasize the importance of selecting high-performance insulated packaging and increases the relevance of developing a partnership with packaging manufacturers and suppliers. With increased monitoring and tracking requirements, there is expected to be an increased need for packaging that performs to tight specifications, even in harsh ambient environments or through unanticipated delays. “Companies will need packaging that is proven to maintain temperatures consistently and for longer periods of time, in some cases, using this packaging to control temperature throughout the last mile,” says Christy Ogrean, director of marketing, American Aerogel (Rochester, NY), a producer of aerogel-based insulation products used in thermal packaging systems.

Fig. 2. ThermoSafe’s family of passive shipping containers. 

		Over the past five years or so, the momentum for innovative shipping solutions has been in “active” containers—essentially mobile, battery-powered or plug-in refrigerators. The field was pioneered by Envirotainer (Upplands Vasby, Sweden); CSafe (Akron, OH) is a rising competitor, as is PharmaPort, exclusively licensed to UPS. The units are generally regarded as reliable, but expensive when used as “unit-load devices” (ULDs) in the bellies of widebody aircraft. More recently, there are the beginnings of a countermovement back to “passive” (non-powered) containers, including ones that can hold a pallet-size shipment.

		Innovations in passive containers include hard-cased and reusable systems, vacuum-based insulation panels, composite container walls that are more compact, and a growing variety of phase-change materials, which are used in gel packs to provide cooling. “Advanced technology such as vacuum insulated panels and phase change materials, if designed and handled properly, are proving to be a superior method of providing passive protection,” says Kevin Lawler, VP of sales and marketing, Minnesota Thermal Science (Plymouth, MN; Minnesota Thermal is now a subsidiary of Pelican Products, Inc.). “The technology allows for efficiency advantages, results in much more cost-effective solutions, and in regards to use, results in a much simpler container to prepare and pack out.”

		Each type of passive cooling system provides its share of benefits and drawbacks, experts say. “For many shipments that do not require strict temperature performance, one of these passive systems may provide cost savings over an active solution,” says Brian Kohr, CEO at CSafe (which also markets the AcuTemp line of passive containers). “It all depends upon the payload size, desired thermal performance, dimensional weight charged by the airlines, whether the system needs to be repositioned in transit.”

		Sonoco ThermoSafe offers innovative passive solutions for the cold chain industry, as evidenced by its patented convection and Stratta technologies. “A great deal of our research and development focuses on new insulation materials and refrigerants,” Krupnick says. “Ultimately, we want to provide our customers with the lowest total cost of ownership solutions available to meet their exact requirements.”

		Weight and size are among the biggest cost determinants in air freight, and being able to optimize the balance between container size and actual payload is key to providing a cost-effective solution, experts say. Minnesota Thermal Science’s Credo Cube reusable thermal packaging allows clients to ship product or clinical trial materials in containers that can be 50% smaller in outer dimension, with up to 50% larger payload areas and 30%+ lower tare weight. “Combined with the advanced performance of the packaging, it allows the client to ship more product with less packaging, at a lower service level, that in the end can save 30 to 50% on transportation,” Lawler says.

		Further cost reductions are being realized through greater use of bulk or pallet-sized shippers. The trend is driving packaging manufacturers to expand their product offerings to cover additional sizes, durations and temperature ranges. “This is due to the globalization of the pharmaceutical industry which is requiring more products to be shipped to various locations worldwide in bulk,” Sonoco ThermoSafe’s Krupnick says. “Meanwhile, outsourcing trends in manufacturing and the growth in clinical trials in BRIC countries are also contributors.”

		In addition to cost, sustainability initiatives to reduce waste from used packaging materials are also impacting selections by pharma companies. “We are seeing increased interest for our reusable passive packaging,” CSafe’s Kohr says, “as our ability to ensure packaging performance prior to each re-use ensures the integrity of a qualified solution while providing the cost savings that supply chain managers seek.”

		Cryopak Industries, a division of TCP Reliable (Edison, NJ), a packaging solutions provider, reports clients are being asked to implement qualified packaging faster that best addresses their green initiatives. “This includes packaging that is smaller, lighter and simple to condition and pack out,” says Bill Hingle, marketing director. “These needs are coupled with the continued need to be cost effective to implement and be done in a short timeline for development.”

		Cryopak offers Cryo-Gel gel packs, which are re-usable, and said to last longer than ice, while the refrigerant gel is designed to protect products from freezing or over-heating for safe transport of healthcare products. It is available in a durable, laminated, plastic pouch, or a Cryo-Gel 2 “no-sweat” paper material to protect against condensation touching the product.

Fig. 4. American Aerogel’s vacuum-panel shipper. 

Articles

Cold chain packagers balance cost, performance and compliance approaches

New cold chain solutions meet regulatory, shipper requirements

Credit: Top: Almac Clinical Services; Bottom: PCI

		The size of clinical trials continues to expand, observers say, creating a ripple effect in pharmaceutical packaging. More emphasis is being placed on secondary packaging design to minimize risk of product damage or activation during shipment. Studies are also becoming larger, as regulators encourage the pharmaceutical industry to test a greater number of patients.

		The challenge is preparing supplies that prompt compliance, as many clinical studies have complex dosing regimens and require packaging components to be flexible and applicable for all study countries. “We are now seeing more requests to design packaging for injectable investigative drugs, all requiring different packaging from what is typically used for solid dose formats,” observes Ed Bani, technical service manager, Rondo-Pak (Norristown, PA), a manufacturer of cGMP compliant pharmaceutical folding cartons. “But regardless of the medicine form, clinical trials customers want the best of both worlds for their packaging: patient-friendly packaging with clear, concise labeling for patient compliance that still maintains the rigid standards for filling, assembly, storage, stability and containment of the product.”

		The most common types of packages for clinical trials are blisters, bottles, pouches, syringes and tubes, industry members say. Each may be assembled in different configurations, so as to drive study compliance. “Since a majority of clinical supplies require a high degree of human interaction with the unique package designs, none pose a particular set of issues over the other types,” says Joe Morris, president, Sharp Clinical Services (Allentown, PA), a provider of clinical trial materials services to the pharmaceutical and biotechnology industries.

		Medication adherence is having a substantial impact on the approval criteria for drug candidates, according to published reports. FDA recently provided a draft guidance specifically addressing adherence strategies, including encouraging sponsors to implement adherence practices, such as using smart bottles to monitor medication use. Since pharma companies can control the packaging, as such, it is viewed as a key tool for driving patient adherence.

		“MWV’s Aardex Solution uses a ‘smart’ technology called MEMS Caps, which is used to measure adherence patterns of clinical trial subjects,” notes Tom Grinnan, senior director, global patient adherence, MeadWestvaco Healthcare (MWV; Richmond, VA), a designer and producer of integrated primary and secondary packaging solutions for the healthcare and pharmaceutical industry. “The Aardex Solution provides the technology, analytical tools and analysis to monitor patient adherence in a trial and show the impact.” Better understanding of patient adherence during a trial can lead to improved trial efficiencies and optimized trial outcomes, experts say, and boosts the chances of the drugs being commercialized.

		To meet study compliance requirements, the use of blister packaging along with CR wallet cards is reportedly common for later phase studies. Generally, blisters are more compliant, especially if titration is involved or the patient needs to take two different products. A blister may also be required due to the stability of a drug.

		Wallet-style blister packs are used for solid oral medications and available in child-resistant formats, such as MWV’s Dosepak. The manufacturing and filling processes for wallets and blister packs can be automated, experts say, although handwork usually occurs for portions of these processes. “An increasing number of trial packs are used for injectable and inhaled medications,” Grinnan observes. “These package types tend to be highly customized ‘kit’ packages that require manual fulfillment.”

		The same wallet card format may contain different product strengths—including placebo and comparator product&mdash;that all look the same to protect product “blinding” for the study. Everything&mdash;from the positioning of any printed elements to the color&mdash;has to look exactly identical, to ensure no one will be able to spot any differences. By comparison, commercial drugs are packaged one dosage strength/product at a time. “A select group have the knowledge of what is actually contained in the package by virtue of the product identifiers,” says Bob Misher, general manager and senior vice president, clinical services, Packaging Coordinators Inc. (PCI; Philadelphia), a provider of pharma commercial packaging solutions and clinical trial services. As a result, the controls to manage different products that look identical are rigorous.

How clinical packaging, commercial packaging runs differ

		On the surface, clinical trials and commercial runs appear to be similar in that each requires a robustly tested match of product and the primary package. However, clinical runs differ in that a package may contain multiple products within the same pack, industry members say. The process can vary widely, depending on the package and run volume.

		“The items typically being packaged and labeled are managed at a serialized level, where each package is often intended to be unique, as opposed to commercial packaging, where the batch sizes are notably larger and all packages are intended to be identical to each other,” Sharp’s Morris says.

		Setting up the clinical packaging run tends to be much smaller in scale, experts say, but balanced by highly variable requirements imposing hazards on standardization. “It must relate to all rules for investigational products,” notes Jonathan Calderwood, global marketing manager, Almac Clinical Services (Craigavon, UK), which specializes in packaging, distributing and delivering supplies for clinical protocols.

		Packaging runs can be “one shot deals”—such as early phase studies with fewer supply requirements&mdash;and are typically impacted by several factors, such as length of the trial, duration of dosing, availability of study drugs, expiration date of the study drugs and/or comparator product. Based on these variables, some studies may require multiple time-phased campaigns to ensure continuity of drug supply for the duration of the clinical trial.

		“As drug development models change, we must match packaging to new trial realities—such as adaptive studies&mdash;and build as flexible of an approach as we can,” Calderwood says. “Companies are not strictly outsourcing packaging, but component aspects of the IMP supply chain, and rely on expertise to manage getting investigational products from clinical bulk production to finished product available across the globe.”

		Late-phase studies require a greater number of subjects over a longer period of time, so multiple packaging campaigns are common. “Reasons for multiple packaging campaigns include limited product availability from the sponsor company and limited expiry data,” PCI’s Misher points out. “In most cases ‘just-in-time’ (JIT) packaging is not required.”

		JIT concepts apply less to the manufacturing and packaging of the clinical supplies, experts say, but are more relevant in labeling operations and distribution of clinical materials. PCI offers a “rapid response” program that addresses the needs for projects requiring completion in less than four weeks from award. “Timelines in the CT world are very aggressive, as pharmaceutical companies look to expedite commercialization of drugs in their pipeline,” Misher reports. “So opportunities to expedite supplies for studies are critical.”

		For example, a sponsor company may have several studies running concurrently using the same packaging format. “To maintain a flexible supply and have drugs available for all studies,” Misher says, “the protocol number is not included on the original supply labeling. It is added at the time of distribution with a supplemental protocol number label.”

		From a regulatory standpoint, manufacturing and packaging of all pharmaceutical products must comply with cGMP requirements, regardless of clinical or commercial applications. The guidelines to perform a function such as kitting are the same for the warehousing and distribution of finished goods in healthcare, observers say. All such activities must be done under the guidance of a compliant quality system that would include general inventory-control aspects, such as cycle counting, traceability and product identification.

		Although regulatory requirements are similar for packaging implemented for commercial uses vs. clinical trials, there are differences. For instance, “there are some unique regulatory differences that apply to clinical label requirements and additional regulatory requirements for products being used outside of the United States in global trials,” Sharp’s Morris says, noting these can vary by region and country.

		The labeling and kitting processes are different from commercial packaging as well. For example, the double-blinding of clinical packs requires using more barcode labeling and database management on the line. “Clinical runs tend to be short, with extensive documentation and audit trail requirements, so line set-ups can be long,” MWV’s Grinnan observes. “The longer runs of commercial packaging require investment in automated quality control, such as scanners for visual inspection.”

Meeting client needs for trial drug, kit with comparator

		Larger and more complex Phase III clinical trials typically involve a study drug, comparator product, and placebo. Additional ancillary supplies or rescue medications may be included in the kits. “It’s important to consider that each component relates to the ease of use for the patient balanced alongside manufacturing efficiencies and supply chain considerations,” Almac’s Calderwood points out.

		Clinical trials are highly dependent on kitting. In this instance, several components are bundled together into one package—such as medication, supplies and directions&mdash;and then shipped to patients involved in the trial. The self-contained package offers all of the necessary components for drug administration.

		Packages utilized for bundling drugs and relevant components together range from plastic trays and bags to corrugated boxes and totes. Many sponsor companies will request vendors to perform primary and secondary packaging to complete the final clinical supply ready for sites and patients. “The use of commercial comparator products is determined by the sponsor company when it designs the clinical trial and identifies their primary and secondary end points,” PCI’s Misher says. “We do commonly help provide comparator products for investigational studies and ensure discrete supply for the study.”

Cold chain shipping of clinical study drugs

		Clinical packaging for temperature-controlled pharmaceuticals may also include insulation to maintain temperature standards. Some clinical study drugs are required to be stored and shipped in either a refrigerated or frozen state. These requirements are usually defined early in the process and the appropriate packaging materials and label stock are specified to ensure proper performance throughout the life of the clinical study.

		“It is common with both oral solids and injectables to use cold chain storage and shipping, which requires some expertise to ensure product integrity during transit,” Misher says. “We work with clients to identify the optimal solution for their product and provide confidence it is delivered to the patient within the parameters it was designated for.”

The size of clinical trials continues to expand, observers say, creating a ripple effect in pharmaceutical packaging.

Clinical trial logistics and packaging

		Depending on your perspective, the pharmaceutical package label is either practically the last thing done on a packaging line, or the first thing a patient sees upon opening a carton. In either case, the label is a workhorse element of pharma packaging: providing basic identification of the drug bottle or carton contents (and, in the near future, unique identification of that package); critical usage instructions for the patient; anti-counterfeiting features (when used); and a linkage for patient education, medication adherence and other desirable tasks for therapy value. As such, the label is of concern not just to the packaging engineer concerned with its placement, but also to brand managers, compliance personnel, distribution workers, pharmacists and, in some cases, prescribing physicians. Hospital systems, now under the gun under healthcare reform to raise their level of patient outcomes, are seeking functional changes in all their suppliers to that aim, including the drugs they purchase. Getting the labeling right is a critical element of successful drug marketing and distribution.

Fig. 1. 3C Packaging’s newly installed flexo press handles multiple label substrates.Credit: 3C Packaging

		“Pharmaceutical companies are looking for intelligent and cost-effective packaging solutions that meet diverse requirements and can be adapted to their specific needs,” observes Gene Dul, president, Schreiner MediPharm US (Blauvelt, NY). “Sophisticated labels can offer special functionalities while decreasing the environmental footprint and helping to ensure drug and patient safety.”

		For years, FDA has emphasized the importance of providing accurate and readable information on drug labels to help educate and involve patients in their care. FDA recently took this initiative one step further by publishing a new guidance covering safety considerations for container labels and carton labeling design for Rx drugs and CDER-regulated biological products. The guidance provides a set of principles and recommendations for ensuring critical elements of a product’s container labels and carton labeling are designed to promote safe dispensing, administration, and use of the product.

		“The guidance mentions design features that can distract the consumer or provider’s attention away from critical drug information, including product name, strength and dosage form,” notes Hung Le, senior director, innovation, MeadWestvaco Healthcare (MWV; Richmond, VA). “Specifically, FDA notes that adequate container label size is critical to enabling container label designs that help minimize medication errors.”

		Patient adherence is a critical issue as industry studies reveal more than $300 billion in avoidable medical spending each year. “While patient attitudes play a significant role in adherence, pharmaceutical companies also share in this responsibility,” says Guillaume Kerboul, business consultant director, life sciences industry, Dassault Systemes (Lowell, MA). “Clear, concise directions on packaging are critical to bridging the adherence gap and directing patients to take medication regularly and call out expiration dates.”

		Indeed, there is a movement among pharma companies to focus their packaging toward the end-user patient as part of an effort to sufficiently engage with them, industry members say. “What that means is rather than including as much information into packaging as possible, pharmaceutical companies are making critical information more accessible through a variety of techniques, including larger fonts and inserts,” Kerboul says. “Focusing on the end user helps pharmaceutical companies play a larger role in helping physicians treat patients.”

		While patient adherence is a major consideration for drug label design, equally important is the effect it will have on deterring drug counterfeiting. In a report released earlier this year, the Institute of Medicine of the National Academies (IOM; Washington, D.C.) cited a drug industry study which revealed 1,623 counterfeiting incidents in 2011, with more than half involving fake packaging. “There is still much more conversation that needs to take place as an industry to obtain buy-in for the logistics of implementing a track and trace program that will function properly across the entire supply chain, including a discussion of data management at each stop along the way,” MWV’s Le says. “There should be discussion to ensure that the technology can be shared and transferred along the way as the drug moves from the manufacturer to the retailer.”

		Some of these discussions are taking place on Capitol Hill. In early June, the US House of Representatives approved legislation to establish a track and trace system throughout the pharma supply chain. Supporters hope to reconcile the US Senate version, the Pharmaceutical Distribution Supply Chain Act, in time to submit to Pres. Obama in mid- to late summer, according to published reports.

Figs. 2, 3. Schreiner MediPharm’s Pharma-Tac Plus label (left) offers patient-administration advantages, and its Pharma-Comb Security labels (right) provide enhanced brand protection. Credit: Schreiner.

		The House version of this bill, the Safeguarding America’s Pharmaceuticals Act of 2013, would establish a national standard of tracking requirements for drug makers, distributors, pharmacies and re-packagers based on changes in ownership. Products are to have serial numbers attached to the individual unit level, and to have some mechanisms in place to trace a drug lot through the distribution process. At the same time, the bill proposes to supplant multiple state laws with a uniform national standard—a desired goal for manufacturers and distributors, who would otherwise contend with a mishmash of varying state laws. However, there is widespread concern that the House bill undercuts the goals of the California e-pedigree law, set to go into force in 2015, which would enhance safety and eliminate redundant regulations, according to published reports.

		The Senate bill, ratified by committee on May 22, would create a plan for transitioning from a lot-level to unit-level tracing system. During a seven-year period, the major areas of the supply chain would pass and maintain transaction data and history, as applicable, for individual pharma products. At the same time, FDA would create a guidance for industry participants on uniform standards to build an interoperable electronic tracing system.

		Industry watchers say anti-counterfeiting solutions aimed directly at protecting the patient from fraudulent medication are commonly incorporated into the drug’s primary packaging label. The best security features meet the common sense criteria of “hard to duplicate, easy to authenticate.” Which raises the question of whether anti-counterfeiting features will be necessary if the serialization mandate is approved.

		The answer, experts say, largely depends on the details of the mandate and how it will be enforced. In California, for example, the state drug pedigree law for prescription drugs will take effect in 2015, requiring product serialization and electronic pedigrees to accompany/validate drug distributions to prevent the entry of counterfeit medicine. “Many pharmaceutical manufacturers are not waiting for a serialization mandate,” says Kregg Albrecht, vice president, solutions engineering, Nosco (Waukegan, IL). “They have built security features into their printed packaging to protect their brand and patients alike.”

		In the near future, some observers predict the combination of anti-counterfeiting efforts, regulatory aspects, and Obamacare will meld into a formidable force that will demand unique serialization. “The minimum mandatory requirement of the lot and batch of the medical device will make the implementation of unique serialization a logical step for corporate entities to limit liabilities and fight counterfeiting,” says Ken Koldan, new business development manager, FLEXcon (Spencer, MA).

		Customized brand protection can be ensured by multi-level security systems. For example, 3C Packaging (Clayton, NC) says it develops a unique brand security strategy for each client to safeguard against medication errors. Schreiner MediPharm’s new Pharma-Comb Security label combines diverse overt and covert features. “Depending on the customer’s specific demands, the label could, for instance, be equipped with holograms, color-shifting security inks and guilloche patterns as well as covert features like voiding effects and LaserSecure, which uses special pigments that are only visible with the help of a reading device,” Dul explains. “Integrated, detachable label parts with additional security features make authentication checks possible, even after the label has been attached to the patient’s medical records.”

		Traditionally, packaging managers make a choice between generating label information on the packaging line (through various printing technologies that “convert” the label from a blank to a meaningful message, or to obtain pre-coded labels from a dedicated label converter. Label generation is now an example of “variable printing” whereby each label can be a unique identifier of the pharma package. Making the choice between dedicated label generation and outsourced generation is case-specific to each drug and how it is to be used, say industry experts.

		There are many critical elements to developing a proper serialization program, experts say, starting with the physical printing of the code itself. Ideally, the code needs to be durable so it won’t scuff or abrade during its lifecycle and requires a reliable print method that does not add to packaging line down-time or bottlenecking. “One solution that should be considered is sourcing labels that are pre-printed with the serialized data,” Nosco’s Albrecht says, “thereby removing the headaches of variable printing in-line.”

		Nosco offers pre-serialized labels produced digitally at a high resolution, protected by an abrasion and chemical resistant coating, and vision-inspected and verified. One challenge to consider with pre-serialized codes is the logistics associated with lot and expiry data. “Currently, some pharma companies have chosen to include this information within the variable barcode and others have not,” Albrecht points out. “If the pre-printed codes are to contain lot and expiry data, then a rapid cycle time model must be deployed, i.e. a digital print model.”

		A major benefit of utilizing pre-coded labels is minimal capital equipment investment. The use of pre-printed labels does not require special printers or software. “The labels come ready to apply,” notes Russell Hill, technical innovations manager at 3C Packaging. “So there is no additional equipment to maintain and no need for validating new equipment.”

		Some industry members believe on-demand printing may be the best way to go, as it allows changes to be made quickly and—if the label is designed as a template that draws its information from a database&mdash;without additional time for design or changes. “There will, of course, be the initial capital cost associated with new equipment,” Hill says. “But the overall residual label cost would be less, especially over an extended period of time.”

		On the flip side, pre-coded labels can be expensive, as there are charges for performing services such as art work and die cut. And while pre-coded labels may save time at the packaging stage, there is concern about serializing labels that are not associated directly with product. “It brings into question how pre-coded labels will be managed and secured,” MWV’s Le says. “On the other hand, the use of pre-coded labels could provide drug packagers with an easier solution, as there would be less retrofitting required on their existing packaging equipment.”

		Propagating data through the supply chain while maintaining record connectivity to the source data element is considered critical. Some companies will outsource that label data storage to a converter of label material and then use the pre-printed labels to increase line speed and throughput. “The downside is the loss of control that could stop the line and inventorying point a company is creating in the supply chain,” FLEXcon’s Koldan says. “There is no one-size-fits-all solution.”

		While many packaging lines are outfitted with ink jet printers, lasers, or other marking equipment, efficiencies will be challenged with the added complexity of variable printing. If and when serialization becomes a mandate, packagers may have to think broadly, experts say. “How will hand packed items be coded?” Albrecht asks. “What about specialty items—is there enough space and tolerance for small containers? In this regard, pre-serialized labels can be a complementary solution and fill the voids that are incapable or not practical for in-line serialization.”

Besides the ongoing debate over serialization, drug labels are playing a greater role in anti-counterfeiting, preventing medication errors and improving patient adherence

Drug labels acquire more functionality to improve health outcomes

It’s been said that seeing is believing.

		Such is the case with pharmaceutical companies, who for many years held the belief, but lacked the scientific evidence, concerning the impact of using compliance prompting packaging. Now following the release of two significant studies coupled with patient-cliff and healthcare-reform initiatives, demand for compliance prompting formats in both starter-pack style physician samples and commercial packaging are gaining wider acceptance as a means for generating better health outcomes, experts say.

		“There have been studies in the news in the last year that have shown unit dose packaging (UDP) does contribute to increased patient compliance,” says Frederick Lutz, a regional sales manager at Constantia Flexibles (Vienna; US HQ in Blythewood, SC), a flexible packaging supplier. “Additional studies are ongoing and promising.”

		Last year, Walmart (Bentonville, AR) adopted two types of calendarized blister packs for its pharma products as part of its commitment to help customers “live better,” according to published reports. This included MeadWestvaco’s (MWV; Richmond, VA) new Shellpak Renew, which features a tear-resistant, recyclable outer carton, an easy-slide blister, an integrated calendar for patients to track their medications, and billboard space for patient education. The package is available at more than 5,500 major retail pharmacies nationwide, including Walmart.

		MWV says Shellpak Renew was developed based on feedback from pharmacists and patients. “Medications prepackaged in Shellpak Renew make dispensing medications quicker and easier so that our pharmacists can spend more time counseling our patients, including providing instructions on how to take their medications,” says Sandy Kinsey, VP, pharmacy merchandising at Walmart. “In addition, the calendared packaging helps reinforce to our customers how to take their medications safely and effectively for the best outcome.”

		Walmart’s increased adoption of unit dose compliance prompting formats served as a major endorsement of UDP and reportedly helped create an uptake in the use of these packaging solutions. “Certainly, Walmart’s adoption of this style of packaging has fueled this momentum, and you are seeing that now with other major chain pharmacies,” observes Justin Schroeder, a senior director at AndersonBrecon (Rockford, IL), a contract packager. “The light bulbs are coming on.”

		The proof is in the pudding, as recently published research reaffirms what UDP suppliers have been preaching to the pharma community for years: Increasing patients’ adherence to their medications through the use of compliance prompting packaging can positively impact patient health outcomes. Case in point: a first-of-its kind study published in the May 2011 issue of peer-reviewed journal 

 conducted by Venebio and funded by MWV found that when used alone, MWV’s Shellpak calendar blister packaging demonstrated a statistically significant impact over vials, improving adherence and persistence for long-term daily medications. The study reportedly involved more than three million Walmart pharmacy patients.

		Additional studies revealed similar results, proof positive that packaging pills in blister packs are far more likely to enable patients to take their medications. In a 2012 study, published in the journal 

, researchers from Novartis Pharmaceuticals (Basel, Switzerland) and consulting firm Xcenda (Charlotte, NC) examined pharmacy claims from more than 9,000 patients taking hypertension drug Diovan HCT over the course of one year.

		Approximately half the patients received their medication in MWV’s Shellpak, a calendared blister pack, says Hung Le, senior director, innovation, at MWV Healthcare; the other patients received their medication in a traditional pill vial. The study found patients using Shellpak refilled their prescriptions five days sooner and stayed on their medication 22 days longer.

		While such new developments are promising, several hurdles stand in the way of greater adoption of compliance packaging for pharma products. One of the biggest relates to cost, as production, shipping and storage expenses may be viewed as unnecessary. And there remains resistance in the pharmacy community, observers say, which is reluctant to change traditional practices.

		While additional evidence needs to be gathered to ascertain whether it is more cost-effective to utilize blister packs in drug-regiment adherence, some industry members believe this is negligible when you consider the annual cost of nonadherence. This figure in the US alone is estimated at nearly $300 billion, or roughly 13% of total healthcare expenditures per year. A 2012 study by Capgemini and HealthPrize Technologies, a medication adherence technology developer, saw a 

 between current US pharma revenue and the revenue level assuming full compliance. Drug makers can reap financial benefits from greater refill adherence. “We foresee a trend that pharmaceutical companies who utilize adherence packaging solutions during clinical trials will see the benefit in continuing to use similar packaging for the commercialized drug,” MWV’s Le says. “It’s important that adherence is encouraged from the very first time a patient interacts with a medication and its packaging—whether it’s in a clinical trial, a physician sample or a commercialized drug.”

		The core function of compliance-prompting packaging is to ensure a patient takes their medication as prescribed by their healthcare provider. This includes dosing, frequency, timing and conditions. But approximately one-third to one-half of all patients do not adhere to their prescribed treatment plan and almost one-fifth of new prescriptions go unfilled, according to industry studies.

		Poor medication adherence can lead to worsening of disease, serious and avoidable health risks, increased hospitalizations and even death. An estimated 10—25% of hospital and nursing home admissions are a direct result of medication non-adherence and 23% of long-term elder care admissions in the US are a consequence of failed adherence.

		“Medication packaging has been scientifically proven to have a positive impact on patient adherence, both when used alone or in combination with other adherence interventions,” Le says.

		UDP is widely used for sample packages as an important brand-communication experience and considered a near-necessity for drugs with different titrations over the course of a therapy, notably birth-control pills. But a major objective for suppliers is expanding UDP into more conventional multiday-dose regimens. Walmart and Kroger (Cincinnati, OH) are among the pharmacies where blister packs with calendar markings for pills are already used for certain medications.

		“Unit-dose packaging is more diverse and has the capability to protect the product, not only from environmental factors, but also serve or solve compliance issues, brand identity issues, counterfeiting problems and communication issues,” says Ajith Nair, SVP of research and development, Bilcare Research (New Castle, DE), a packaging solutions provider. While such benefits position UDP as an attractive alternative to other packaging solutions, such as bottles, it is harder to navigate the safety requirements of the Consumer Products Safety Commission (CPSC), which pushes manufacturers to provide both “child-resistant” and “senior-friendly” packaging, and has testing protocols for both. This is a necessity for many over-the-counter cough/cold/allergy products.

		“Functionality is always an issue, as care must be taken into design to maximize the child-resistant aspect of the package while still ensuring that adults—and especially seniors&mdash;can access the medication without great difficulty,” Constantia Flexibles’ Lutz says. “It is always a fine line to walk, but design elements can be engineered into the blister&mdash;such as greater land area, good access to peel area, clean perfs, etc., to meet both objectives.”

		Achieving the appropriate child resistance level by dexterity and overcoming cognitive barriers to accessing the actual blister card are said to be among the biggest benefits of new compliance packaging solutions. There has been a great deal of work done in recent times to improve functionality in compliance prompting packaging, particularly related to consumer friendly features. “The industry has long ago accepted that packages will need to have F1 Child Resistance (CR) ratings,” says Walter Berghahn, executive director at the Healthcare Compliance Packaging Council (HCPC; Bon Air, VA). “The features required to make packages F1 frequently increase the difficulty for adults to access as well as the intended audience of children under 48 months.”

		In the last few years, there has been increasing interest in new ways to package drugs in F1 CR/Senior Friendly formats in a blister. Companies such as MWV, Constantia Flexibles, AndersonBrecon, Keystone and many others spend a great deal of time designing, testing and redesigning features to increase the senior friendliness of the package without compromising the F1 CR rating.

		For instance, Constantia Flexibles developed its “Easy-Piesy” CR blister material which utilizes film instead of paper, Lutz says, allowing for a cleaner peel, and keeps paper fibers out of the equation. Keystone Folding Box (Newark, NJ), a producer of paperboard packaging solutions, has introduced a child-resistant F1 senior-friendly compliance package called Ecoslide-RX made from 100% recyclable material. Ecoslide-RX enters the market as a solution for Rx products, physician samples and clinical trial materials that meet and exceed sustainability objectives adopted by an increasing number of organizations, according to the company.

		On the Rx side of the business, suppliers report utilizing higher barrier films, as more products require better protection, both in thermoformed and cold-formed “foil-foil” structures. This would also include films with integrated desiccant and/or oxygen scavengers due to the moisture or oxygen sensitivity of some newly developed molecules. The use of desiccants and oxygen scavengers are driven by the stability needs of the drug.

		This form of “active” packaging—which interacts, in some fashion, with the tablet&mdash;is reportedly gaining traction in the pharma community. “This is certainly being explored, along with ways to better interact with users/patients,” says Victor Dixon, president and COO, Rondo-Pak (Eagleville, PA), a designer and producer of cGMP compliant pharmaceutical folding cartons. “Active packaging and interactive technologies, such as digital watermarking, can combine to provide a host of benefits to both the brand owner and the consumer/patient.”

		There are suppliers who support several commercial programs using desiccated materials or integrated oxygen scavengers within the packaging. For example, AndersonBrecon reports having commercialized blister designs using PET films as well as high-barrier applications with such materials. AndersonBrecon is planning to launch the first commercial application of its IntuiPac CR/SF design as well as for an NDA product, pending FDA approval of the drug. “The IntuiPac has an intuitive push-thru access to the patient and requires no special patient instruction to access the product,” Schroeder explains.

		Active packaging can also mean intelligent packaging with embedded electronics, providing prompting for the consumer or links to other “smart” devices. The latest developments in this area are being driven largely in response to the complexity of products produced. “As drugs become more complex, they are often more susceptible to environmental impact—moisture, oxygen, and light&mdash;and can require special packaging features to protect them and their efficacy until the patient uses them,” HCPC’s Berghahn points out. “But this discussion should not be limited to complex features embedded in materials or housed in the package.”

		Smart packaging is considered a reliable and proven method for electronically capturing and analyzing patient adherence data. MWV offers several smart packaging solutions, including its Medication Event Monitoring family of products: MEMSCap, Cerepak and Helping Hand. “These products are currently used primarily as part of our adherence monitoring and analysis solutions for clinical trials,” Le says, “but are also available for commercial usage.”

As improved medication adherence gains more focus in healthcare, the advantages of compliance packaging are becoming clearer