Hallie Forcinio is packing editor for Pharmaceutical Technology and Pharmaceutical Technology Europe, editorhal@sbcglobal.net.

Hallie Forcinio

Hallie ForcinioWhatever the packaging requirement, chances are there’s a solution waiting at INTERPHEX, the annual pharmaceutical industry trade show scheduled for April 23-25, 2013, at the Javits Center in New York. This year’s show is noteworthy for productivity enhancements, anticounterfeiting technology, and quality control options. 

On a single-rotary tablet press from Fette, the design of the compression stations, drive, turret, and tablet discharge cuts changeover time and improves productivity. For example, turret removal requires no tools and takes only 15 minutes. In addition, upper and lower compression rollers and pressure and position settings adjust automatically by means of commands from the operator interface; operators do not need to make manual adjustments after a turret change. The turret also features a coded tablet scraper and coded filling-cam detection as well as a central, multifunction connector for oil, air, and electricity. Equipped with up to 51 stations, the system produces up to 367,000 tablets per hour. The rotor design also supports quick changeover, maximizes yields, and minimizes product loss. The machine is clad in easily detached, FDA-certified, high-performance polymer panels and offers 360-degree access. 

Geometrically optimized surfaces and an integral vacuum system expedite cleaning. User-friendly operator interface provides swift access to the machine’s most important functions via 12 pictogram buttons (FE35 Tablet Press, Fette Compacting America).  

A high-performance liquid-filling machine from Cozzoli Machine combines a small footprint with peristaltic pump and single-use technologies. Single-use elements eliminate cleaning, cut costs, hasten setup, and reduce waste. Designed for Class 100 cleanrooms, the fillers rely on existing overhead laminar air flow and may be specified with two, four, six, or eight heads (VR2PP Series liquid fillers, Cozzoli Machine). 

A single-use filling system from Filamatic equips a benchtop filler, compatible with a piston, peristaltic, gear, or lobe pump, with a peristaltic pump. In this configuration, fluid flows in a flexible tube fitted inside a circular pump casing. Since the pumped fluid contacts only the inside surface of the disposable tubing, cleanup is quick and easy. The peristaltic pump works best with moderate to large (50 mL to >1100 mL) fill volumes and achieves +/- 1% accuracy (AdaptaFil semiautomatic benchtop filler, Filamatic). 

Romaco’s family of liquid filling machines includes six models that handle vials and bottles ranging from 2–500 mL at speeds of up to 200 containers per minute. Features include multiple dosing system and volumetric pump options, adjustable positive container transport for fast changeover, multiple closure stations and cap feeding systems, and programmable setup and recall of product recipes and production parameters. The systems integrate seamlessly with labelers and cartoners (Romaco Macofar LF-200 Series liquid filling machines, MG America, subsidiary of MG2). 

 Figure 1: Groninger’s aseptic vial-filling line offers contact-free container handling. FIGURE 1 COURTESY OF GRONINGER USAGroninger’s high-speed, aseptic vial-filling line handles 400 vials per minute. Compatibility with time-pressure, rotary piston, and peristaltic pumps increases system flexibility and allows it to fill different products. A vial-handling system eliminates damage and noise associated with glass-to-glass contact (see Figure 1). A three-fold camera checks for glass particles, residues, or deposits inside the vial to prevent contamination of the product and also can inspect filling and closing steps (Kombi Filling Rack on vial filling line, Groninger USA). 

A high-speed line from Marchesini Group, capable of filling parenteral products at 400 vials per minute, consists of a rotary washing machine, depyrogenation tunnel, and filling/stoppering machine. The eight-station rotary washer cleans ampules, vials, and other round containers and features quick size-changeover. A modular design accommodates the addition of an ultrasonic prewasher, silicone applicator, heat exchangers, filters, automatic valves, automatic drainers, pressure transmitters, and unloaders to tunnel or tray. The continuous-motion depyrogenation tunnel relies on modular design as well as hot-air flow. A pressurization system independently controls conditions in different sections of the tunnel. Proprietary cooling-zone sterilization cuts cycle time in half. The continuous-motion, in-line filler/capper features an ultra-clean balcony design and is compatible with restricted access barrier systems and isolators, as well as clean- and sterilize-in-place configurations. Other features include contact-free vial handling, camera inspection, and checkweighing. Pump options include peristaltic, time-pressure, and volumetric (WR24 washing machine, Depyr601 tunnel and Stery LC filling/stoppering machine, Marchesini Group). 

 Figure 2: An AlpVision app enables product authentication via smartphone. FIGURE 2 COURTESY OF ALPVISIONSmartphones help fight counterfeiting with an app designed to authenticate products in three seconds. As shown in Figure 2, the phone is positioned over packaging or molded parts to detect and verify covert safety features (e.g., taggants or microprinting, which looks like part of the graphics but reveals a message when examined under magnification). The verification action also can deliver information to the user/consumer about product features, user data, and market (smartphone authentication app for Cryptoglyph and Fingerprint covert safety features, AlpVision). 

 Figure 3: Schreiner MediPharm’s Pharma-Comb Security Label helps prevent counterfeiting. FIGURE 3 COURTESY OF SCHREINER MEDIPHARMSchreiner MediPharm’s peel-off label for vials now includes a security version with overt and/or covert features to authenticate product and help prevent counterfeiting (see Figure 3). The mix of security elements can be customized and often can be added without changing the label design. Options include overt elements, such as holograms, color-shifting security inks, and guilloche patterns, as well as covert tools, such as voiding effects and LaserSecure, which relies on pigments that only can be “seen” by a dedicated handheld reader. The label also incorporates detachable segments for patient record updating and other purposes. For extra security, removal of detachable sections from the substrate reveals the message, “peel-off part has been removed” (Pharma-Comb Security Label, Schreiner MediPharm). 

Another anticounterfeiting tool, a proprietary, two-dimensional barcode from Complete Inspection Systems, matches and verifies GS1 codes printed during packaging operations. The data-intensive barcode can provide information about the location of covert codes used for product authentication (HD P.A.S.S. Barcode Solution, Complete Inspection Systems). 

Figure 4: A carton from RondoPak has a tamper-evident design. FIGURE 4 COURTESY OF KÃRBER MEDIPAK.Rondo-Pak’s tamper-evident carton design opens and recloses as easily as a standard folding carton and can be erected and loaded at the same speed as a conventional folding carton (see Figure 4). Perforations cause the lid and dust flaps to tear. The design reportedly surpasses first-opening verification security requirements of the Falsified Medicines Directive 2011/62/EU, which take effect in 2016 (tamper-evident folding carton, Rondo-Pak). 

Figure 5: Pharma Technology’s AIO All In One Deduster and Tester System measures tablet characteristics. FIGURE 5 COURTESY OF PHARMA TECHNOLOGY.A quiet (less than 70 decibels), compact tablet-deduster and testing system from Pharma Technology combines multiple functions such as segmented deduster spirals and metal detector on one base (see Figure 5). The high precision, in-process tablet tester checks weight, hardness, and thickness by sampling at regular intervals and feeds test data to the tablet press for recording into the batch record. Testers can be positioned on three sides of the base and offer push-fit, cable-free connections for power and data storage. A washable, exchangeable deduster module minimizes changeover time (AIO All In One Deduster and Tester System, Pharma Technology). 

Articles

The annual INTERPHEX show presents end-to-end packaging solutions.

Previewing Packaging Innovations

Implementation of serialization is so essential, drug makers’ future “right to do business” depends on it, according to Daljeet Sahni, associate director, Global Supply Chain at Bristol-Myers Squibb (BMS) in a webinar conducted on February 27, 2013 (1). On the downside, there is no single path to full serialization. Risks are high due to regulatory volatility and the sheer number of touch points and technologies involved. 

Existing and pending regulations continue to evolve and vary worldwide. Three regulatory models currently exist:

Authentication – The patient scans a serialized code and confirms authenticity 

Change of ownership – Documentation occurs each time the product changes hands.

Track and trace – Documentation occurs not only with each new owner, but also whenever the product changes location.

The track-and-trace model, which is the most complex, meets California requirements taking effect in 2015 and 2016. Since achieving track-and-trace capability will likely enable BMS to meet any less stringent regulations that follow the authentication or change of ownership models, it is the scenario the company has decided to follow. “With no agreement at the regulatory level, we’re trying to build flexibility into our approach,” Sahni explained. 

Other hurdles toward serialization include the lack of agreement about how supply chain partners will exchange data, management of the vast amounts of data that will be generated, and the formidable capital investment and manpower requirements associated with new technology, packaging equipment, process changes, program management, central data repositories, and revision of standard operating procedures. Further complicating the situation is the relative scarcity of vendors with the knowledge, skills, and bandwidth that will be needed to implement serialization on approximately 7000 lines worldwide. As a result, Sahni advocates a multi-vendor strategy to mitigate risk.

Despite the challenges, “We have no option [but to move forward],” Sahni stated. He is confident it will be a worthwhile journey. Ultimately, he predicts, serialization will generate tremendous value by creating a transparent supply chain, enabling personalized medicine, supporting just-in-time logistics, improving service levels and inventory management, and reducing counterfeiting and diversion. 

“Serialization will not prevent counterfeiting, but will be a major step forward,” he said. Other anticounterfeiting tools still will be needed, he added, noting BMS has a group focused on ways to protect consumers and products from counterfeiting. With the counterfeit market probably underestimated at $35 billion to $75 billion per year with a 6–20% growth rate, it will remain an “issue we must address,” he said.

BMS embarked on its serialization journey in 2011 and has already completed a pilot. However, Sahni warned, “As scope increases, complexity increases.” With impact felt internally and externally, “change management requirements are humungous,” he added. As a result, he recommends paying careful attention to how data standards are built, harmonization of internal processes and data standards, establishment of data governance, and building in scalability to manage large volumes of data. 

As regulations take effect, he said, “There also will be a need to manage serialized and non-serialized product at the same time for some period of time.” So systems must be able to handle either type of product, at least short term.

D. Sahni, “Serialization in Pharmaceuticals,” Xtalks Webinars (Feb. 27, 2013).

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Bristol-Myers Squibb embarks on a multi-year journey to overcome the challenges of serialization and reap the benefits.

Preparing for Serialization

Serialization, the application of a unique item-level code that provides traceability and serves as the backbone of pedigree records, depends on integrated hardware and software plus data collection and access up and down the supply chain. With pedigree requirements in place or pending in several parts of the world and less than 24 months before the California E-pedigree Law begins to take effect on Jan. 1, 2015, it seems prudent for any current packaging-line equipment purchases to be serialization-ready so, when implementation time comes, the transition is as seamless as possible. The California law applies only to prescription drugs sold in the state. Unless and until FDA writes national regulations, however, industry observers predict the California law will serve as the 

 United States standard because it will easier to serialize all prescription products rather than segregating and serializing product destined for California. 

Fortunately, it’s not that difficult to find machines that are serialization-ready. One checkweigher integrates printing of unique codes and verification with the weighing function. A single operator interface controls all action from one screen to simplify operation. Capable of weighing up to 550 packs per minute with an accuracy of ±50mg at 3 sigma, the checkweigher is compatible with a variety of coders and vision systems, giving brand owners the flexibility to specify their favorite models. Adjustable side belts maintain control of the bottle or carton moving through the machine to ensure correct positioning during marking and verification. Two reject systems, one working with the vision system and one linked to the scale, ensure only properly coded and filled packs continue down the line (Versa RxV Checkweigher, Thermo Fisher Scientific).

A label applicator applies serialized single, dual, or wraparound labels at rates up to 200 bottles per minute. An onboard, ultraviolet-inkjet printer prints two-dimensional barcodes on the labels and an integrated vision system verifies code quality and correctness. An Ethernet connection delivers serialized code data to e-pedigree software. The labeler also handles labels equipped with radio frequency identification (RFID) tags and can be configured to apply labels to round, square, or oval containers ranging from 1 to 14 in. (25 to 356 mm) high and 5/8 to 7 in. (16 to 178 mm) in diameter. Integration with shrink bundler, print-apply labeler, and case packer results in a serialization-ready line. Options include hot-stamp or thermal-transfer coders, barcode readers, and missing label detectors (Model 130 Bronco Labeler from NJM Packaging and TrackSafe hardware and software from Optel Vision). 

A coding equipment supplier provides hardware, software, and services, including serialization-ready inkjet printers, laser coders, and line controllers. The line controller operates the code marking systems, cameras, reject mechanisms, and other external devices on the packaging line and helps aggregate codes for item, multipack, and case levels of packaging. For maximum flexibility, the line controller and software work with a variety of printers and cameras. The software also accommodates rework by deactivating the code on a rejected product and assigning a new code after rework (IMprints Track & Trace Solution, Videojet). 

Another provider of serialization hardware and software supplies all necessary packaging line modules. The first module applies a unique, alphanumeric or two-dimensional DataMatrix code to primary containers, which proceed through a bundler. Codes on containers in the bundle are aggregated and bundles are labeled. Bundles are loaded into cases and aggregated, and cases are labeled. Cases are palletized, and pallets are aggregated (DataMatrix Station XMV bottle/carton marking or Bottle Serialization Station, Advanced Bundle Station, Shipping Case Station, Pallet Aggregation Station, Pilot Device Manager, Pilot Line Manager and Pilot Site Manager software from Mettler Toledo). For less automated lines, a standalone system, equipped with a scanner and printing equipment, provides a location for code marking and aggregation of codes on primary packages, bundles, cases, and/or pallets (Manual Aggregation Station, Mettler Toledo). 

Equipment purchased today for the packaging line should be serialization-ready in preparation for upcoming requirements.

Be Prepared for Serialization

Pharmaceutical manufacturers devote considerable time and resources to implement effective cold-chain practices that protect products, especially sensitive biopharmaceuticals, blood products, and vaccines, from damage. Although efforts have traditionally focused on refrigerated (2–8 °C) and frozen (-20 °C) products, there is growing attention to controlled room temperature (CRT) products, which require maintenance at 15–25 °C to ensure quality and efficacy.  

 Maria Toutoudaki/Selahattin BAYRAM/Getty Images; Dan Ward 

The emphasis on CRT shipments, expanding volumes of biologics, and rising demand from emerging markets are spurring strong growth for goods and services related to temperature-controlled logistics, particularly in Asia and the southern hemisphere. According to the 2012 

, published by Pharmaceutical Commerce, cold-chain logistics spending is forecast to grow approximately 12% from $6.5 billion in 2010 to $7.6 billion in 2013 and increase another 12.6% to reach $8.9 billion in 2016. Packaging, including instrumentation, accounts for about 37% of the dollars spent on cold-chain logistics. The focus on CRT shipments is particularly strong in Canada, Israel, Ireland, the European Union, Turkey, Saudi Arabia, and South Korea, according to Prakash Mahesh, vice-president of marketing and business development at Sonoco Protective Solutions, ThermoSafe Brands, formerly part of Tegrant.  

Regulations involving the cold chain are undergoing change. "South America, Mexico, South Africa, Saudi Arabia, and others are enforcing strict label claims," says Mahesh. In fact, he says, the European Medicines Agency (EMA) is pushing toward strict label claims and "will likely require 'proof' of protection come 2013."  

With evolving regulations worldwide and dramatic growth in the number of temperature-sensitive products, it's more essential than ever to manage conditions in storage and transit. "Late-phase clinical development teams understand the need to maintain strict temperature adherence to ensure the positive outcomes in their trials as well as maintaining patient safety," says Andrew J. Mills, CEO of Americas for Intelsius, a DGP company and supplier of temperature-controlled packaging. He explains that some of the drugs coming on the market "can become toxic if frozen...or lose efficacy very quickly if warmed."  

 In addition, he says, "The increased FDA/EMA collaboration in overseas inspections is making the need for good cold-chain practices felt all over the globe." He explains, this regulatory attention is not only encouraging adoption of good cold-chain practices from new sectors of the marketplace, but also "bringing emerging markets up to speed with good distribution practices (GDP) compliance faster." 

An e-pedigree law, scheduled to go into effect on Jan. 1, 2015 in California, is encouraging drug makers to adopt technologies that will implement traceability and cold-chain management simultaneously. A number of organizations offer resources to help companies follow GDP, including the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) (1). For links to these resources, see the online version of this article at 

Innovation is leading to better insulation products, the ability to maintain a specific temperature range for longer time periods, and in-transit monitoring that doesn't require the package to be opened, thereby lessening the risk of counterfeiting and diversion. Pharmaceutical packagers rely on a host of tools to maintain products at the proper temperature. Options include phase-change materials (PCMs), insulating materials, environmental data loggers, software for monitoring and tracking shipment conditions, three-dimensional modeling software to optimize package design, integration of temperature protection/monitoring by logistics providers, and temperature-controlled bulk containers to protect larger shipments.  

Shippers combining vacuum-insulated panels with refrigerants based on PCMs have captured market share from traditional expanded polystyrene (EPS) and polyurethane (PUR) structures and gel packs or dry ice (2). The PCMs liquefy or solidify (freeze) at specific temperatures and recharge as ambient temperatures fluctuate. PCMs are typically preconditioned in a freezer or refrigerator before use, protect longer than gel packs, and eliminate the replenishment requirements and off-gassing hazards associated with dry ice. In addition, a single PCM unit typically replaces multiple gel packs, thereby reducing the size and weight of the transport container.  

 Data loggers are going to be more important in the future because of the trend toward greater scrutiny of the data from each shipment, says Mills of Intelsius. With data being more carefully evaluated, there will be "greater pressure on temperature-controlled packaging providers to do a better job of qualifying their solutions against multiple temperature ranges," he adds.  

Data loggers record conditions the shipment experiences and can quickly indicate if a problem occurred. In some cases, units can deliver a proactive alert so that action can be taken to protect the shipment before the product becomes unusable.  

Ease-of-use is maximized by features such as an onboard USB connection. "When plugged in, the logger provides PDF data files," explains Rich Ellinger, vice-president, life sciences at PakSense, the maker of a label-like data logger (BIOmed XpressPDF Temperature Monitoring Label). "No additional infrastructure is needed," says Ellinger.  

With wireless technology, a container does not even have to be opened to access temperature data. Keeping the shipper closed not only helps maintain the environment around the payload, but also means, "there's no need to change supply-chain practices to collect information," explains Kevin Payne, senior director of marketing at Intelleflex, a provider of radio-frequency identification (RFID) tags and related software for temperature monitoring.  

Data can be read or written to a Class 3 battery-assisted passive RFID tag at distances up to 300 feet. This stronger penetration power allows readability through ice and insulation, for example (TMT-8500 temperature monitoring tag, Intelleflex). The credit-card-size tag, which measures approximately 0.25-inch thick, will gain functionality in 2013 with the addition of humidity and light-monitoring features. "Light monitoring is important because recipients can tell if the box has been opened during its travels," explains Payne.  

Interest in RFID-based monitors is increasing, according to Tom Dolan, director of sales at RURO, a supplier of turnkey RFID systems. Because hundreds or even thousands of RFID tags can be scanned at the same time, the technology offers potential for high-speed automated data collection not possible with traditional barcodes. In addition, Dolan says, RFID "costs have come down, and there are more vendors in the market." Furthermore, performance improvements allow RFID tags to work reliably despite metal interference and other challenging conditions like cryo environments.  

A reusable, credit-card-size tag relies on ultra-high-frequency (UHF) RFID, a five-year battery, and a tactile button to monitor temperatures from -30 to 55 °C within +/- 0.2 °C . An onboard microprocessor enables a variety of calculations, including remaining shelf life, mean kinetic temperature, and multiparameter alarms. Custom product configurations are written to each tag and easily updated in the field. Pressing the button turns the unit on, checks for compliance with preset parameters, or records the temperature at that moment. When the button is pressed, if the light-emitting diode (LED) on the tag blinks red, a temperature excursion has occurred. If the LED blinks green, programmed parameters have been met. Tags are read with a handheld or stationary reader and deliver data instantly to a 

 21 Part 11-compliant, web-based data system. A single click identifies exceptions that may need immediate attention, and all data are archived for review and analysis. The tag, which can log thousands of time/temperature points while affixed to a package, case, or pallet, can be read and restarted at any time to record new segments, owners, or temperature parameters (UHF RFID tag and web-based monitoring system, TempTRIP).  

To be actionable, temperature data must be accessible. A cloud-based data-sharing application provides access to anyone (with clearance) anywhere so timely decisions can be made about a shipment. For example, if an excursion occurs, an alert can provide instructions to move the package into the proper environment (ZEST Data Services, Intelleflex).  

A provider of intelligent, reusable transport packaging relies on this data-sharing application to provide real-time alerts about potentially damaging deviations from required environmental parameters (Supply Chain Technology Solutions, Rehrig Pacific). According to Kaley Parkinson, technology sales manager at Rehrig Pacific, this high level of visibility economically addresses the industry's need for better in-transit monitoring. In fact, he predicts that future systems will integrate "with a broader range of existing systems that will streamline and simplify the transfer of information across various platforms for all...users."  

Cold-chain management has become an important business for logistics providers. In fact, many airlines, parcel delivery services, and common carriers run dedicated cold-chain operations that offer high levels of environmental control and shipment visibility.  

Clinical-trial specialists also are firmly focused on cold-chain services. One global supplier has expanded its cold-chain storage and distribution capacity in Pennsylvania, the UK, and Germany to maintain frozen and refrigerated products at the proper temperature (Clinical Supply Services, Catalent Pharma Solutions). "The steadily increasing number of biological products in development, particularly in prefilled syringes, is fueling the need for refrigerated storage and distribution," explains Frank Lis, vice-president and general manager of clinical supply services for Catalent Pharma Solutions.  

Almac, another clinical-supplies specialist, has added refrigerated labeling facilities in the UK, thereby minimizing product exposure to temperatures outside the 2–8 °C range. The capability is mirrored at the company's US headquarters in Pennsylvania. The Northern Ireland-based firm also offers a smaller, lighter cold-chain shipper along with a temperature monitoring system (refrigerated storage/labeling areas, temperature-controlled shippers, Shipping Temperature Electronic Monitoring System, Supply Chain Management team, Almac Group). Sharon Courtney, head of distribution at Almac, reports, "In the first six months since implementation, the shippers achieved an impressive, less than 0.33% excursion rate across the board." 

 The need to manage shipments of larger volumes of sensitive products is encouraging development of temperature-controlled pallets, totes, and containers. Because less packaging is generally involved, shipping larger volumes can cut material and freight costs as well as the product/company's carbon footprint.  

One family of bulk containers maintains entire pallet loads at refrigerated or controlled room temperatures for up to 120 hours. Easily assembled with lightweight insulated panels, the units hold half- or full-pallet loads (including the pallet) and can be single use or reusable. In-house testing confirms that each container performs to shipper or third-party specifications and is delivered with full documentation (Repak line of pallet shippers, Cryopak, division of TCP Reliable).  

PUR-insulated pallet shippers with self-supporting panels require no more than 15 minutes for assembly. Patented components provide structural stability and air flow for top and bottom refrigerants. The design is "a first in the industry," says Vicki Arthur, vice-president of Sonoco's Protective Packaging Division, and "can use the same configuration for all seasons" (ThermoSafe SPS Series Pallet Shippers, ThermoSafe Brands, a unit of Sonoco).  

AbbVie, the newly spun-off biopharmaceutical operations of Abbott, has adopted Sonoco's ThermoSafe PUR-insulated pallet shippers for 2–8 °C shipments from its home base in Chicago to Latin America. Two types of PCM serve as the refrigerant. The PUR/PCM system replaces a PUR/water system, which is itself a replacement for an EPS/water configuration. Requirements included maintaining 2–8 °C for 96 hours in summer and winter conditions encountered in the company's preferred transport/distribution model. The shippers also needed to be able to maintain 2–8 °C if refrigerated anytime before 96 hours. Tests showed that the system, with small variations in the arrangement of the PCM units, maintains the payload at the proper temperature for 120 or more hours regardless of the season or size of the shipper (e.g., pallet, half-pallet, parcel). Because the PCM weighs less than the water refrigerants used previously, it increases the system's weight-to-payload-efficiency and payload-to-box ratios. The PUR/PCM system also simplifies pack-out, accommodates transport delays, and reduces total cost of ownership. "The shipping system works as well and in many cases better than active shipping systems," reported Arminda Montero, then Abbott's (now AbbVie's) global distribution quality assurance program manager during a presentation in September 2012 at IQPC's Cold Chain & Temperature Management Global Forum in Chicago (3). In fact, the PUR/PCM configuration performed so well on the Chicago/Latin America route that it is now used for all of the company's international shipments.  

Cardinal Health has adopted temperature-controlled totes for its 2–8 °C products. Available in two sizes, the totes feature an insulating liner and lid of EPS and replace gel packs with two types of pillow-like PCM panels. The orange PCM panels are preconditioned to refrigerator temperatures (to protect from freezing conditions) while the green PCM panels start out frozen (to protect from heat). The orange panels absorb the energy from the green panels (as well as external winter temperatures) and begin to solidify (freeze) at approximately 4 °C, protecting the product from experiencing temperatures below the labeled range. As the temperature inside the tote changes, the physical state of panels shift between solid and liquid to maintain the shipment at 2–8 °C. Product is bagged to protect it from condensation or a leak of PCM. The nontoxic PCM is derived from renewable resources and considered a bio-preferred product by the US Department of Agriculture (4). 

Eventually, temperature-controlled shipping standards will be harmonized internationally. Near term, scrutiny will increase on every point in the supply chain, including mail order pharmacies. In fact, Ellinger of PakSense predicts, "more tracking of products throughout the entire cold-chain continuum—including the 'last mile.'" Bill Hingle, director of marketing at Cryopak, a division of TCP Reliable, agrees, noting that the many variables involved with protecting product to the point of use make the last mile the weakest link in the cold chain.  

Hingle also forecasts a shift from looking at packaging costs alone to considering all expenses related to maintaining products at the proper temperature during storage and transport. This change in financial tactics will coincide with a move away from more generic temperature-controlled packaging options to "truly qualified and validated solutions," says Mills of Intelsius.  

The stronger emphasis on the big picture will prompt more partnerships among carriers, pharmaceutical manufacturers and distributors, and logistics providers to proactively monitor the cold chain. As a result, we'll see greater use of smart containers that can compensate for unexpected events like summer-time temperatures in February in New York City or a diverted flight that translates into eight extra hours on the tarmac in extreme heat or cold. "You don't want to lose high-value product or product that's in short supply or critically needed," concludes Payne of Intelleflex.  

 1.  MHRA, "Good Distribution Practice," 

www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodDistributionPractice

 3. A. Montero, P. Mahesh, and K. Maltas, "Case Study: Designing 2–8 °C Shippers for International Shipments from US to Latin America," presentation at IQPC's Cold Chain & Temperature Management Global Forum (Chicago, IL, 2012).  

 4. Cardinal Health, "Cold Chain–Refrigerated Tote Qualification," 

Cold Chain IQ, a sub-group of Pharma IQ,  

European Union, “Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03),” 

http://ec.europa.eu/health/files/eudralex/vol-4/gdpguidelines1.pdf

Health Canada, “Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069),” 

http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0069-eng.php

International Air Transport Association, “Air Transport Logistics for Time and Temperature Sensitive Healthcare Products, Chapter 17” in Perishable Cargo Regulations, 

http://www.iata.org/publications/Pages/perishable-cargo.aspx

ISPE, “Good Practice Guide: Cold Chain Management,” 

Medicines and Healthcare Products Regulatory Agency, “Good Distribution Practice: Guidance and Legislation,” 

http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodDistributionPractice/Guidanceandlegislation/index.htm#9 

Pharmaceutical Cold Chain Interest Group, 

USP General Chapter 659, “Packaging and Storage Requirements,” (will be official in USP 37-NF 32 in May 2014), 

USP General Chapter 1079, “Good Storage and Shipping Practices” (2012), 

USP General Chapter 1083, “Good Distribution Practices – Supply Chain Integrity,” (being reworked based on comments received from the Pharmacopeial Forum proposal and a public workshop in May 2012), 

USP General Chapter 1118, “Monitoring Devices-Time, Temperature, and Humidity” (2013), 

World Health Organization, “Guidelines on the International Packaging and Shipping of Vaccines,” 

http://www.who.int/vaccines-documents/DoxGen/H5-CC.htm

Medication safety and efficacy depend on maintaining products at the proper temperature.

Seeking Cold Chain Efficiency

Pharmaceutical manufacturers devote considerable time and resources to implement effective cold-chain practices that protect products, especially sensitive biopharmaceuticals, blood products, and vaccines from damage. Although efforts have traditionally focused on frozen (−20 °C) and refrigerated (2–8 °C) products, there is growing attention to controlled room temperature (CRT) products, which require maintenance at 15–25°C to ensure quality and efficacy. Dramatic growth in the number of temperature-sensitive products, as well as evolving regulations worldwide, make it more essential than ever to manage conditions in storage and transit. 

Data loggers, which record conditions the shipment experiences and can quickly indicate if a problem occurred, are increasingly being used to meet this need for tracking and managing conditions. The trend is toward greater scrutiny of the data from each shipment says Andrew J. Mills, CEO, Americas for Intelsius, a DGP Company and supplier of temperature-controlled packaging. With data being more carefully evaluated, there will be “greater pressure on temperature-controlled packaging providers to do a better job of qualifying their solutions against multiple temperature ranges,” he adds.

Ease of use for data loggers is maximized by features like an onboard USB connection. “When plugged in, the logger provides PDF data files,” explains Rich Ellinger, vice-president, Life Sciences at PakSense, the maker of a label-like data logger (BIOmed XpressPDF Temperature Monitoring Label). “No additional infrastructure is needed.”

With wireless technology, a container doesn’t even have to be opened to access temperature data. Keeping the shipper closed not only helps maintain the environment around the payload, but also means, “there’s no need to change supply-chain practices to collect information,” explains Kevin Payne, senior director of marketing at Intelleflex, a provider of radio-frequency identification (RFID) tags and related software for temperature monitoring. Data can be read or written to a Class 3 battery-assisted passive RFID tag at distances up to 300 feet. This stronger penetration power allows readability through ice and insulation, for example. The credit-card-size tag, which measures about 0.25-inch thick, will gain functionality in 2013 with the addition of humidity and light-monitoring features (TMT-8500 temperature monitoring tag, Intelleflex). “Light monitoring is important because recipients can tell if the box has been opened during its travels,” explains Payne. 

Interest in RFID-based monitors is increasing, according to Tom Dolan, director of sales at RURO, a supplier of turnkey RFID systems. Since hundreds or even thousands of RFID tags can be scanned at the same time, the technology offers potential for high-speed automated data collection not possible with traditional barcodes. In addition, Dolan says, RFID “costs have come down, and there are more vendors in the market.” Furthermore, performance improvements allow RFID tags to work reliably despite metal interference and other challenging conditions like cryo environments. 

For more about this topic, read Hallie Forcinio’s cover story, “Packaging Innovations Aid Cold-Chain Efficiency” in the upcoming February 2013 issue of 

Advances in data loggers and radio-frequency identification tags help meet the increasing need for managing the pharmaceutical cold chain.

Logging the Cold Chain

The fight against counterfeit and gray-market drugs is worldwide. Under the 

, signed by President Obama in July 2012, the Attorney General shall give increased priority to efforts to investigate and prosecute counterfeiting. In addition, the US Sentencing Commission is to consider increased penalties for drug counterfeiting (1). In the European Union, the Falsified Medicines Directive 2011/62/EU takes effect on Jan. 2, 2013 (2). The Directive requires authentication features on individual prescription-drug packs to enable verification throughout the supply chain. It also strengthens requirements for control and inspection of manufacturers of active substances. Manufacturers also must report any suspicion of falsified medicines. Other provisions give penalties for the manufacturing, distribution, import, and export of falsified medicinal products and point out the dangers associated with sale of medicines via the Internet.

With a significant percentage of medicines purchased from Internet sites found to be counterfeit, FDA has embarked on a public education campaign, BeSafeRx: Know Your Online Pharmacy (3). Another tool used by FDA is its October 2011 

Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

 (4). FDA is also training field agents in the use of a handheld device to check for counterfeit products and packaging arriving at ports of entry. The CD3 (Counterfeit Detection Device #3) emits light in 10 wavelengths to check API and drug samples against stored scans. It also detects package tampering.

The World Health Organization’s (WHO) Working Group of Member States on Substandard/Spurious/Falsely-Labelled/Falsified/Counterfeit Medical Products takes a three-pronged approach: education, norms and standards, and technical support to countries (5). WHO also supports the International Medical Products Anti-Counterfeiting Taskforce, a group it launched in 2006 with a wide range of partners including, international organizations, nongovernmental organizations, enforcement agencies, pharmaceutical manufacturers’ associations, and drug and regulatory authorities.

The US Agency for International Development (USAID) provides technical assistance worldwide to identify fake and substandard products and help legitimate manufacturers meet internationally recognized good manufacturing practices. In some cases, its efforts are implemented by the United States Pharmacopeial Convention (USP).

USP also is finalizing General Chapter <1083> "Good Distribution Practices—Supply Chain Integrity". It will outline best packaging practices to combat counterfeit drugs and medical devices. Likely topics include tamper-evident designs, authentication technologies, serialization, pedigrees, machine-readable data carriers, repackaging, and information retention and security.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) is collaborating in efforts to combat counterfeit drugs. One project, the European Stakeholder Model, advocates the use of two-dimensional barcoding technology to authenticate products and comply with the Falsified Medicines Directive. This serialization system will be run by stakeholder organizations on a nonprofit basis.

“Potential advantages include the possibility of allowing for the automated checking of expiry dates, better pharmacovigilance, a reduction in the number of fraudulent reimbursement claims, higher effectiveness in preventing recalled products from being supplied to the patient, more efficient handling of product returns, and improved stock management processes for pharmacies,” said Camilla Kent Hansen, market access manager for EFPIA, in a recent article (6).

For brand owners and makers of generic-drug products and dietary supplements, a constantly evolving array of anticounterfeiting technologies help discourage counterfeiting and authenticate products. Read the 

 online at PharmTech.com for details on packaging technologies, such as taggant- and ink-based approaches, holograms, security materials, and labels containing both covert and overt features.

S. 3187, US Senate, 112th Congress, 2nd Session (Washington, DC), June 27, 2012.

Buying Medicines Online? Be Wary, FDA Says

,” Consumer Updates, accessed Oct. 3, 2012. 

Medicines: Spurious/Falsely-Labelled/Falsified/Counterfeit (SFFC) Medicines, Fact Sheet N°275, May 2012

Tackling the Rise of Counterfeit Medicines

Overt and covert packaging technologies have evolved to authenticate drugs and fight counterfeits.