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

Hallie Forcinio

INTERPHEX, the annual pharmaceutical trade show, always presents a wide array of packaging innovations. The 2014 show (March 17-19 in New York City) included equipment designed to meet serialization requirements.  


  Videojet 8610 thermal inkjet from Videojet prints nonporous substrates like coated paperboard, blisters, film, and foil with fast-drying, solvent-based inks. The key is a patented ink cartridge designed to jet methyl ethyl ketone (MEK)-based inks “Formerly, you had to have a knock-out area for water-based thermal inkjets,” said Jim Kerper, North American sales manager for the Systems Solution Group at Videojet Technology, in an interview with 

. A shutter-based mechanism controls the printhead, which prints at a resolution of 240 x 240 dots per inch at speeds of up to 102 m/min (333 ft/min). Character height with a single printhead is 12.7 mm (0.5 in), but up to two printheads can be ganged. Higher print quality on the nonporous surfaces aids the inspection process. In addition, the unit’s preset font packages help the vision system recognize the code (e.g., to distinguish “O” from zero or “B” from 8). The serialization-ready thermal inkjet prints alphanumeric characters, as well as linear and two-dimensional barcodes including QR codes and the GS1-compliant DataMatrix code specified in serialization requirements. The printer can be supplied with an installation- and operation-qualification validation package. 


  Another serialization-ready system consists of a print/apply labeler from Domino Amjet integrated with the Intelli-Pac Manual Case Aggregation System from Omega Design. The stainless steel machine handles loose or bundled bottles and cartons. The process begins with placement of a case on a table or in a case former. A plunger-equipped printer/applicator applies a serialized label. One camera reads the case label and another captures the codes of each item in the case to establish a parent/child hierarchy. Configurable for manual or semiautomatic operation, the ergonomic system seamlessly integrates to layer-aggregation technology, case-label printer, operator touchscreen, data-management system, case-loading table, and handheld scanner. Other capabilities include unit-to-bundle data syncing, case-to-pallet data syncing, and case-forming and taping. Domino also offers equipment for applying serialized codes to primary containers. 


An advanced quality-control (QC) tool bundle from Global Vision inspects text, artwork, spelling, Braille, and barcodes and provides annotation functionality. Web-based software deploys on an on-premise or private cloud server and provides enterprise-wide access to packaging QC tools. “Proofware gives any enterprise instant access to everyone involved in the security of their brand copy and artwork throughout the enterprise,” explained Reuben Malz, president of Global Vision in a press release. “With Proofware a new level of collaboration is achieved between different teams within the organization, their customers, and suppliers” (1). Other features include report management tools to organize inspection reports and easy integration with artwork, document, and product-lifecycle management solutions. Software permits multiple inspections to be run with the same set of files. Proofware also supports e-signature, call-outs, stamps, measurement, and color inspection.


1. Global Vision, “Global Vision Releases Proofware, the First All-in-One, Cloud-Based, Packaging Inspection Suite,” Press Release, Feb. 11, 2014.

For further discussion, read the PackForum article in the June 2014 issue of 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Articles

Printing, labeling, aggregation, and inspection equipment meets serialization requirements.

Packaging Innovations Displayed at INTERPHEX 2014

Many exhibitors at INTERPHEX, held Mar. 18-20, 2014 at the Javits Center in New York, plan to showcase packaging innovations. 

 INTERPHEX marks the North American debut of the 

 labeling system from Schreiner MediPharm. This diverse portfolio of overt, covert, and machine-readable security technologies provides multiple levels of protection against counterfeiting. Overt options include complex holograms with custom artwork, two- and three-dimensional effects, dynamic structures, and micro/nano text; ShiftSecure color-shifting ink; and thermo-reactive print, which changes colors at a certain temperature. Covert features include combinations of luminescence and digital watermark, which are visible under ultraviolet light. Invisible, machine-readable LaserSecure and Laser HighSecure security pigments can be integrated into any graphic element. For more stringent requirements, the two-step DNA-Secure with red luminescence authenticates product using a handheld reader and DNA laboratory analysis. KeySecure encrypts data in human-readable text, barcode, or DataMatrix code for authentication by phone or internet. A plug-and-play system expedites implementation and simplifies integration with information technology. 

. A 266-Panel Outsert from Platinum Press offers an expanded number of panels to provide more space for product information and instructions and eliminate the need for piggybacked outserts or “twinserts.” Despite the number of panels, the 266-Fold Outsert measures approximately 20% thinner than traditional outserts. Easier to handle both manually and mechanically, the more compact printed piece increases production speeds while reducing production, storage, and shipping costs. Platinum Press also plans to show a carton with integrated insert. A window on the carton makes the insert visible for quality assurance inspection. Merging two packaging components increases line speeds and cuts costs. 

 Compliance-prompting packaging will be displayed by several members of the Healthcare Compliance Packaging Council (HCPC): Aphena Pharma Solutions Inc., Constantia Flexibles, Howell Packaging, IMA Life North America Inc., Platinum Press, Pharma Packaging Solutions, Uhlmann Packaging Systems, and Winpak Heat Seal Packaging Inc. HCPC executive director, Walt Berghahn, will give a presentation at INTERPHEX, “Improve Patient Adherence with Compliance-Prompting Packaging.” Berghahn will provide data showing improved patient adherence with compliance-prompting packaging, offer an overview of successful pharmaceutical compliance-prompting packaging, and discuss trends in smart adherence packaging. 

 The 2060 Unipac Tube Filling System from Romaco North America is a high-speed, modular machine, equipped with a 12-station turret, which handles aluminum and polyethylene laminate tubes as well as various closure shapes. The unit features an easy-to-replace upper head, quick size-changeover, and a lightweight, easy-to-disassemble dosing pump. A high-capacity, ergonomic tube loader requires no changeover and is easily accessible at the side of the machine. Options include a servo-driven dosing pump and diving nozzle.

Filamatic plans to display its economically priced Econofil System and its versatile AdaptaFil Benchtop Filler. Capable of filling with accuracy of at least 0.5%, the two-head, piston-pump-equipped Econofil System reaches speeds of 60 containers per minute. If desired, the piston pump may be replaced with a peristaltic pump. The semiautomatic AdaptaFil Benchtop Filler is equipped with a touch-screen operator interface and accommodates a piston, peristaltic, gear, or lobe pump on the same base. With the multiple pump options, the unit can fill a range of products, volumes (milliliters to gallons), and viscosities (aqueous to viscous). 

 Domino Amjet will show one of its print/apply labelers integrated with Omega Design’s Intelli-Pac Manual Case Aggregation System for serialized cartons or bottles. Featuring an ergonomic design and stainless-steel construction, the machine handles loose or bundled bottles and cartons and is configurable for manual or semiautomatic operation. The system also allows seamless integration to layer-aggregation technology, case-label printer, operator touch-screen, data-management system, case-loading table, and handheld scanner. Other capabilities include unit-to-bundle data syncing, case-to-pallet data syncing, and case-forming and case-taping capabilities. 

. The web-based Proofware suite from Global Vision consists of tools to inspect text, artwork, spelling, Braille, and barcodes. The Proofware suite also enables e-signature, annotation, call-outs, stamps, measurement, and color inspection. Deployed on an on-premise server or private cloud server, the web-based system offers instant access to everyone involved in the development and use of brand copy and artwork. As a result, it enhances the level of collaboration among teams within and outside a brand owner’s organization. Other features include report management tools, the ability to run multiple inspections with the same set of files, and easy integration with artwork, document, and product lifecycle-management systems. 

Displays will include new products for anticounterfeiting, labeling, and compliance packaging and new equipment for filling, aggregating, and quality control.

INTERPHEX Features Packaging Innovations

Visual inspection ranks as an essential operation in parenteral drug production to ensure the safety of the drug product in its container, such as a vial or syringe. The industry is seeing an increased emphasis by regulators on having a well-characterized and robust inspection process, especially with regard to particulates, says John Shabushnig, PhD, principal consultant at Insight Pharma Consulting. 

 spoke with Shabushnig, who is also the group leader for the Parenteral Drug Association (PDA) Visual Inspection of Parenterals Interest Group and a member of the United States Pharmacopeial Convention (USP) Visual Inspection Expert Panel, about available technologies, current trends, best practices, and work at industry associations that aims to improve understanding and define guidelines.  
  
  

 What flaws are typically identified by visual inspection? 

 Visual inspection identifies crucial container integrity defects such as cracks, missing or misapplied stoppers and seals, foreign material such as particulate matter, precipitation or discoloration of the product, over- or under-filled containers, and cosmetic defects such as scratches or dirt on the outside of the container. Specific defects will vary by product and container type. 

However, when discussing inspection and rejection of defective units, it is just as important to consider defect prevention. The data obtained from the visual inspection program should not only ensure removal of defective units, but also provide information for process improvement to reduce and prevent such defects in the future.

 Have the number of recalls associated with visual flaws increased or decreased in the past five years? To what do you attribute this change? 

There has been an increase in recalls due to visual defects. This is driven by recalls for particles, especially glass particles. I believe this was influenced by a renewed concern about the risk of glass delamination or the formation of glass lamellae due to interaction of the liquid product with the interior surface of the glass container. This has expanded to a broader concern with other types of hard particles including metallic particles as well as glass. Increased regulatory activity is pushing an upward spiral with companies taking increasingly conservative actions and recalling batches that would have been acceptable in the past. In the absence of good clinical studies on the risk posed to patients by small numbers of visible particles, we must base any risk assessment on anecdotal reports. I believe this lack of quantifiable data has led to the very conservative regulatory and industry position we see today. It also has led to a wide range of differing practices within the industry, often based on a company’s recent regulatory experience. Through education and guidance developed by PDA and USP, I hope we will see more consistency in this area and ultimately reduce the number of recalls associated with visual defects.
  
  

Comparing manual and automated inspection

 Can human inspectors work as effectively as automated equipment? If so, what tools and practices are essential to inspector success? 

 Both humans and machines can provide effective inspection of parenteral products. Originally, automated systems were limited to detecting particulate matter in solutions, but current systems can also detect container and seal defects. Although human inspectors and automated systems can achieve similar levels of sensitivity, each has different strengths and weaknesses. 

Human manual inspection, however, is still the reference standard for visual inspection and is the method stated in the 

 of the Council of Europe (Ph. Eur.) and the pending 

 <790> (1, 2). Human inspectors are flexible and can respond to something they have never seen before or something that ‘doesn’t look right.’ They can also more easily tolerate normal variation in containers, especially those formed by molding, reducing the number of falsely rejected good product. However, people are more limited in the rate of inspection (i.e., the number of containers per minute or hour that they can inspect). They also suffer fatigue and require frequent breaks to maintain a high performance level. These limitations all lead to greater variation in manual inspection results, but this variation can be minimized through good training and operating procedures.

Machines have the advantage of speed, and some are capable of inspecting 600 units/minute. Equipment is validated to provide consistent performance at any time and on any day or shift. But machines are not very flexible and generally unsuited to products in molded containers. In addition, the high cost of automated systems may be unjustifiable if product volumes are low or there is a mix of many different products. Automated systems are best suited to high volumes of a limited number of products. These considerations are similar to those encountered in other forms of automation.

 What are the most common visual inspection technologies in use today? How do they overcome inspection challenges? 

 The most common inspection technologies use machine vision, the combination of video and computer technologies, to capture and quickly analyze images of product. Today’s automated inspection systems use several cameras to inspect specific regions of a vial or syringe in detail. These inspection stations include specialized lighting to highlight specific types of defects.

There are also semiautomatic inspection systems in use. Available for a number of years, these systems rely on a human inspector to inspect the product and make the quality decision, but automate the material handling, transporting, and rotating of the container under controlled lighting in front of the inspector.

 What new visual inspection technologies look promising? 

 For manual inspection, more inspection stations are being equipped with light sources based on light-emitting diode (LED) technology. LED lighting offers a cool, stable, and long-lived source of illumination.

There has always been a desire to see inside difficult-to-inspect products and packages such as freeze-dried powders, suspensions, and darkly colored solutions as well as translucent or opaque containers. X-ray technology is being investigated for this purpose, and recent advances in X-ray sources and detectors are bringing this technology closer to routine use. The deployment of this technology must be coupled with an understanding of how the exposure to very low X-ray doses affects the stability of a specific product.

 Are combination systems (e.g., visual inspection/leak detection systems) gaining ground?  

 Yes, the availability and usage of combination systems is growing. Combination systems are a good example of the synergy possible when different technologies work together with each performing the task(s) they do best. For example, when compared to machine or human visual inspection, leak detection systems, whether based on high voltage, vacuum decay or headspace analysis, offer greater sensitivity when confirming container integrity. This sensitivity level also is achieved with lower false-reject rates. When using vision alone, it is often necessary to tune the system to such a high sensitivity to detect small cracks that high false-reject rates result. By combining technologies, it is possible to reduce the sensitivity of the visual inspection and false-reject rate while maintaining sufficient sensitivity to catch visual defects. In combination systems, higher overall sensitivity with lower false rejection can be achieved. Such combinations can be expensive, and thus, a high volume of a limited number of products is necessary to support purchase, validation, and operation of these systems.

 What regulatory activities are influencing visual inspection? 

The increased emphasis on the inspection process by regulatory inspectors has certainly focused attention on visual inspection. The upward trend in recalls also has brought visual inspection concerns to the forefront. USP and PDA have worked to bring a better understanding of the inspection process to the industry and help set practical guidelines for routine inspection.

What is the status of USP’s draft chapter <790> Visible Particulate Matter in Injections? If approved, how will it update current practices? 
  Shabushnig: The development of USP General Chapter <790> was initiated in 2009 with the publication of a stimuli article (3). A Stakeholders Forum was held in 2010, and subsequent drafts were published for public comments in 2012. The chapter has been approved, is scheduled for publication in April 2014 in the first supplement to USP 37, and should become official in August 2014.

This chapter will offer important guidance on inspection method and acceptance criteria. It defines critical parameters (e.g., illumination intensity, inspection time, backgrounds, and movement) for a reference inspection method. These parameters are harmonized with the method currently found in 

. In addition, a sampling plan and acceptance criteria are provided to better define the current expectation that ‘every lot of parenteral preparation is essentially free from visible particulates’ (4). These acceptance criteria recognize the serious concern regarding particles in injectable products but also current process capabilities with contemporary manufacturing and filling equipment and packaging materials.

A companion Information Chapter <1790> Visual Inspection of Injectable Products is also currently under development. This chapter is expected to provide guidance on good practice for visual inspection. A draft is expected to be published in

What best practices have been identified by PDA’s Visual Inspection of Parenterals Interest Group? 

 There are many opportunities for improvement of the inspection process in the pharmaceutical industry. We have learned much about these processes through benchmarking surveys conducted through PDA. The most recent was in 2008, and we are planning to update this survey in 2014.

Best practices include a detailed list of defects with a risk assessment to support the risk category chosen (e.g., critical, major, or minor). This list supports training of human inspectors, validation of automated inspection equipment, and lot assessment through acceptance sampling (i.e., acceptable quality-level inspection).

Training of inspectors should be confirmed with a robust challenge with a set of good containers seeded with known defects. A well-characterized test set is needed for this purpose. This test set also should establish the detection probability of a range of typical defects. During routine inspection, the illumination intensity of the inspection station should be measured regularly to confirm operation within the compendial range, and inspectors should take frequent breaks to avoid lower performance due to fatigue.

For automated systems, a comprehensive validation should include a challenge with a broad range of defect samples to document the detection probability. In routine use, a small set of both good and defective product should be used to challenge the system to assure performance at the level observed during validation.

Upgrading visual inspection of parenteral products

What are the three most important considerations when updating or upgrading visual inspection of parenteral products? 

 When updating or upgrading visual inspection of parenteral products, a thorough understanding of expected defects and unique product characteristics is needed. This knowledge can be obtained from production history, complaints, review of similar products, and ‘what-if’ discussions. Inspection is made more difficult by high viscosity, foaming (i.e., forming bubbles), highly colored, suspensions, powders, and molded, colored, or opaque containers. These more challenging to inspect products will likely result in a higher false reject rate with automated inspection.

Secondly, successful implementation of visual inspection depends on a realistic assessment of product mix and production volume to identify the optimum technology (manual, semiautomatic, or automated).

Finally, successful visual inspection requires sufficient expertise and resources to evaluate and support the inspection process and technology chosen.

, 8.0, 2.9.20, “Particulate Contamination: Visible Particles” (EDQM, Strasbourg, France, 2013) p. 323.
  2. 	

 In-Process Revision: <790> “Visible Particulates in Injections [New],” 

 38 (6) (2012).
  3. 	R. Madsen, R. Cherris, J. Shabushnig, and D. Hunt, 

 General Chapter <1>, “Injections, Foreign and Particulate Matter” (US Pharmacopeial Convention, Rockville, MD, 2013).

Using best practices for manual or automatic inspection can improve the inspection process.

Trends and Best Practices in Visual Inspection

Eight trends driving pharmaceutical packaging in 2014 can be encompassed in three broader categories. Product-protection trends include rising demand for anticounterfeiting tools, traceability technology, barrier containers, cold-chain maintenance practices, and quality-assurance equipment. Productivity boosters emphasize downtime reduction and include adoption of modular components and single-use product-contact parts. Patient adherence is aided by compliance packaging designs and easy-to-use, self-dosing devices like auto-injectors. 

Despite some victories in the war against counterfeit products, counterfeit pharmaceuticals continue to pose a hazard for patients. Orders from online pharmacies are especially risky, but no product is safe from counterfeiting. During 2013, for example, counterfeit Botox (1) and Lamisil (2), an antifungal antibiotic, were discovered in the marketplace.  

Under the new European Union Anti-Falsification Directive, virtually all prescription medicines must carry a unique code number plus a feature showing that the outer package has not been tampered with. These requirements take effect in 2017 (3). In the United States, the Drug Quality and Security Act (H.R. 3204), signed into law by President Obama on Nov. 27, 2013, establishes similar serialization requirements and outlines data collection and sharing responsibilities for drug manufacturers, wholesale distributors, dispensers, and repackagers. The unique item-level code makes it possible to trace each package through the supply chain from manufacturer to consumer and enables quick authentication.

Packaging suppliers are preparing to meet these requirements. For example, August Faller, a Germany-based manufacturer of secondary packaging for pharmaceuticals, has developed barcodes and alphanumeric and DataMatrix codes for folded boxes and labels for the serial coding of packaging materials. An inkjet coder applies the serialized information. 

An umbrella organization for five German medicinal product-distribution associations, securPharm, relies on the two-dimensional DataMatrix code. Manufacturers print a DataMatrix code containing a unique number to make each package “one of a kind.” All assigned numbers are stored in a shared manufacturer database. At the pharmacy, each package code is scanned and checked against the database before the medicine is given to the patient, thus allowing quick identification of counterfeit products. This system passed a practical test involving 280 participating pharmacies, 24 cooperating pharmaceutical companies, more than 3.5 million serialized packages, and more than 30,000 authentications. “With newly coded packages of selected drugs, we achieved system accessibility 99.5% of the time,” reported Reinhard Hoferichter, spokesman for the securPharm Executive Board (3). 

Machinery manufacturers also support traceability initiatives. For example, Marchesini Group, an automation specialist headquartered in Italy with US offices in New Jersey, has developed a track-and-trace solution with a module capable of applying codes on both sides and the top of folding cartons at the rate of 400 cartons per minute. A camera then checks and verifies the codes. The data are stored in a central server for retrieval at any time for quick product authentication (3). 

 Product quality also depends on compatibility of the product and container. Biopharmaceuticals, which are currently experiencing double-digit sales increases and forecasted for continuing growth during the next decade, can present challenges to conventional packaging. Some biomolecules readily decompose, and others are highly aggressive and attack the surfaces of the primary package, spurring interest in containers with improved barrier properties and enhanced impact resistance (3).

To provide the barrier properties needed by biopharmaceuticals, Schott has developed glass vials with a thin lining of silicon dioxide on the inside. In a chemical vapor deposition process, a precursor gas reacts with oxygen at high temperatures and deposits silicon molecules on the glass wall. “The silicon layer prevents protein interactions with the package surface and protein adsorption—sensitive biopharmaceuticals thus stay stable,” explained Christina Rettig, spokesperson for Schott (3).

Multilayer plastic bottles are another alternative for biopharmaceuticals requiring barrier protection. Some polyolefins are as transparent as glass but protect better because their surface cannot be attacked by alkaline liquid medicines. These polymers, however, are relatively expensive (3). 

Schott’s TopPac series of prefillable syringes is made from cyclo-olefin copolymer (COC). Sizes range from 1-50 mL and include 10-, 20-, and 50-mL large-volume syringes for intensive care applications. The latter sizes are compatible with syringe pumps for infusion therapy. 

Multilayer plastic containers, such as the Gx MultiShell vial from Gerresheimer, offer higher barrier properties for parenteral drugs with alkaline pH ranges as well as potent pharmaceuticals. Uniting the best properties of plastic and glass, the cyclic olefin polymer (COP)/polyamide/COP structure shown in 

does not interact with alkaline liquids, leaches virtually no organic substances, and is more break-resistant than the equivalent glass container. Gerresheimer also offers ClearJect COP syringes. The heavy metal-free COP is particularly well-suited for sensitive oncology and ophthalmology medications.

 Because many biopharmaceuticals need to be maintained at certain temperatures to protect quality and efficacy, growth in this market segment is also generating demand for cold-chain products and technologies. As a result, logistics providers, such as UPS, and contract supply-chain service providers, such as BioConvergence, are expanding services to ensure that temperature-sensitive products are maintained within the specified temperature range for the duration of their travels. 

Suppliers of temperature-controlled packaging and data loggers are equally active in the development of products, which maintain required temperatures longer and are easier to use. To simplify transition to thermal packaging, some suppliers have developed prequalified systems. Cold Chain Technologies (CCT), for example, has developed a range of prequalified shipping systems for both parcel and bulk applications. The KoolTemp GTS Rx, Express, Excel, Extreme, and Evolution shipping systems offer simple loading and conditioning and modular designs with common refrigerants. Created with the aid of CCT’s KoolDesigns Thermal Modeling software and powered by its proprietary Koolit Advanced PCM phase-change material, KoolTemp GTS shipping systems include refrigerated, frozen, and controlled-room-temperature options and a variety of sizes that range from 4-52-L small parcels to half- and full-pallet bulk shippers. 

A rising level of recalls and a changing regulatory landscape are stimulating attention on quality assurance/control. Visual inspection is increasingly automated, as discussed in an interview with John Shabushnig, principal consultant at Insight Pharma Consulting, in another article in this issue. Machinery builders are automating other inspection functions too. During processing and packaging of pharmaceuticals, 100% in-process checks are often necessary, as it is essential to ensure that precisely the right proportion of active substance is contained in each vial, syringe, or carpule. To maintain filling precision, Bausch + Ströbel has worked with sensor specialist visiotec to develop a process that continuously controls filling without impacting output. Instead of removing vials for inspection, online sensors check the fill without slowing the line (3).


  The ability to inspect online at line speeds dovetails with the ever-present need to maximize productivity with strategies such as reducing changeover time. Bausch + Ströbel, for example, designs machines to minimize downtime related to changeover. A fully automated labeler, capable of labeling up to 350 bottles per minute, permits reel changes without stopping the machine (3). 

Changeover time also shrinks with the adoption of single-use product-contact parts because components that ordinarily would require cleaning are simply removed and replaced. A number of companies supply single-use, disposable systems including Bosch Packaging, Colanar, Cozzoli, and Flexicon A/S. Flexicon’s asepticsu sterile, single-use fluid path works in conjunction with its peristaltic filling technology to deliver precise filling accuracy with rapid product changeover. The single-use system also minimizes risk of cross-contamination and simplifies validation. Gamma-sterilized components arrive double-bagged and ready for use.  


  Better patient adherence is one way to address pressures to reduce healthcare costs and improve outcomes. It can be challenging, however, to deliver the correct dose of medication at the correct time. Compliance packaging designs can help consumers take their medication properly. Self-dosing devices, such as autoinjectors, shift medication delivery to the consumer’s location from more expensive, labor-intensive settings like a doctor’s office. 

Designs feature built-in safety features, such as dose monitors and safety needles, which retract immediately after injection to prevent accidental needlesticks. 

The packages of the future will be even more versatile. The Finnish-Swedish packaging manufacturer Stora Enso and Göteborg’s Chalmers University of Technology, for example, are developing an intelligent package designed to simplify communication between patients and doctors. The package records precisely when a tablet is removed. If the doctor’s prescription is not observed, the patient receives a wireless reminder, which can be sent to a mobile phone, for example (3). 

,” accessed Jan. 27, 2014. 
  2. 	The Counterfeit Report, “

,” accessed Jan. 27, 2014. 
  3. 	Messe Dusseldorf, “New Pharmaceuticals Packages Protect Proteins and Prevent Counterfeiting,” Interpack 2014: Technical Article No. 1 (Nov. 2013). 

 Packaging Forum editor, 4708 Morningside Drive, Cleveland OH 44109, tel. 216.351.5824, fax. 216.351.5684, 

Trends driving pharmaceutical packaging include product protection, productivity boosters, and patient adherence improvement.

Eight Trends to Watch in 2014

With the Jan. 1, 2015, California e-pedigree deadline less than 14 months away and federal traceability legislation likely to take effect, pharmaceutical manufacturers are focused on writing specifications, conducting pilot tests, and implementing full-scale serialization solutions on one or more packaging lines. 

The California deadline is likely moot. The US House of Representatives passed the Drug Quality and Security Act (H.R. 3204) on Sept. 28, 2013, and sent it to the US Senate on Sept. 30, 2013 (1). The Senate passed it on Nov. 18, 2013. (See PharmTech's blog "

Senate Finalizes Drug Compounding, Tracking Legislation

.") The bill, which was not amended by the Senate and has widespread support from industry, now awaits President Obama’s signature. 

Title I of H.R. 3204 clarifies FDA’s authority over compounding of human drugs and requires the agency to collaborate with state authorities to ensure the safety of compounded drugs. Title II of the bill would create a uniform national standard for drug supply-chain security to protect against counterfeit drugs. This standard would involve establishing a framework for supply-chain security and provide a 10-year transition to a unit-level tracking system (2).  

If signed by the President, as expected, H.R. 3204 “will preempt the current California regulations,” says John DiPalo, COO of Acsis, a provider of turnkey serialization solutions and software, in an interview with 

. “Companies that were developing a strategy just for California will now need to incorporate all operations across the entire supply chain. For example, if a company was looking to initially outfit a West-coast distribution center…to serve California, that will no longer be an option. In addition, it appears that the phased approach is no longer available and 100% of product moving through the supply chain will need to be serialized,” he explains. 

Broader than the California regulations, H.R. 3204 “…affects all of the stakeholders in the process, including manufacturers, distributors and retailers,” notes DiPalo. Manufacturers would be required (by Jan. 1, 2015) to capture and provide transaction history, transaction information including a lot number, and a transaction statement. Four years after enactment, manufacturers would be required to affix a product identifier (e.g.,  two-dimensional barcode) to a package and homogeneous case. Manufacturers would also be required to have a serialized numeric identifier (SNI), lot, and expiration date. The regulation also spells out requirements for distributors, dispensers, and repackagers regarding information they must have to accept a product and information they must provide to the subsequent owner.

Even as federal regulations were being hammered out in Washington DC, work has been continuing on serialization implementations. One company with a serialization pilot in progress, Daiichi Sankyo, is installing a turnkey solution from Acsis on a line at its packaging plant in Pennsylvania. The Acsis Serialization Management Suite includes line management, site management, and serial aggregation management software and is integrated with vision inspection from Cognex, printing equipment from Domino, material handling technology from Omega Design, and labeling technology from Weiler Labeling Systems. In addition to managing all aspects of implementation and support, Acsis prebuilt integration with Daiichi Sankyo’s SAP Auto-ID Infrastructure and Object Event Repository so product data can be shared and tracked in real-time throughout the supply chain.  

Automates and      manages application of serialized codes on the packaging line

Tracks and      controls all parent-to-child relationships

Provides real-time      access to current and historical posting reports, reconciliation reports,      and serial-number status reports

Supports commissioning,      decommissioning, aggregation, and deaggregated events, as required,      regardless of component hierarchy. 

Acsis also works with Kodak to deliver integrated, end-to-end solutions that securely, cost-effectively, and reliably authenticate, track, and trace product. The collaborative effort, announced on Sept. 4, 2013, integrates Acsis Serialization Management software with the Kodak Traceless System and its viewers and Smartphone apps to create dual serialization marking and coding on the packaging line via a visible code for aggregation and distribution processes and an invisible covert code for investigation and enforcement. “[Acsis software]…has the level of granularity needed for item-level serialization that addresses both the packaging line requirements and tracking throughout the entire distribution chain,” says Randy Young, global director, Kodak Brand Protection Solutions (3).  

The solution integrates to enterprise systems and can be implemented with minimum downtime, and without a major retooling of manufacturing or packaging processes. If needed, Acsis can provide its turnkey Serialization in a Box system, which integrates its Enterprise Serialization track-and-trace software with smart vision cameras and handheld barcode readers. 

Whatever serialization solution is chosen, DiPalo advises allowing extra time for implementation. “Everything takes a little longer than you think, and you need to allocate adequate time and resources for validation,” he explains. He also recommends dedicating resources to the project instead of adding serialization responsibilities to existing duties. “Serialization affects many different areas of an operation, and it is a big job to keep track of all the moving parts. You are introducing new technology into the packaging world as well as additional information-technology requirements that typically the team members haven’t had to deal with in the past,” he notes. 

Despite the rigors of implementation, serialization can achieve true supply-chain visibility and offer benefits beyond regulatory compliance. “There is some immediate payback in the areas of returns management and recall management that can provide some immediate, tangible benefits,” concludes DiPalo.  

H.R. 3204, US House of Representatives, 113th Congress, 1st Session (Washington, DC), Sept. 30, 2013.   

US House of Representatives, Energy & Commerce Committee, “Backgrounder-H.R. 3204, The Drug Quality and Security Act,” 

energycommerce.house.gov/fact-sheet/hr-3204-drug-quality-and-security-act

Kodak, “Kodak Names Acsis, Inc. as Serialization Software Partner of Choice,” Press Release, Sept. 4, 2013. 

The Drug Quality and Security Act creates national standards for serialization of drug products to protect against counterfeiting.

Serialization Efforts Move Forward

The North American market for drug-delivery technologies is projected to grow 8.9% per year through 2017, according to a report published by MarketsandMarkets (1). With such a positive forecast, it’s not surprising there is a constant flow of drug-delivery innovations involving metered-dose inhalers, needle-free injectors, autoinjectors, nasal sprays, transdermal patches, nebulizers, infusion pumps, drug-eluting stents, sustained-release formulations, ocular implants, and related packaging. Interest is particularly strong for dry powder inhalers, needle-free injectors, auto and pen injectors, orodispersible tablets, transdermal patches, and buccal transmucosal tablets, notes the report. 

Suppliers are boosting capacity to meet rising demand in North America and around the world. In January 2013, Catalent Pharma Solutions announced a $20-million investment in its Inhalation Center of Excellence in Research Triangle Park, NC. The project will expand production capabilities for clinical and commercial pressurized metered-dose inhalers. 

SHL Group (Sweden) is spending $40 million to expand production of autoinjectors and pen injectors in Taiwan. “Our customers are bringing more biologics to market,” explained Roger Samuelsson, chief executive officer of SHL, in a press release (2). SHL’s injector product range includes disposable and reusable devices with fixed or variable dosing, enhanced precision, and the ability to accommodate high-viscosity liquids. SHL also makes inhaler systems. 

The need to accommodate biologics with higher viscosities and patients with limited dexterity prompted Unilife to develop the Unifill Assure injector. An extended finger flange with a soft, rubberized, non-slip grip and an easy-to-press thumb button on a strengthened plunger improve ergonomics. Compatible with standard fill/finish lines, features include automatic user-controlled needle retraction. The automatic needle retraction eliminates the need for ancillary needle sheath-based safety products, ensures patients have an unobstructed view of the drug from any angle during all stages of use, reduces the risk of needlestick injuries or the aerosolization (splatter) of blood or tissue residue, and helps minimize the size of the injector and waste disposal requirements. Audible, tactile, and visual indicators simultaneously confirm full-dose delivery and activation of the retraction mechanism. After retraction the plunger locks preventing reuse or needle re-exposure. 

Ease of use is an important attribute for virtually all drug-delivery segments. For inhalation products, Aptar Pharma Prescription Division has developed the simple-to-use, easy-to-clean Twister dry-powder inhaler. Introduced at Pharmapack Europe, Feb. 13-14, 2013, in Paris, France, and also displayed at Pharmapack North America, June 18-19, 2013, in Philadelphia, the design improves access to medication as well as patient compliance. Molded and assembled in a class ISO 7 cleanroom at the company’s production facility in Suzhou, China, the device is suitable for early-phase clinical trials and for medication that treats asthma and chronic obstructive pulmonary disease. It works in three steps: insert, twist, and inhale. The twisting action crushes a capsule to release the drug. Patients can observe the processing of the capsule and powder through the transparent container and also receive audible and visual feedback confirming that the full dose has been properly delivered. 

MarketsandMarkets, “North American Drug Delivery Technologies Market (Metered Dose Inhalers, Needle-Free Injectors, Auto-Injectors, Nasal Sprays, Transdermal Patches, Nebulizers, Infusion Pumps, Drug Eluting Stents, Sustained Release, Ocular Implants) – Forecasts To 2017,” (Dallas, TX, July 2013).  

SHL Group, “SHL to Invest 40 Million USD in 2013 to Significantly Expand Production Facilities | Auto Injector, Pen Injector & Drug Delivery Devices,” Press Release, Feb. 22, 2013. 

Capacity expansions and new products meet needs for inhaler and injector systems.