Hallie Forcinio is BioPharm International's packaging editor, editorhal@sbcglobal.net

Hallie B Forcinio

Prefilled syringe innovations increase patient and caregiver safety and efficiency and reduce waste of product and packaging materials. “Since it is already packaged ready for the injection, the prefilled syringe saves time and avoids unneeded handling prior to the actual application, minimizing the risk of the injection errors, dilution errors, or non-sterility issues [that are a risk in] multi-dose containers,” explains Wenzel Novak, global senior director of business development at Gerresheimer Medical Systems. Novak estimates that prefilled syringes currently account for 10–15% of the parenteral market and anticipates rising demand.

“If you look at the top 40 injectable products, all are being used with prefilled syringes,” reports Dr. Nicolas Brandes, director of product management, Polymer Prefilled Syringes and Vial Containment at West Pharmaceutical Services.

Prefilled syringes can be made of glass or plastic such as cyclic olefin polymer/cyclic olefin copolymer (COP/COC) or polypropylene (PP). Glass dominates in most markets. Novak predicts, however, that the share of co-injection-molded COP/COC prefilled syringes will grow from 2% to more than 5% during the next decade.

“We have seen more approvals for products in plastics especially during the past five years,” reports Brandes. He notes plastic syringes often are chosen for specific applications such as contrast imaging agents, hyaluronic acid, and Botox as well as for products that are sensitive to silicone oil. Plastic syringes also function well in auto-injectors.

According to Novak, about 60% of prefilled syringes are staked-in needle syringes, but there are considerable regional variations. The most common prefilled syringes are 1-mL long and 1-mL short. The most prevalent applications include anti-coagulant (glass 1-mL long), vaccines (glass 1-mL short), and isotonic solutions where PP is the material of choice. “With the existing COVID-19 challenge, a significant increase in vaccines is expected worldwide,” says Novak. This growth will stem from COVID-19 vaccines as well as heightened interest in established vaccines (e.g., flu).

Prefillable syringes are delivered as bulk goods or ready-to-fill (RTF). Gerresheimer’s bulk syringes are provided as unsterilized glass bodies in flat (Rondo) trays or customized packaging designs (e.g., bags). Its Gx RTF syringes are presented as washed, sterilized RTF components to pharmaceutical and contract manufacturing operations and are available in glass or plastic. Fill volumes range from 0.5 to 5.0 mL, with the most common volumes falling between 0.5 mL and 3.0 mL.

Innovations from suppliers accentuate the ease-of-use attributes of prefilled syringes and focus on adding sizes (particularly for larger volumes), reducing waste, and patient and caregiver comfort and safety.

Gerresheimer has expanded its range of prefillable polymer syringes for sensitive biologics, biosimilars, and biobetters to include a Gx RTF ClearJect COP needle syringe, 1.0-mL luer lock.

At West Pharmaceutical Services, line extensions include insert needle syringes (the plastic version of a staked needle glass syringe) and more needle sizes and product volume options. “In the past three to five years, we have seen more approvals in the larger 2.5-mL format,” reports Brandes. The larger volume reduces the number of syringes needed per dose and improves efficiency and comfort. There’s a trend toward finer needles too. “Smaller, thinner needles mean less pain,” he explains.

User-friendliness is the goal behind a collaboration between Gerresheimer and Stevanto Group whereby Stevanato supplies its ITC twist-off closure system for Gerresheimer’s Gx RTF luer lock syringes. The integrated seal cap consists of an elastomeric component, which is available in different formulations, and a rigid, translucent polymer cap. Advantages include greater stability and shelf-life protection versus traditional luer cone systems (1).

Prefilled syringes offer sustainability benefits by eliminating multi-dose vials and related production and handling as well as product waste associated with leftover product. Still, says Brandes, “there’s a lot of room for improvement. Current systems create a lot of waste.” But efforts are being made to reduce scrap rates and to recycle tubs that hold nested containers during the fill/finish process. 

To meet the priority of product safety, suppliers seek designs to prevent needlestick injuries and to protect product quality by minimizing particulates and eliminating product interaction with tungsten or silicone residues. For tungsten-sensitive products, Gerresheimer Biological Solutions offers a metal-free manufactured syringe. With this patented technology, the pin used for conical shaping is made of a ceramic rather than tungsten or another metal.

Silicone oil is commonly used to facilitate syringe performance but can cause aggregation and particulate problems for sensitive biologics. “There’s a push by ophthalmologists and regulatory bodies to move away from siliconized formats,” reports Brandes. “Some patients have reactions to silicone, and over time with repeated injections, the material can accumulate [in the eye],” he explains.

One silicone-free option combines ImproJect plungers from W.L. Gore & Associates with syriQ BioPure silicone-free syringes from SCHOTT. The system opens the door for many sensitive products to move into the prefilled syringe format. Until the advent of a silicone-free design, “Pharmaceutical manufacturers seeking to avoid silicone-induced aggregation and sub-visible particles have had to choose vials even when they wanted to offer other delivery options,” said Christiane Gumera, product specialist at W.L. Gore & Associates. Careful attention to syringe geometry and dimensions of the syriQ BioPure syringes helps ensure a consistent gliding force and injection duration over the shelf-life of the product and maintains container/closure integrity without the use of silicone. Ultra-low tungsten residuals and minimal cannula adhesive residuals further reduce the extractible profile and the risk of container/drug interactions (2). 

To prevent potentially hazardous accidental needlesticks and comply with regulations in various parts of the globe, some syringes like Gerresheimer’s InnoSafe product incorporate a pre-applied, passive safety device. With the pre-applied device, there’s no need for post-filling assembly equipment or for healthcare professionals to install a guard before an injection is given. Advantages include improved compatibility with auto-injectors and a completely hidden needle that gives patients with needle-phobia a better experience. The design also prevents accidental reuse and runs on existing fill/finish lines without any additional equipment or process steps.

Finally, COVID-19 has spurred the development of prefilled syringes, particularly with regard to low-temperature storage. Brandes predicts, “Right now all COVID-19 vaccines are in vials, but in the next two to four years we will see a novel type of syringe that handles -80 ºC.”

1. Stevanato Group, “Stevanato Group Sings an Agreement with Gerresheimer to Provide Its Integrated Twist-off Closure System Solution, ITC, for Gx RTF Syringes,” Press Release, Oct. 6, 2020,

Glass Syringe System Reduces Injection Force without Silicone

Articles

Innovations in glass and plastic syringes reduce waste and increase safety. 

Prefilled Syringes Meet Growing Demand

Many ophthalmic products for the diagnosis and treatment of eye problems rely on droppers to deliver a dose to the eye. Physics limits the size of the smallest dose to approximately 40 microliters (μL), an amount that can cause side effects. Dropper delivery also requires the patient’s head to be tilted, and the product can become contaminated if the dropper touches the eye or face. Product waste is common because it can be challenging to accurately aim a droplet into the eye, particularly when self-administering.

To overcome the disadvantages encountered with droppers, Eyenovia has developed the Optejet touchless dispenser, which is capable of repeatably and precisely dispensing micro-doses of 7–9 μL directly on the cornea from four to five inches away. It works in a horizontal orientation rather than the vertical orientation of the dropper and is easy to operate, reports Michael Rowe, chief operating officer at Eyenovia.

The proprietary Optejet system consists of a base unit and replaceable product cartridge and is protected by multiple patents related to the technology and system. The base unit houses the core of the design, a piezoelectric ejector, plus electronics and battery, and is designed for two or three years of service. A Bluetooth connection allows the Optejet dispenser to be paired with smartphones or tablets and enables dose data to be collected and analyzed in a Cloud-based system so caregivers can monitor usage and adherence. A timeout feature can lock the device until it’s time for the next dose. “Future applications may include dosing reminders,” reports Rowe.

The replaceable cartridge contains a product-filled bladder, which collapses as it empties, eliminating the need for pressurization, preventing air ingress, and minimizing the chance of contamination. In operation, a unique electric waveform pattern is applied to a piezoceramic disk, which vibrates a plastic membrane with a concentric array of 109 40-micron-diameter nozzles. The fluid is ejected from these nozzles in a wave of micro drops, which is called a micro-dose array print. The low-velocity dispersion and a dispensing duration of fewer than 100 milliseconds, quicker than the blink reflex, enhance ease of use. The low-velocity dispersion also makes dose delivery more comfortable. To ensure the dispenser never comes in contact with the face or eye, the nozzle array is recessed and covered by a shutter when not in use (see 

). Eyenovia plans to add an in-house commercial fill/finish system to its existing sub-assembly manufacturing operation.

Figure 1. CLICK TO ENLARGE. A replaceable product cartridge fits on the reusable Optejet base. A shutter protects the nozzle array. To dispense medication, the patient or caregiver opens the shutter, positions the dispenser at eye level, and presses the button to dispense a micro-dose mist. Image Property of Eyenovia, Inc. Used by Permission. 

The Optejet micro-dose dispenser has been designed for a trio of ophthalmic products under development at Eyenovia. The first product likely to be commercialized is MydCombi, a combination product (tropicamide 1% and phenylephrine 2.5% solution) for mydriasis (pupil dilation) during eye exams. On March 2, 2021, Eyenovia announced that FDA accepted its new drug application for MydCombi, and the agency’s review is expected in the fourth quarter of 2021. The other two products destined for Optejet dispensing include MicroPine micro-dose atropine to prevent progressive myopia in children, and MicroLine micro-dose pilocarpine to help improve near vision in adults with presbyopia. The MicroPine product has been licensed to Bausch Health in the United States and Canada. Eyenovia also has partnership agreements with Senju and Arctic Vision to help commercialize the micro-dose technology. “We are open to additional partnerships that bring the benefits of the technology to other areas in ophthalmology and/or the world,” says Rowe.

Smart packaging opens doors to new products for diagnosis and treatment of eye problems. 

Packaging Delivers Micro Dose

The pharmaceutical industry has been on the leading edge of anticounterfeiting and brand protection efforts for many years. “Anticounterfeit solutions are usually tailor-made according to the needs of the brand owner,” says Paavo Sillanpää, senior business manager, Pharma at UPM Raflatac.

A diverse strategy considering threat scenario and product is needed. “Most pharma companies have a multi-layered approach,” notes Joe Farrell, life sciences expert at Loftware. The most common physical solutions are tamper-evident labels and packaging materials, designs that prevent the placement of a counterfeit product into the original packaging, serialization, and overt and covert authentication methods such as holograms, invisible markers, and taggants.

“Ideally, multi-level security concepts should be used that are individually tailored to a specific use case, combining analog and digital features, which can be verified by different stakeholders within the supply chain,” says Gene Dul, president of Schreiner MediPharm US.

This article was excerpted from H. Forcinio, “

There is heightened interest in tools and technologies that go beyond the package to protect patients, such as on-dose solutions. In addition, says Peter Wong, chief operating officer at TruTag Technologies, “the industry is increasing its public awareness campaigns of the problem of fake and unsafe medicine in an effort to educate consumers about the dangers of unauthentic drug products.”

As a result, John Pitts, key account manager for Antares Vision, predicts an increased focus on consumer engagement. He notes, “Enabling the end consumer and the dispenser to authenticate their products is powerful on so many levels. It makes counterfeiting more difficult, provides vital and real-time data to the consumer, and can offer the manufacturer feedback.”

Labeling plays an important role in the fight against counterfeit products. As the passport for moving products through the global supply chain, it contains any track-and-trace or authentication information. “In the label business, we have seen an increased interest in various tamper-evident (TE) solutions and holograms,” reports Sillanpää. One new product from UPM Raflatac combines heat resistance, advanced adhesion, and conformability. Designed primarily for the European market where cartoned blister packaging is common, the heat-resistant TE label won’t shrink in heat tunnels used to produce multipacks. UPM Raflatac has also introduced sustainable TE labeling. It’s produced from Forest Film, which Sillanpää says is “the world’s first wood-based plastic labeling material.” Benefits include performance equivalent to traditional plastic film label materials and the ability to help pharmaceutical brands achieve sustainability goals.

Demand for more sustainable products extends to RFID and near-field communication (NFC) tags. Eco-friendly RFID and NFC tags from Identiv feature paper-based transponder inlays that reduce polyethylene terephthalate content, resulting in a repulpable substrate (1).

RFID technology is integral to the Cap-Lock plus RFID cap adapter and label combination from Schreiner MediPharm. The label-integrated RFID inlay provides digital proof of integrity and first-opening evidence for syringes as well as product authentication. Dul explains, “The adapter is placed on top of the syringe’s primary closure and interlinked with it to equalize the diameter differences of the syringe body and closure. The label wraps around the syringe body and cap adapter and—once opened—provides irreversible tamper evidence due to an integrated perforation.”

Magnetic ink is another potential anticounterfeiting tool. Technology from Inspectron relies on a proprietary reader, track-and-trace software, and magnetic ink, long used on checks to facilitate automated sorting. The magnetic ink is used to print a barcode, which is detectable even if it’s not visible to the eye. That means the code, which may be serialized, can be hidden on the inside of a carton or under a label and still be read. The current reader works from a distance of up to 2 mm, but units with longer read ranges are under development. “However, longer read ranges require bigger codes,” notes Nathalie Muller, head of Innovation at Inspectron. Although the first commercial application of the technology inkjets the codes on paper to enable identification of diverted product, Muller says, the permanent magnetic codes could be printed on plastic or glass containers and potentially support tasks like vial tracking. Also under development is a hybrid one- and two-dimensional barcode that would hold more data.

On-dose technology enables authentication at the product level. Edible microparticles coupled with the Smart Medicine solution from TruTag Technologies confirms product authenticity and can help boost patient adherence and outcomes. A new Pharma Mobile App allows patients to scan each dose with their smartphone, authenticate it, and record that it was taken. If desired, the record of the dose can be shared with healthcare providers. The system also can link to other product information.

In April 2020, FDA accepted molecular tagging technology from Applied DNA Sciences into its Emerging Technology Program (2). The company says that its technology is a multilayered platform that gives both the dose and the packaging an immutable identity for authentication.

On Nov. 30, 2020, AlpVision launched its Alpvision COVID-19 Initiative to protect COVID-19-related therapeutics and vaccines against counterfeiting. Under the program, AlpVision provides pharmaceutical companies and their suppliers with the tools to deploy its Cryptoglyph digital security feature on their packaging. Invisible to the human eye, the Cryptoglyph feature can be authenticated via smartphone. Adopting the technology does not change the production process or involve additional consumables. In addition, the smartphone applications connect to AlpVision’s Brand Monitoring System, a centralized server platform that enables real-time monitoring of product authentication activities. AlpVision plans to provide this service for free until the World Health Organization declares the pandemic has ended (3).

1. Indentiv, “Identiv Launches Eco-Friendly RFID, NFC Tags,” Press Release, Jan. 23, 2020.

2. ADNAS, “Applied DNA Accepted into US FDA’s Emerging Technology Program, Creating Pathway for Molecular Tagging of Pharmaceuticals and Packaging,” Press Release, Apr. 30, 2020.

3. AlpVision, “AlpVision to Offer Free of Charge Security Feature to ProtectCOVID-19 Relevant Medicines against Counterfeiting,” Press Release, Nov. 13, 2020.

Hallie Forcinio is packaging editor at Pharmaceutical Technology, 

Labeling, printing, and on-dose tagging technologies provide a multi-layered approach to anticounterfeiting for pharmaceuticals.

Counterfeiting Countermeasures

The never-ending battle against counterfeit pharmaceutical products has become fiercer with the pandemic. With product protection a constant concern, the market for anticounterfeiting technologies is strong, regulatory efforts are ongoing, and authentication and anticounterfeiting technologies are evolving. As a result, the anticounterfeiting packaging market is projected to grow at a 7.8% compound annual growth rate to $189.9 billion in 2026 (1). A major driver for this growth is the expanding use of e-commerce platforms, which make it easy to set up shop to sell fraudulent products and are largely unregulated. A study by Local Circles noted that approximately 20% of all products sold on e-commerce sites are counterfeit (1).

Anticounterfeiting laws and regulations, such as the European Union’s Falsified Medicine Directive and the US’s Drug Supply Chain Security Act (DSCSA), safeguard prescription drugs available from pharmacies. “However, pharmaceutical manufacturers should be aware that these measures alone will not guarantee a product’s integrity and authenticity,” says Gene Dul, president of Schreiner MediPharm US. He says, “Only additional counterfeit-proof authenticity features can provide a comprehensive approach against fraud, misuse, and tampering.”

Unfortunately, the coronavirus pandemic has increased the opportunities for counterfeiting. “In a survey issued by IDC in June 2020, 70% of companies agreed that their supply chain is ‘very vulnerable’ to suffering more problems if the COVID-19 crisis lasted more than a couple of months longer, and 75% of companies agreed that the COVID-19 pandemic has ‘greatly increased/will greatly increase’ problems with diversion, theft, and counterfeiting of critical products such as test kits, vaccines, and antivirals,” reports Aimee Genzler, vice-president, Corporate & Brand Communications at TraceLink, the study sponsor (2). 

In fact, in anticipation of a spike in counterfeiting, the US Immigration and Customs Enforcement Homeland Security Investigations (HSI) has launched Operation Stolen Promise 2, to halt the production, distribution, and sale of illicit COVID-19 treatments and vaccines. HSI reported that its agents have seized illicit proceeds and goods, made arrests, and shut down fraudulent websites (3), including the seizure of two domain names in December 2020 (4).

The proliferation of counterfeit goods stems in part from the shift to e-commerce, which has been accelerated by stay-at-home orders and advisories and reduced access to physical retail pharmacies. “The emergence of on-line pharmacies poses a significant threat of escalation in counterfeit pharmaceuticals and underscores the urgent need for on-dose countermeasures,” reports Peter Wong, chief operating officer at TruTag Technologies, which recently entered a partnership with Colorcon to provide advanced security coatings for on-dose use.

“Counterfeiters are opportunistic,” explains John Pitts, key account manager for Antares Vision, noting, “COVID-19 provided the ‘perfect storm’ for the counterfeiters: panic in consumers; product shortages from the brand name ethical providers; desire and, in many cases, requirement to purchase via e-commerce; and lack of and often conflicting information from the media and authorities.”

Joe Farrell, life sciences expert at Loftware, concurs, “It seems clear that whenever there are high-value pharmaceutical products, there will be people trying to profit illegally. The fact that the COVID-19 vaccines need to be shipped in stringent cold storage containers with radio frequency identification (RFID) temperature sensors along with specialized transportation methods will make it more difficult for counterfeiters to enter the supply chain, but not impossible.”

With COVID-19 vaccines now rolling out in limited quantities, demand will outstrip supply in the coming months. “This will create a ripe environment for unscrupulous parties to offer fake product,” says Wong, noting, “Distribution of the COVID-19 vaccine is designed to go to many more points of dispensing than for a normal pharmaceutical drug, as governments seek to deliver vaccinations broadly and as quickly as possible while maintaining demanding cold-chain requirements. These logistical requirements will create higher than normal transition points in the overall supply chain, which in turn create increase opportunities for diversion, adulteration, and fake product to reach the patient.”

A diverse strategy considering threat scenario and product is needed. “Most pharma companies have a multi-layered approach,” notes Farrell. The most common physical solutions are tamper-evident labels and packaging materials, designs that prevent the placement of a counterfeit product into the original packaging, serialization, and overt and covert authentication methods such as holograms, invisible markers, and taggants. “Ideally, multi-level security concepts should be used that are individually tailored to a specific use case, combining analog and digital features, which can be verified by different stakeholders within the supply chain,” says Dul.

There is heightened interest in tools and technologies that go beyond the package to protect patients, such as on-dose solutions. In addition, says Wong, “the industry is increasing its public awareness campaigns of the problem of fake and unsafe medicine in an effort to educate consumers about the dangers of unauthentic drug products.”

As a result, Pitts predicts an increased focus on consumer engagement. He notes, “Enabling the end consumer and the dispenser to authenticate their products is powerful on so many levels. It makes counterfeiting more difficult, provides vital and real-time data to the consumer, and can offer the manufacturer feedback.”

Demand for more sustainable products extends to RFID and near-field communication (NFC) tags. Eco-friendly RFID and NFC tags from Identiv feature paper-based transponder inlays that reduce polyethylene terephthalate content, resulting in a repulpable substrate (5).

In April 2020, FDA accepted molecular tagging technology from Applied DNA Sciences into its Emerging Technology Program (6). The company says that its technology is a multilayered platform that gives both the dose and the packaging an immutable identity for authentication.

On Nov. 30, 2020, AlpVision launched its Alpvision COVID-19 Initiative to protect COVID-19-related therapeutics and vaccines against counterfeiting. Under the program, AlpVision provides pharmaceutical companies and their suppliers with the tools to deploy its Cryptoglyph digital security feature on their packaging. Invisible to the human eye, the Cryptoglyph feature can be authenticated via smartphone. Adopting the technology does not change the production process or involve additional consumables. In addition, the smartphone applications connect to AlpVision’s Brand Monitoring System, a centralized server platform that enables real-time monitoring of product authentication activities. AlpVision plans to provide this service for free until the World Health Organization declares the pandemic has ended (7).

Physical technologies are common anticounterfeiting tools, but counterfeit and diversion prevention also relies on software. Farrell reports, “At Loftware, we are being asked for help in getting the correct information onto the label. It’s important to have an enterprise labeling solution that integrates with a company’s sources of data to make sure the correct approved information is automatically applied to the labels. This includes languages, barcodes, regulatory symbology, and regional product information. You also need a labeling solution that can aid with approving, managing, and promoting electronic information for use [data] to help speed the process for a faster time to market for these critical products.” Although not specifically an anticounterfeiting product, Loftware Spectrum software integrates with serialization solutions and ensures labeling is consistent, accurate, and contains the right serialized data and barcodes. “The use of global templates in an enterprise solution also helps our life sciences customers to globally standardize on the look of their supply chain labels to help identify counterfeited products,” he explains.

The scalable Track My Way platform from Antares Vision offers single-unit, batch, and custom traceability; provides direct consumer engagement; and can extend from raw materials tracking to end-of-life package disposal/recycling. Geolocation functionality can track the harvesting of the raw materials, packaging locations, the movement of products through the supply chain, and the point-of-sale location.

In April 2020, TraceLink released an anticounterfeiting tool called Smart Distribution Tracking. By integrating the Internet of Things with product serialization, Smart Distribution Tracking provides full track-and-trace visibility for the secure delivery of vaccines, test kits, and high-value products.

Another software tool, the Summit Authentication Platform from Microtrace Solutions, is a customized system consisting of a self-authenticating, encrypted barcode; a Spectral Taggant; and a handheld detector plus a smartphone mobile app. “Our Spectral Taggant is a chemistry formulated into an ink that, when printed, is a highly secure ‘signature’ or ‘fingerprint,’” explains Brian Brogger, president at Microtrace Solutions. This signature can be authenticated instantly via the handheld spectrometer or smartphone without an Internet connection. For vaccines and therapeutics, the barcode and Spectral Taggant can be applied to security labels. The mobile app is then able to verify that the barcode was genuinely issued and the Spectral Taggant verifies that the barcode has not been copied. The system also can provide real-time reporting and analysis.

The latest release of the Systech Brand Protection Suite from Systech International, the software solutions division of Markem-Imaje, delivers a fully integrated solution to combat counterfeiters, identifies product diversion, meets regulatory compliance, and provides analytics. The centerpiece of the suite, the company’s non-additive e-Fingerprint technology, turns any existing barcode into a unique, digital identifier to provide end-to-end visibility and actionable information as a product moves through the supply chain. New functions include the ability to push unique responses and content to users and smartphone authentication of e-Fingerprinted products. Responses can be tailored to the user, location, time, and safety of the product, and include photos or other information. A new analytics platform, Systech Insight, offers a series of Information on Demand dashboards and an analytics data pool (8).

Fortune Business Insights, “Anticounterfeiting Packaging Market Size to Hit USD 189.9 Billion by 2026; Increasing Focus on Brand Protection by Companies to Fuel the Market Demand, Fortune Business Insights,” Market Study, April 2020.

IDC, “Supply Chain Agility in the Pharmaceutical Industry,” White Paper, tracelink.com, October 2020.

ICE, “Operation Stolen Promise 2.0,” www.ice.gov/topics/operation-stolen-promise, accessed Jan. 4, 2021.

ICE, “ICE Investigation Led to Seizure of 2 Fraudulent Websites Purporting to be Biotechnology Companies Developing Treatments for COVID-19 Vaccine,” Press Release, Dec. 18, 2020.

Indentiv, “Identiv Launches Eco-Friendly RFID, NFC Tags,” Press Release, Jan. 23, 2020. 

ADNAS, “Applied DNA Accepted into US FDA’s Emerging Technology Program, Creating Pathway for Molecular Tagging of Pharmaceuticals and Packaging,” Press Release, Apr. 30, 2020.

AlpVision, “AlpVision to Offer Free of Charge Security Feature to ProtectCOVID-19 Relevant Medicines against Counterfeiting,” Press Release, Nov. 13, 2020.

Systech, “Systech Announces Comprehensive Updates to Its Market-Leading Brand Protection Solutions,” Press Release, July 9, 2020.

Volume 45, No. 2
February 2021
Pages: 43–45

When referring to this article, please cite it as H. Forcinio, “Countering Counterfeiters and Diverters," 

Anticounterfeiting technology protects the supply chain from manufacturer to patient.

Countering Counterfeiters and Diverters

The globalization of pharmaceutical products, a constant flow of regulations from 150 regulatory bodies worldwide, and increased demand for quality and compliance are prompting pharmaceutical companies to consider deploying a label management system (LMS). Such systems can integrate with enterprise resource planning systems and automate the label management process, replacing manual procedures. 

Compliance is a major driving force in the adoption of an LMS, along with eliminating errors, shrinking time to market, and cutting costs. “There has been increasing regulatory focus on labeling, in recognition of the important role labels play in patient-centricity and the need for accurate labeling to ensure patient safety,” reports Simon Jones, vice-president Global Product at Prisym ID.

Orchestrating labeling processes “optimizes time and resources, mitigates risks, and sets course for [a] competitive edge,” adds Julian Backhouse, associate director of Regulatory Technology at IQVIA. “Fragmented information, disparate processes, and lack of collaboration are no longer acceptable or viable,” adds Cham Williams, associate director of Business Systems at IQVIA.

Digitalization gains importance in the COVID era when many staff members are working remotely. “Being able to approve and review labeling digitally makes ensuring compliance a much more simple and fluid process,” said Wendy Payne, senior product manager, Loftware (1).

When selecting an LMS, suppliers agree life sciences experience is essential so there is an understanding of regulatory compliance demands, such as GxP and FDA requirements. “The supplier should understand forthcoming changes in … regulations, such as the EU’s [European Union’s] Clinical Trial Regulations and Falsified Medicine Directive, emerging market trends including e-labels, electronic instructions for use, [and] the new GS1 Clinical Trials barcode standard,” says Jones.

He continues, “The best systems have life science best practices integrated into the software, such as the ability to mandate label watermarks and supervisory sign-off. These should be highly configurable, but also provided with defaults set representing how pharma and medical device customers typically use them.” Other important features include the ability to confirm label designs are compliant with regulations, compatibility with character-level vision inspection systems to ensure print accuracy, and functionality for electronic records and electronic signatures.

An LMS should be able to provide alerts to label changes in real-time and automate execution. IQVIA’s Williams reports, “Technological advances such as artificial intelligence, machine learning, and natural language processing are paving the way for automation-enabled label management solutions. Regulatory intelligence arms life science professionals with real-time notifications indicating where, when, and how labels need to be changed. Core change control capabilities help teams optimize execution workflows including authoring, content management, and activity planning and tracking capabilities. Additionally, organization-wide consistency is a must-have. An ideal label management solution will enable real-time data integration and data-sharing with, for, and from the various … stakeholders who contribute to the label management process.”

Jones adds, “GAMP V [good automated manufacturing practice from the International Society for Pharmaceutical Engineering] emphasizes that suppliers should assist in validating the system. Suppliers without expertise in pharma-regulated labeling are unlikely to be able to provide the … objective evidence-based test results, or IQs/OQs [installation and operational qualifications], increasing the effort required to validate a system and the associated compliance risk.” Costs are likely to be greater too. “The cost of validating general enterprise labeling software to make it fit for use in an FDA-regulated environment can easily equal the price of the software itself,” he explains.

As a result, prevalidated, Cloud-based platforms and browser-based apps are becoming the preferred option for many organizations. “Implementing a Cloud-based system typically requires less personnel time and hardware,” reports Mari Waldron, product and enterprise marketing director at NiceLabel. “There is no need for servers, for example, nor the need to update software, as this is all done for you,” she adds.

As one example, Boehringer Ingelheim implemented a Cloud-based LMS from NiceLabel at production sites in Ingelheim, Germany, and Sant Cugat, Spain, and the company continues to roll out the LMS to other production sites as well as locations devoted to warehousing and quality management (2). NiceLabel reports that Boehringer Ingelheim now uses label templates in the label design tool rather than multiple legacy systems. Document management functionality replaced manual quality control procedures and provides security, approval workflows, and label change and print history. Integration between the LMS and ERP centralizes updating of label information, provides a single source of label data, and reduces labeling errors. NiceLabel serves as the printing tool and the company’s enterprise resource planning system serves as the printing trigger (3). 

The biggest pitfalls in the implementation of an LMS include under-estimating the amount of time, attention, and planning needed to implement change management; lacking a clear objective; taking a siloed or department-centric approach; and failing to recognize the role people play. “People are a crucial success factor,” says Williams of IQVIA. 

Successful implementation requires continuous change management, content management, and scalable technology that includes internal and external stakeholders. Williams says, “To effectively accomplish this, companies must lead with top-down support and champion system implementation while also securing stakeholder buy-in, managing expectations, … and paving the way for alignment on future-state updates. All the while, there must be checkpoints for knowledge transfer and purpose-built development and upgrades.”

Stakeholders include clinical, quality, regulatory affairs, safety, manufacturing, legal, marketing, and artwork department personnel, as well as local entities, information technology architects, and system owners. “This [wide range of stakeholders] is a major factor in why the orchestration of label management holds so much promise—it enables the streamlining of information between many disparate parties,” explains Williams.

When planning the rollout of an LMS, Waldron recommends hiring professional services support. She concludes, “The specialists can advise on best practices, help to scope the project thoroughly, and get the new system deployed fast. Trying to do it on your own … leads to lengthy projects and … [failure] to follow best practice.”

Loftware, “Supporting Production Pivots,” 

NiceLabel, “Boehringer Ingelheim Chooses NiceLabel Solution to Help Support Standardized Labeling Worldwide,” Press Release, Dec. 2, 2019. 

NiceLabel, “Helping Boehringer Ingelheim Create a Global, Standardized Labeling Process,” Case Study, 

Software automates the labeling process, ensures compliance with regulations, prevents errors, and cuts costs. 

Systems Simplify Label Management 

Sterilization of primary packaging, an essential step in delivering a safe, beneficial vaccine, ranks as a critical factor in the timely distribution of a COVID-19 vaccine. Options include gamma radiation, e-beam, ethylene oxide (EtO), and x-rays, among other technologies. Greater adoption of the e-beam sterilization process could help prevent bottlenecks associated with sterilization constraints.

“At present, e-beam technology accounts for up to 4–6% of the industrial sterilization market. At about 40% of the market, gamma radiation ranks second with EtO at number one with roughly 50%. Steam, heat, and x-ray are examples of sterilization methods that account for the remainder. However, with widespread concern about residues and toxicity, EtO is unlikely to be used for vials [for vaccines] given the nature of the product,” says Gustavo Varca, manager of new applications development at E-BEAM Services.

That leaves gamma and e-beam sterilization as the primary methods to treat packaging for COVID-19 vaccines. “The requests for conversion from gamma to e-beam sterilization have increased considerably in recent months,” reports Varca. He attributes this activity to e-beam’s faster turnaround, lower costs, and more accessible capacity. In addition, he says, E-BEAM Services is giving priority to qualifying and sterilizing COVID-19-related products.

Both gamma and e-beam radiation sterilization methods are governed by the ANSI/AAMI/ISO 11137 standard (1) and may be performed by the manufacturer of the primary packaging or component, the fill/finish operation, or a third-party service. Varca explains, “Gamma sterilization uses the decay of radioactive cobalt-60 to generate photons. In contrast, e-beam uses high-energy, machine-generated electrons to penetrate the products. Each radiation technology sterilizes with the same dose, typically around 15–30 kGy. E-beam delivers a much higher dose rate than gamma (several orders of magnitude higher), which generally means less degradation to sensitive products. Processing time is much faster with e-beam; it might only take a matter of minutes or even seconds with e-beam to achieve the same dose that would take hours to achieve with gamma.” However, he notes, “Gamma has better penetration than e-beam, . . . which makes it a better fit for high-density products.”

With its dependence on cobalt-60, the gamma process is experiencing constraints due to a limited supply and because the material needs to be replaced every eight to 16 months to maintain proper radiation levels. According to Nordion, the dominant supplier of cobalt-60, capacity has risen during the past five years and investments are continuing, but demand currently exceeds supply by approximately 5% (2).

Meanwhile, although E-BEAM Services currently has capacity available, it has been working to expand beyond the five beams currently operating in North America. Starting up a new e-beam facility takes between 24–30 months from design concept to qualified operation and requires high capital investment, licensing, and training. “It’s not a simple feat,” concludes Varca.

ANSI, ANSI/AAMI/ISO 11137, Sterilization of Health Care Products.

Medical Design Briefs, “Inside Story: Nordion,” Oct. 1, 2020, www.medicaldesignbriefs.com, accessed Oct. 27, 2020.

Hallie Forcinio is packaging editor for 

This article appeared as a sidebar to “Is the Packaging Supply Chain Ready?” in

Vol. 44, No. 12
December 2020
Pages: 47–50

When referring to this article, please cite it as H. Forcinio, “E-beam Process Could Offset Sterilization Constraints” Pharmaceutical Technology 44 (12) 2020.

Sterilization of primary packaging is important for vaccines.