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

Hallie Forcinio

Sustainability concerns rank high with biopharma companies. According to the 2020 Biopharma Cold Chain Logistics Sustainability Survey by Pelican BioThermal (now known globally as Peli BioThermal), the biopharma industry is increasing its pace to prioritize sustainability in business and operational strategies. Nearly half of all respondents say that they always factor sustainability into cold-chain purchasing decisions, and 53% indicate that it’s very important to choose cold-chain packaging options that advance their organization’s sustainability profile. According to the survey, attributes that address sustainability needs include recyclability, weight reduction, and energy-efficient designs (1).

Many pharmaceutical products must be maintained at room, refrigerated, frozen, or deep-freeze temperatures. Preventing temperature excursions during distribution depends on maintaining the product within the required temperature range for the time it is in transit. Temperature-controlled packaging (TCP), or thermal shippers, typically consist of a coolant, insulating material, and outer shell. Designs can be one-way or reusable. Both formats are growing rapidly.

Kelly Cinelli, director of Marketing at Packaging Technology Group, reports, “We are finding the demand for single-use, curbside-recyclable shippers for direct-to-patient medication is at an all-time high.” However, she adds, “Reusable shippers also are in high demand due to the COVID-19 pandemic and supply-chain constraints.” 

A study of the pharmaceutical industry by Precedence Research estimates reusable packaging constitutes 74% of the market, and demand for it is growing faster than for single-use units (2). This demand for reusables is “due to the additional protections pharmaceutical products need including more robust packaging [and] stronger temperature control as well as the need for verification of temperature using a data logger or other temperature recording device,” says Mark Sawicki, president and CEO of Cryoport Systems.

Several suppliers cite sustainability as the major reason reusables are gaining market share. Ranjeet Banerjee, CEO of Cold Chain Technologies, reports, “A lot of customers have a very clear goal around reducing their environmental footprint. Reusables go a long way toward meeting that goal.”

“One easy way to reduce carbon footprint is to reduce materials,” explains Emilio Frattaruolo, vice-president of Innovation–Passive Systems at CSafe Global. Because reusables make multiple trips, less packaging waste is generated.

Reusable TCP also can offer cost and performance benefits. Although initially more expensive than a single-use unit, “the cost per use is equal or less,” says Frattaruolo. In addition, leasing programs can eliminate the capital investment required to buy shippers. Leasing also makes it easier to accommodate market growth or seasonal variations. “Our market research indicates that reusable TCP is significantly increasing its use of rental models,” reports Sean Austerberry, group research and product development director for Softbox Systems. He notes, “10% of spending was rental in 2020, and we estimate 25% of spending will be rental in 2024.”

Despite strong interest in reusables, there is ample demand for single-use TCP. “Single-use shippers are often a cost-effective solution in situations where a return/reuse program is either impractical or impossible,” explains Banerjee.

The decision between reusable and single-use depends on the application. Questions to consider include:

How many shipments go to that destination? How often?

How long will the shipment be in transit?

What temperature conditions will be experienced?

What preconditioning of refrigeration is required?

How is the shipment monitored and tracked?

What inventory management software is available?

For reusables, what percentage will be returned?

Is the end customer prepared to play its role in the return process?

Is there sufficient space and manpower available to prepare shippers for reuse?

What is involved in preparing the shipper for reuse (i.e., cleaning, inspection, and repair)?

For single-use, are end customers agreeable to disposing of the shippers?

How easy is the disposal process and how long will it be available?

Will the shipper chosen meet current and short- to medium-term needs?

Frattaruolo recommends mapping out the supply chain as the first step in deciding between reusable and single-use shippers. It is likely to be easier to recover shippers from distribution centers or intra-company operations. “Some remote areas don’t have the infrastructure to get reusables back … or won’t be receiving shipments [frequently] enough to justify a reusable,” explains Alex Arabea, marketing manager at Lifoam Industries, a business segment and subsidiary of LifeMade Products. Single-use also makes sense for many direct-to-consumer scenarios.

During the decision-making process, “It is important to understand that a reuse approach affords pharma manufacturers the ability to utilize higher-performance, more durable packaging material than is typically used in single-use shippers,” explains AeroSafe Global CEO Jay McHarg. He adds, “And since total cost is amortized over many turns, the investment in reuse can be quite comparable to single-use alternatives. Other cost factors to consider include possible fees, from shipper recovery to refurbishment. Conversely, there are cost items that reuse eliminates or reduces, such as stickers (printing and application), warehouse space, and sometimes even usage of freezers since, in the case of AeroSafe Global, we can supply preconditioned thermal material.”

If the decision is made to adopt reusables, time will be needed to plan and implement the recovery and refurbishment process. “A reuse model only works if the shippers are retrieved,” says McHarg. Another important consideration is that the buyer of the packaging usually is not the final recipient. “As such,” he advises, “retrieval programs must be tailored to the needs of the end user—clinician or patient—in both ease and simplicity.”

In situations where retrieval is not practical logistically or economically, a hybrid solution might be the answer. Dr. Joachim Kuhn, CEO and founder of va-Q-tec, explains: “va-Q-tec’s disposable solutions are manufactured for non-return, but due to their stability, they can be qualified for reuse. For example, our lightweight box, the va-Q-one, can be used several times for temperature-controlled transports when shipped to Africa. It only has to be requalified on-site.” 

Other important considerations in the review of reusable vs. single-use shippers include timing, product value, and stability range. Thus, a single-use design can provide adequate protection for a commodity product with a wide stability range and short hold time, but a higher performance reusable TCP is likely to perform better for an expensive, sensitive product with several days to travel. 

Consider the following pros and cons for reusable shippers in pharmaceutical packaging applications.

Equal or lower cost per trip if return rate is good

Can help meet corporate sustainability goals

Often consist of higher-performing materials

Tend to be more durable and resistant to damage

Costs increase if shippers or components are not returned

More work on the front end is needed to justify and identify the impact on internal and end-user processes

Must establish a practical process for return and preparation for reuse

End customer must be willing to participate in the returns process

Can be difficult to recover from direct-to-consumer applications

Requires inventory management system to prevent traceability and tracking issues

Custom configurations take longer to develop

Standardized sizes may not suit some payloads

Doesn’t generate costs/carbon emissions associated with return and refurbishment

Potential for on-site requalification at destination

Components can be environmentally friendly

Quick scale-up because no molding or tooling is required

Frequent decision making to determine correct packout for day/origin/destination/weather

Users must consider the specifics of their application when deciding whether the best option for TCP is a single-use or reusable model.

1. Pelican BioThermal, “Pelican BioThermal Survey Reveals Biopharma Companies’ Focus on Sustainability in Cold Chain Partnerships,” Press Release, July 28, 2020

2. Precedence Research, “Pharmaceutical Temperature Controlled Packaging Solutions Market Size, Share & Trends Analysis Report by Type (Reusable Solutions and Single Use Solutions), Application (Temperature-Sensitive Pharmaceuticals, Vaccines, Others) By Region, and Segment Forecasts, 2020–2027,” Market Report, www.precedenceresearch.com/pharmaceutical-temperature-controlled-packaging-solutions-market, accessed June 30, 2021.

Articles

Manufacturers seek more sustainable options for temperature-controlled packaging. 

Cold-Chain Shippers: One-Trip vs. Multiple Trips

Prefilled syringes continue to evolve to enhance operation, support increased automation of the fill/finish line, and boost productivity and output. Syringe innovations also 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. A market study by Emergen Research predicts sales of prefilled syringes will expand at a compound annual growth rate of 8.9% between 2019 and 2027 to nearly double in value to $9.11 billion in 2027 (1). Driving forces include vaccine production as well as the adoption of self-administered biologics for chronic conditions such as diabetes and auto-immune diseases (1).

“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 (2).

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 (3). 

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.”

Innovations on the fill/finish line focus on automation and flexibility for higher output, greater efficiency, and faster return on investment. As batch sizes shrink, demand for flexibility rises. Brandes explains, “Flexibility makes it possible to fill a batch of 10,000 units in vials and then switch to a different packaging format and drug on the same line. There’s no need to invest in separate lines for vials, cartridges, and syringes.” 

Driving forces behind automation include consistency, regulatory needs, and labor requirements. “Automation greatly increases consistency and decreases the possibility for human error, and also can provide opportunities for enhanced inspection capabilities—including those that consider visual attributes, weight, and fill volume,” says Deborah Smook, vice-president of Marketing & Business Development at TurboFil Packaging Machines. She notes, “FDA preferences are another consideration. FDA prefers less—ideally no—touching of syringe components for aseptic filling/processing. Finally, automation decreases labor requirements, diminishes the difficulties of working in a cleanroom with full personal protective equipment, and reduces the likelihood of repetitive motion injuries.”

A $50-million expansion at Baxter Biopharma Solutions in Bloomington, Ind., will boost efficiency and enhance product quality with the installation of a high-speed automated syringe fill line capable of handling up to 600 units/min and other improvements (4). A fully automated debagging system for RTF syringes has been installed on the newest fill line, and an automated inspection machine has replaced an older system. “[Secondary] packaging lines also feature new packaging options that are plastic-free, as well as tamper-evident,” reports Wendy Saffell-Clemmer, lead scientist and senior director, Baxter. In addition, she says, “Both one-dimensional and two-dimensional online barcode printing is available. Lastly, information technology systems supporting serialization can communicate with the customer’s system to ensure that the serial numbers applied are unique and traceable across the network of product manufacturing sites the customer may be using.” 

The new systems were carefully evaluated with particular attention to prior experience with the instrument manufacturer, anticipated customer requirements, and the available footprint for installation. “New automation technologies were selected to enhance efficiency as well as product quality,” says Saffell-Clemmer. “For example,” she reports, “the newly installed inspection machine has the latest vision systems, which can reduce the false detection rate as well as offer a solution to detect particles in heavy suspension products such as vaccines.”

Civica Rx is building a greenfield, 120,000-ft2 aseptic fill/finish operation in Petersburg, Va., as part of a manufacturing partnership with Phlow Corporation, AMPAC Fine Chemicals, and Virginia Commonwealth University’s Medicines for All Institute. The plant in Petersburg will start up with one syringe- and one vial-filling line with space available for another vial or syringe line. The syringe line is rated at up to 50 million units/yr. Isolator-equipped automated fillers with automatic vision inspection are designed to minimize manual intervention and maximize quality, compliance, and assurance levels. Automation “allows the product to be washed and filled at tight tolerances with no human touch,” reports Stan Benson, vice-president and general manager, Civica Petersburg.

In-process control and weighing of each syringe before and after filling ensure precise fill volumes. Automatic micro-adjustments maintain fill accuracy throughout the batch. Vacuum-assist stoppering minimizes oxygen levels within the headspace (i.e., the distance between the product and the plunger). The low oxygen levels and small headspace enhance product stability and protect product potency.

All product contact surfaces—from the compounding vessel to the filling needles—are single-use and arrive gamma-sterilized and ready to use. “Single-use systems eliminate the need for clean-in-place and sterilization processes that consume testing and energy [resources],” explains Benson. Each syringe will undergo automated visual inspection to confirm container and closure integrity and fill volume and check for container flaws and particulates. High-voltage leak testing will help check for glass deterioration.

On the equipment side, TurboFil Packaging Machines offers several syringe filling options including rotary indexing monoblocks, walking beam fillers, and robot-assisted parts assembly. “Syringe formats are more varied than vials and require a more flexible approach to overcome the challenging filling issues surrounding product viscosity, air evacuation, leakage, and of course, accuracy,” explains Smook.

Employing a versatile yet precise setup that accurately fills syringes via a ceramic piston, peristaltic pump, or direct draw from a reservoir bag, TurboFil’s SimpliFil syringe filling and assembly system handles small to medium batches. Its walking beam indexing configuration provides intuitive operation and simplified, recipe-based changeover. For heightened precision, TipFil technology allows syringes of all types to be filled through the tip—a step-saving innovation that eliminates the need to insert plungers post-filling.

Offering full control of filling parameters in single or dual operation, the benchtop TipFil syringe filler accurately and consistently fills up to 12 units/min. A servo-driven piston mechanism draws the needle back via the plunger, with the distance the plunger is moved dictating the amount of drug filled. Among other benefits, this method eliminates the need to clean an extraneous metering device. A key attribute of the system is its versatility. The unit can perform through-the-tip filling for liquids or viscous products for typical infeed scenarios including hoppers and reservoirs. An optional attachment makes it possible to fill bottles or vials. Suckback control heightens fill accuracy, and all product contact parts are fully disposable. 

1. Emergen Research, “Prefilled Syringes Market Share Growing Rapidly with Recent Trends and Outlook 2020–2027,” Press Release, April 5, 2021.

2. 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

4. Baxter International Inc., “Baxter BioPharma Solutions Announces $50 Million Investment to Expand Sterile Fill/Finish Manufacturing Site in Bloomington, Ind.,” Press Release, Nov. 24, 2020.

When referring to this article, please cite it as H. Forcinio, “Innovations Meet Growing Demand for Prefilled Syringes,” 

Container and equipment innovations expand applications.

Innovations Meet Growing Demand for Prefilled Syringes 

On the Internet, dual-level authentication delivers more secure transactions. A similar multi-level strategy is needed to ensure the pharmaceutical product being dispensed to the consumer is the same one that left the factory.

The enhanced protection is needed because the COVID-19 pandemic and other forces are spurring growth in counterfeiting and gray market diversion. “Changing tariffs and Brexit also encourage counterfeiters,” reports Mark Manning, chief executive officer at iTRACE Technologies, a supplier of product authentication technology and partner with Global Automation and Identification Group, a specialist in anti-counterfeiting programs.

“Securing the supply chain must be part of the manufacturing process,” says Manning. Meeting the requirements of the Drug Supply Chain Security Act (DSCSA) in the United States and the European Union’s Falsified Medicines Directive (FMD) won’t completely solve the problem of counterfeiting. Loopholes in the laws mean “the supply chain isn’t as secure as we want it to be. Additional security steps will be needed,” explains Manning.

He advises starting at the beginning of the supply chain to secure the factory and production. He says, “Security needs to start before the product is made. Brand owners need to be able to validate the factory is secure. Starting with the ingredients enables a secure product all down the line to the patient.” Authentication from the beginning of the supply chain serves as the foundation of trust and depends on data. Then security must be maintained at each level of the supply chain, and each level has to work together.

Manning suggests that blockchain-based systems provide a solution. “Blockchain provides irrefutable proof of the existence of the product and tracks and traces it at every step so you know the product at the bedside is the same one that left the factory,” he explains. “That level of visibility is not something that can be done with a barcode or Datamatrix code. Barcodes and Datamatrix codes are open-source technologies and easily replicated and read by anyone. If I’m a counterfeiter, I can create my own barcode, based on the structure stipulated by the FMD or DSCSA.”

Unfortunately, says Michael Cizek, managing director and founder of Global Automation and Identification Group, “If the carrier for data can’t be trusted, then the data can’t be trusted.”

A multi-level strategy is needed. The iTRACE 2DMI technology is a hybrid technology relying on closed-source, proprietary software and an open hardware platform so the code is readable by virtually any reader, including smartphones. An iTRACE 2DMI code can be printed or laser etched by virtually any system, including desktop printers. Options include reproduction in very small (near-nano) spaces and with ultraviolet ink if covert coding is desired. When read, if the data generated by the iTRACE code matches the serialization, barcode, or Datamatrix code on the package, the product is authentic.

Another recent development in authentication technology, Covectra’s next-generation StellaGuard smart label and mobile authentication system, works in conjunction with its AuthentiTrack track-and-trace system. A free app allows consumers, field inspectors, and customs officials to scan a product barcode with their smartphone and verify authenticity in seconds (1).

The StellaGuard smart label combines a serialized QR barcode with a three-dimensional image of holographic “stars” embedded in a random, non-repeatable pattern at various levels and positioned inside a patented film. On the packaging line, cameras capture the star pattern on each product label and store it in the AuthentiTrack Cloud. When it’s time to authenticate the product, a smartphone scan of the label is compared to the scan captured on the packaging line (1).

1. Covectra, “Covectra Introduces Next Generation StellaGuard Smart Label and Mobile Authentication Solution to Combat Counterfeiting of Products,” Press Release, Feb. 22, 2021.

Drug product security requires anti-counterfeiting techniques such as authentication throughout the supply chain.

Package Authentication Depends on Multi-Level Tactics

	Stability tests determine if specific packaging choices will protect a pharmaceutical drug product for its required shelf-life-typically two to three years. Traditional time-based studies can take years and often involve testing many package variations. Data-based modeling, however, can streamline the package selection process, determining such factors as the lowest-cost options for package material, number of doses, and amount of desiccant. Modeling identifies the optimum configuration for the required shelf-life, assuring a high probability of passing the stability test, thereby eliminating the need to put more than one or two packaging options through the traditional test process. The modeling also prevents over-packaging and offers the potential for cutting costs since higher barrier materials tend to carry higher price tags.  

	Such modeling can be used for any product-solid doses, gels, ointments, small molecules, peptides, and biologics, according to Ken Waterman, president of FreeThink Technologies, a specialist in stability studies and supplier of the ASAP

 accelerated stability assessment program software. Results generated by the software have been proven to correlate well with traditional stability tests and have been accepted by FDA as proof that a post-approval packaging change will meet shelf-life requirements (1). Blister packaging provider Aptar CSP Technologies uses the program to help determine shelf-life as part of its 

 Development Services (2). Klöckner Pentaplast’s BlisterPro XCEL package design and prototyping services also rely on ASAP

	In a webinar on June 9, 2020, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Waterman explained that the accelerated stability assessment program takes less than one month to complete. It exposes the product to temperature, relative humidity (RH), and oxygen to the failure point; models stability performance via an isoconversion method; determines packaging impact based on the calculated environment inside the package; and calculates the probability of passing the stability test. Ideally, he said, “you want a >95% confidence level in the shelf-life [projection].” The software also can account for conditions the package will experience in different climate zones, for example, when shipping to the tropics. Other parameters can be calculated, such as whether a desiccant is necessary and what size it should be (1). 

	The physical testing involves ovens to control temperature and saturated salts to control RH. With exposure to different temperatures and RH levels, a drug product is examined for changes that indicate its stability has been affected, such as degradant formation, assay (potency) loss, dissolution changes, crystal growth, and appearance change (1). 

	Humidity can cause a sudden failure, including a phase transition, such as deliquescence or hydrate formation. In deliquescence, as soon as a product exceeds its critical RH, it begins taking water from the air to make a solution. “This is a sharp transition that depends on temperature,” said Waterman. But RH is more likely to work in a continuous fashion to shorten shelf-life. “This is because humidity impacts the mobility of the molecules and increases reactivity,” he explained (1). 

	Humidity sensitivity is, thus, a critical factor in determining shelf-life and optimizing the package structure. A calculation based on a modified Arrhenius Equation determines how humidity sensitivity affects shelf-life. In one example, a product with a high humidity sensitivity had a projected shelf-life of 3.0 years at 60% RH but only 9.3 months at 75% RH. Such a product would require packaging with high barrier properties (1). 

	With the humidity sensitivity and product degradation rate known, the RH inside the package must be determined with the knowledge that this level changes over time. Waterman said, “Headspace is not important,” but surface-to-volume ratio and moisture sorption by the dosages are. This means that larger bottles will provide a longer shelf-life with the same percentage fill. Several other factors impact the package RH level over time including water vapor transmission at temperature; the RH outside and inside the pack; moisture sorption vs. RH of the dosage, mass, and initial water content of dosages; and moisture sorption vs. the RH of any desiccants. Desiccants can absorb a lot of water vapor. In fact, under certain circumstances, a high-density polyethylene bottle with a desiccant can outperform a foil/foil blister (1). 

	Drug degradation is influenced by oxygen as well as RH. As with RH, oxygen’s impact is time-sensitive and temperature-dependent. Oxidation of the product consumes oxygen. As the oxygen in the package decreases, its transmission rate increases until oxygen consumption slows and a steady-state is reached. An equation similar to the one used for the RH calculation predicts oxygen consumption, sensitivity, and permeability as a function of initial conditions and sensitivity to moisture and temperature (1). 

	With the capability of modeling the impact of moisture, oxygen, and temperature on the product, optimum packaging options can be identified, with a high level of confidence that product quality will be protected for the required shelf-life (1). 

	1. K. Waterman, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Webinar (June 9, 2020).

	2. Aptar CSP Technologies, “Thank You For Joining the Rethinking Oral Solid Dose Packaging Live Webinar Last Week,” Email (April 2, 2019).  

	3. Klöckner Pentaplast Group, “Pentapharm BlisterPro XCEL Services,” www.kpfilms.com, accessed July 1, 2020. 

Data and software identify optimum pharmaceutical packaging choices for the required shelf-life.  

Modeling Streamlines Package Stability Testing

	Rising demand for tubes, which are a popular choice for dermatological products, is helping fuel a projected compound annual growth rate of 5.46% for the packaging format between 2020 and 2025, according to a market study by Mordor Intelligence (1). Tubes address a myriad of needs for viscous pharmaceutical products. Recent developments center on enhanced barrier structures and sustainability, more functional dispensing closures and applicators, brand-building labeling and decorating, Braille printing, and variable printing. 

	As demand grows, manufacturers are expanding capacity. ALLTUB Group recently added to its laminate tube production capacity with the startup of an ISO 15378 GMP-certified production line in an ISO 8 (Class 100,000) cleanroom space at its manufacturing operation in Langenfeld, Germany (2). The Langenfeld operation also has invested in a production line for small-diameter (13.5, 19, and 30-mm) tubes, reportedly the first 13.5-mm diameter capability in the European market (3). 

	Another Europe-headquartered tube maker, Hoffmann Neopac, established its first US manufacturing operation in 2019. The 37,000-ft

plant in Wilson, NC, has space for several high-speed tube production lines. Its first production line has an annual capacity of 80 million units and primarily produces small-diameter tubes such as the 13.5-mm Twist’n’use tube, a tamper-evident, small-volume single-dose design. Once the cap is twisted, the tube is irrevocably opened (4).

	Also tamper-evident, the SpringTube design from 3D Neopac, a Hoffmann Neopac subsidiary, features a push-on polyethylene flip-top cap and maintains its shape during use. Available in fill volumes from 40–300 mL, the tubes can be produced with an ethylene vinyl alcohol barrier layer and decorated via digital, flexo, or metallic foil processes. Variable printing can individualize each container at the unit level. Colored or metallized cap options further enhance brand identity (5). 

	The squeezable nature of tubes opens the door to custom dispensing. To provide a cleaner, more hygienic way to apply pain relief medicine, GlaxoSmithKline, Nypro, and Hoffmann Neopac collaborated on a “No Mess” thin-walled tube and applicator for Voltaren gel (diclofenac topical). An intuitive pull/push mechanism allows the massage tip to close by itself after the application and minimizes gel residue on the skin. A handle makes it easier for consumers to apply the gel to their back and shoulders. Other features include a tamper-evident TopStar closure (6).

	An applicator-equipped tube for Canesten cream (clotrimazole topical), an athlete’s foot treatment from Bayer Consumer Health, earned a German Packaging Award in 2019 from the Deutsches Verpackungsinstitut in Berlin. The soft thermoplastic elastomer applicator on the Polyfoil barrier tube from Hoffmann Neopac eases application even to the skin between the toes. A ribbed, rotating ring prevents leakage, protects the product, and simplifies use for all age groups. An On/Off marking indicates whether the applicator is open or closed (6). 

	To simplify dosing of preservative-free ophthalmic drops and prevent contamination of the product during days, weeks, or even months of use, Aptar Pharma and Hoffmann Neopac have developed the SteriDrop tube. When the Polyfoil tube from Neopac is squeezed, the mechanical dispensing system from Aptar Pharma releases a precisely measured drop and prevents any liquid from flowing back into the tube. Caps and flow rates can be customized to meet the required drop formation (6).

	Tube manufacturers also are addressing the need for more sustainable structures. Berry Global Group can incorporate post-consumer recycled (PCR) resin in its recently introduced oval tube. The two-inch tube is extruded, formed, and decorated at its vertically integrated manufacturing facility in Easthampton, MA, and is available with premium decoration including silk screen with up to eight colors, and up to five colors with cold foil (7). 

	CCL Tube, part of CCL Industries, also offers a structure with PCR content. Its Earthtube can contain up to 70% PCR resin in the tube sleeve and head. A three-layer extrusion sandwiches the PCR layer between virgin layers to separate it from the tube’s contents and is compatible with premium decorating and labeling (8). 

	Essel Propack introduced the Platina 250 and Green Maple Leaf 300 Lamitubes in November 2019. The sustainable designs feature a high-density polyethylene (HDPE) barrier structure that meets or exceeds recyclability guidance from the Association of Plastic Recyclers and are recyclable in the #2 HDPE recycling stream. The stiffness of the HDPE also permits resource-conserving downgauging. The two recyclable designs join another sustainable offering from Essel Propack, the Etain tube, which features up to 25% PCR content (9). 

	Hoffmann Neopac offers an EcoDesign portfolio (10) and also plans to launch a recyclable barrier tube before the end of 2020. The Polyfoil MMB (mono-material barrier) tube consists of more than 95% PE with inks, adhesives, and barrier layers that do not negatively affect recycling. A thin-wall structure means a weight reduction of up to 40% compared to standard Polyfoil tubes with aluminum barrier layers. “Technology must play a role in meeting higher recycling standards, and mono-material barrier tubes will represent a sizable step forward in packaging science,” said Martina Christiansen, director Sales Tubes Neopac, in a press release (11). 

	1. Mordor Intelligence, “Tube Packaging Market–Growth, Trends, and Forecast (2020-2025),” www.mordorintelligence.com/industry-reports/tube-packaging-market, accessed June 1, 2020.  

	2. ALLTUB Group, “New Cleanroom Production for Laminate Tubes,” Press Release, April 1, 2019. 

	3. ALLTUB Group, “New Small Diameter Capability for Laminate Tubes,” Press Release, April 1, 2019. 

	4. Hoffmann Neopac, “Neopac Opens First US Facility with Site Tours and Demos of High-Speed Tube Production Line,” Press Release, May 20, 2019. 

	5. Hoffmann Neopac, “At Pharmapack, Neopac to Showcase SpringTube for Skin Health Products,” Press Release, June 1, 2020. 

	6. Hoffmann Neopac, “Neopac Wins Three Prestigious Healthcare Sector Packaging Awards,” Press Release, Sept. 16, 2019. 

	7. Berry Global Group, “Berry Global Introduces Oval Tube Assembled in the United States,” Press Release, Feb. 26, 2020. 

	8. CCL Industries, “Tubes-Earthtube (PCR),” https://ccllabel.com/portfolios/tubes-earthtube-pcr/, accessed June 1, 2020. 

	9. Essel Propack, “Essel Propack Unveils Recyclable Tube Packaging-Platina and Green Maple Leaf Lamitubes,” Press Release, Nov. 4, 2019. 

	11. Hoffmann Neopac, “Continuing Sustainability Efforts, Neopac Moves Toward Mono-Material Barrier Tubes Designed for Recyclability,” Press Release, May 13, 2020.  

New options for pharmaceutical tubes enhance functionality, sustainability, and brand identity. 

Pharma Packaging Focus on Tubes

With the evolution of interactive “intelligent” technologies such as near-field communication (NFC), radio frequency identification (RFID), and two-dimensional barcodes, patients can interact with pharmaceutical products in unprecedented ways. Such “smart” packaging offers the potential to improve patient adherence, safety, and therapeutic success.

	“[Using smart packaging,] wrong applications are prevented, counterfeits can be reliably detected and rejected, processes are automated and secured, and relevant information is available at the point of use,” explains Arne Rehm, product manager RFID/NFC Solutions at Schreiner MediPharm. The technology also supports traceability throughout the processing, packaging, and distribution process as well as implementation of Industry 4.0. 

	Rehm reports, “UHF [ultra-high frequency] RFID offers the advantage of being able to track a large number of individual products or packaging units at once. For example, all products can be recorded within a few seconds for inventory monitoring, which is far superior to optical or manual processes in speed and accuracy.” NFC allows large amounts of data to be stored almost invisibly on the product. It works particularly well in situations where graphic space is scarce and is well-suited for labels for small containers with narrow radii. “A key aspect here is certainly the high level of digital counterfeit protection that can be provided at the same time,” says Rehm. 

	He notes, “RFID and NFC labels have become more powerful and cheaper in recent years. In addition to the greatly improved reading range of new chip generations in the UHF range, various new functionalities have been integrated, from security to sensor technology.”

	A DataMatrix code is the basis for Smart Containers from SCHOTT North America. Laser marking a unique code on the bottom of each vial enables traceability throughout the entire manufacturing process. The unique DataMatrix code is applied during vial manufacturing. After hot forming, advanced laser technologies create the code and inextricably link it to the container. Coded containers may be scanned at various points during the fill/finish process, including after loading, washing, depyrogenation, filling/checkweighing, stoppering, crimping, and labeling, as well as before secondary packaging. “To ensure ease of use, the Smart Container code can be read by conventional camera equipment,” says Diana Löber, global product manager vials at SCHOTT. “Moreover, as the unique identifier is positioned at the bottom of a vial, there is no need to install multiple cameras or to turn the container,” she explains. 

	Scanning the code supports implementation of Industry 4.0 and helps pharma manufacturers unlock the power of machine vision and big data analytics by enabling optimal monitoring and traceability of the vial manufacturing and fill/finish processes. “This means that the technology supports and improves reject management and line clearance, reducing the risk of mix-up and optimizing lyophilization processes and container-based targeted recalls,” says Löber. 

	Caregivers and patients also benefit. With a unique code on each vial, if a product quality problem arises and a recall is necessary, it is easier to identify which vials need to be recalled and remove them more quickly from the marketplace. “This ensures patient safety and high quality up until the drug is administered,” concludes Löber. 

	For labeled containers, particularly vials and syringes with small radius curves, Schreiner MediPharm offers labels equipped with RFID technology, which relies on flexible electronics from PragmatIC instead of rigid silicon chips.. “Until now, conventional RFID/NFC solutions have mainly been utilized in high-value use cases,” said Dr. Thomas Schweizer, president of Schreiner MediPharm. “Due to the cooperation with PragmatIC, we are now able to offer attractively priced, smart pharma labels even for high-volume and low-cost medicines,” he reported (1). 

	For smart cartons, a partnership between Schreiner MediPharm and Edelmann, a folding carton producer, incorporates digital features for fast, reliable product authentication and product protection. BitSecure copy detection technology prints a small, digital security feature based on a high-resolution, random pattern whose intricate details are not discernible by the naked eye. The pattern can be authenticated quickly using a smartphone or handheld reader and analyzed via related software. A closure seal with an integrated NFC chip and an irreversible void effect combines analog and digital technologies, offering double tamper evidence. Before the seal’s initial opening, the user reads the NFC chip using a smartphone and related app to confirm product authenticity. Opening the package without peeling off the seal causes it to break along the perforation. If the NFC chip is read again, the smartphone will warn the packaging has been opened previously. The chip also may link the user to interactive applications for patient information and assistance (2).

	For inhaled products, which are sometimes difficult to dispense correctly, Sanner and Amiko Digital Health are partnering to equip dry powder inhalers with advanced sensor technology. Amiko’s Respiro platform tracks device usage in real-time and facilitates adherence by ensuring the medication is administered following the right technique. “Our digital health tools assist healthcare professionals and empower patients to achieve better respiratory treatment results,” said Duilio Macchi, chief executive officer and co-founder of Amiko, in a press release (3). 

	The partners have designed the plastic part that houses the electronic components, completed prototypes, and set the stage for production. “The engineering of these plastic parts for serial production was quite a challenge,” notes Ursula Hahn, head of Product Management at Sanner. Although commercialization is likely to take some time due to the many sales channels and stakeholders involved, Sanner is confident the add-on will be accepted and successful. In addition, Hahn predicted, this technology “…will certainly be transferred to further areas of application in the near future.” 

	Another respiratory product partnership, this one between Aptar Pharma and Sonmol, an adherence specialist based in Shanghai, seeks to increase patient engagement and provide better treatment outcomes for asthma and chronic obstructive pulmonary disease. The resulting Smart Inhalers will be marketed primarily in China and other Asian markets (4).  

	One intelligent packaging technology that’s already commercial is the I-Smart wallet from Schreiner MediPharm, which is based on the child-resistant and tamper-resistant Dosepak carton from WestRock. A microchip applied to the blister pack uses NFC to send a signal to a smartphone to alert the patient to take his/her medication and monitors adherence. Janssen Cilag, the winner of the award in the Equipment Innovation Category in the International Society for Pharmaceutical Engineering’s 2019 Facility of the Year Competition, runs the I-Smart wallet on equipment from C-Matic and ECCT. On the line, one machine automates and performs virtually every step in the packaging function. Capable of being remotely controlled, the line is designed to be flexible enough to run a range of dosage forms and blister designs for quick changeover and speedy product launches. The result is shorter cycle times, lower labor and material costs, higher capacity, and enhanced process compliance and reliability (5). 

	For the patient, medication intake is electronically documented (time and dose). “When the patient pushes a tablet out of the blister, data are generated in real-time, such as the time of removal, the dose or, optionally, the respective cavity,” explains Uwe Braun, product manager of Patient Compliance Monitoring Solutions at Schreiner MediPharm. These data are automatically stored in the package and transmitted to a database via a smartphone app or a reader using NFC or Bluetooth. 

	For Janssen Cilag, the I-Smart Wallet was customized for its drug. “All electronic features were integrated without any change of the existing package design,” reports Braun. As a result, end-user convenience could be assured because the blister pack use and push-through forces remained unchanged.

	Inline readers on I-Smart wallet production lines and pharmaceutical packaging lines verify all functionalities are working before finished packages are released. “Additionally,” Braun says, “specific data such as lot number, ID codes, and medication name can be stored on the chip inside the package. Finally, a full digital track-and-trace system with security features can be added optionally.

	Smart technologies are not limited to packaging but also can be incorporated directly on solid dosage forms. One technology from TruTag Technologies adds an invisible barcode to each pill. It relies on functionalized microparticles of silica, an FDA-approved pharmaceutical excipient, which forms an invisible, edible, and high-security optical 3D barcode, known as TruTags. In the case of tablets, TruTags barcodes are added as part of the existing film coat (via standard pan-coating processes) or applied through an immediate-release clear topcoat. “TruTags do not impact the release profile or stability of the product nor do they impact tablet elegance,” reports Dr. Michael Bartholomeusz, CEO at TruTag Technologies. In the case of capsules, TruTags barcodes are mixed into existing inks and applied directly on capsules using a standard printing process.  

	TruTags barcodes can be read by a proprietary, enterprise-level portable or handheld unit or a mobile phone equipped with a downloadable app. Bartholomeusz says, “While this phone-based reader can also be used by the brands and manufacturers, it is especially useful as a consumer tool to ensure the authenticity of the product … and as a patient interaction tool for the pharma companies.”

	According to Bartholomeusz, “the TruTag solution can bring profound value to several stakeholder groups-specifically in the area of quality, safety, and security.” He explains, “For patients, the adoption of TruTags on tablets and capsules offers a tangible path toward the mass digitalization of medicines and a future where patients can interact directly with their medicines via cell phones. The potential value of this interaction has been well-documented and includes the ability to: ensure patients are getting the correct product in the correct dosage; communicate prescribing information; monitor and influence patient adherence; and record adverse events and link them directly to specific product batches ([for a] risk evaluation and mitigation strategy).”

	TruTags barcodes facilitate instant and unequivocal identification of products anywhere in the supply chain, which is critical when there is a suspect event. It enables manufacturers and brand owners to determine whether the problem is related to an internal quality failure, an external supply chain issue, or third-party criminal actions such as counterfeiting, diversion, or sale of expired products. Knowing the cause of the problem allows a pharmaceutical company to take specific corrective action. “While efforts to serialize packaging certainly help with this process, once tablets and capsules are removed from their original packaging, serialization is rendered ineffective,” adds Bartholomeusz. Barcoded tablets or capsules can be identified throughout the product’s entire lifecycle.

	Smart packaging will continue to enhance patient safety and counterfeit protection. Hahn predicts, “Track-and-trace will also develop further to ensure a more transparent supply chain.” She also believes demand for integrated smart devices will expand so caregivers and patients will know when a dose was taken and that it was administered correctly.  

	With technology evolving and prices declining, “We … see many opportunities for RFID and NFC labels,” adds Rehm. He predicts, “The possibility of integrating sensor functionalities (temperature, humidity, etc.) will enable a large number of new applications at unit level.” 

	1. Schreiner MediPharm, “Schreiner MediPharm and PragmatIC Announce Strategic Partnership for Smart Pharma Labels,” Press Release, Dec. 5, 2019
	2. Schreiner MediPharm, “Schreiner MediPharm and Edelmann Group Develop Demo Version of Smart Packaging Solution,” Press Release, March 28, 2019.
	3. Sanner, “Sanner and Amiko Partner to Develop Digital Solutions for True Medication Adherence,” Press Release, Feb. 13, 2018.
	4.  AptarGroup, “Aptar and Sonmol Partner to Develop Digital Platform for Respiratory-Related Therapies,” Press Release, April 21, 2020.
	5. ISPE, “2019 Category Winner for Equipment Innovation Janssen Cilag SpA,” www.ispe.org, iSpeak Blog, July 18, 2019. 

	Hallie Forcinio is packaging editor at 


	Vol. 44, No. 6
	June 2020
	Pages: 44–45, 58

	When referring to this article, please cite it as H. Forcinio, "Intelligent Packaging Promotes Interaction with Patients," 

Advances in intelligent technologies for pharmaceutical packaging improve online productivity, authenticate product, and boost patient adherence.