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

Hallie Forcinio

	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. 

Articles

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.

Intelligent Packaging Promotes Interaction with Patients

	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. 

	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. 

	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).

	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.

RFID, NFC, and barcodes on pharmaceutical containers enhance patient safety and adherence. 