	Smart packaging offers benefits to each stakeholder in the pharmaceutical supply chain. It can enhance patient compliance/adherence; confirm authenticity; support tracking, anti-counterfeiting, and addiction prevention efforts; protect shelf life; and bolster sustainability profiles.

	Divided into two segments, active packaging and intelligent packaging, global demand for smart packaging is forecast to grow at a compound annual growth rate of 8% to reach a projected value of $7.8 billion by 2021 (1). Active packaging enhances functionality and includes technology such as scavengers, desiccants, and color-changing inks. Intelligent packaging is more interactive and provides a way to receive, store, and/or deliver information. Associated technologies include QR codes, near-field communication (NFC) and radio frequency identification (RFID), printed electronics, smartphones, smartphone apps, the Cloud, and the Internet.

	“Technological progress is providing new possibilities for drug packaging,” says Benjamin Rist, product manager at August Faller Group. “The Smart Packaging Solutions show how drug packaging will improve patient compliance and facilitate the handling of drugs in the future.” 

	Color-changing BlindSpotz Tamper Heat and Tamper Freeze inks from Chromatic Technologies enable the detection of product tampering by heat and sub-zero temperature exposure. Before the development of the Tamper Freeze inks, most tamper indicators only revealed heat tampering. Lyle Small, the founder of Chromatic Technologies, explains, “Criminals have figured out that the way to get around high-heat tampering indicators is to ‘go cold’ by exposing packaging to very low temperatures. This can ‘delaminate’ many adhesives without activating a tamper-heat indicator. The BlindSpotz Tamper Heat and Tamper Freeze inks eliminate both threats” (2).

	Printable on seals, tape, labels, and packaging substrates, the technology activates within a 5 °C window and can be printed with adhesives and overprint varnishes. The Tamper Freeze ink turns from clear to blue when exposed to temperatures below -10 °C, while Tamper Heat ink turns from gray to orange (or gray to pink) if exposed to heat greater than 65 °C. In addition, Tamper Heat ink maintains color if exposed to high temperatures (greater than 100 °C) and lasts much longer on the shelf than existing “heat-irreversible” systems (2).

	The temperature-sensitive messages are easily incorporated into existing graphics. “If the stakeholder seeks an overt message, it will be easy for everyone in the supply chain to recognize if tampering has taken place. But if an investigation is underway, covert symbols can appear (to confirm tampering) without alerting the bad actors that they’ve been detected,” says Patrick Edson, chief marketing officer at Chromatic Technologies.

	The BlindSpotz line also includes printable freeze alert technology so caregivers and consumers can verify a cold-sensitive drug has not been exposed to freezing and is viable for injection. If the product has experienced freezing conditions, the ink reveals a “Frozen. Do Not Use.” message or a frown-face icon. The technology offers an inexpensive way to monitor the flow of drugs such as cholera, influenza, and HPV vaccines being shipped internationally. “All these vaccines need an easy alert tool to indicate if, at the time of injection, they have been damaged by temperature or tampering,” says Edson. 

	He continues, “Current sensor technology for drugs and pharma requires a separate label or device to be used and can cost $1-$5 each, and then there is the additional cost of application. [Printable technology provides] highly accurate, affordable, and scalable solutions that can be implemented for pennies.” 

	“This is the era of smart-everything,” reports Steve Tallant, director of Product Management and Marketing at Systech. He continues, “It is an expectation and not an option to distribute connected products. And connected does not mean just a printed link to a website. True, two-way communication is an ever-increasing reality and norm. Pharmaceutical packages need to be authentic, safe, and now connected.” 

	As a result, intelligent packaging technology is being incorporated into caps, labels, folding cartons, and flexible packaging materials. These formats offer high potential “for patient compliance, safety, and therapeutic success,” notes Rist. 

	For example, Kisico’s NFCap, equipped with an NFC chip, works with a smartphone app and provides covert product protection. Functions include product authentication, recording of when and where the bottle was opened, presentation of dosage instructions and product information, and dosage and expiration date reminders. 

	Closure Systems International (CSI) has introduced a range of NFC chip-equipped caps through a partnership with Talkin’ Things (3). Instructions in words or pictures on the package label or shrink sleeve direct consumers to use their phone to initiate the interaction. 

	One-stage tags support direct-to-consumer communication, while a two-stage tag adds an anticounterfeiting function. David McCall, Business Development, Diversified Markets at CSI, explains, “CSI’s two-stage Talkin’ Cap provides brands with an extra level of protection and traceability to fight against global counterfeiting. Every day, pharmaceutical companies fight consumer health risks and company financial risks associated with the counterfeiting of their products. Our goal is to work with companies to implement a technology that will minimize and mitigate that very real and costly threat of global counterfeiting.” 

	A partnership between Multi-Color Corp. and Talkin’ Things melds NFC technology with pressure-sensitive, shrink-sleeve, or roll-fed labels. Digitalizing products via NFC labels enables the real-time management of promotions and personalized mobile promotions and provides a way to reward customers directly through the product and increase brand loyalty. Talkin’ Things also can provide Multi-Color with intelligent packaging technology based on RFID, augmented reality, Internet of Things sensors, or electronic article surveillance (anti-theft) protection (4).

	Schreiner MediPharm introduced an NFC-equipped label for autoinjectors in October 2018 at the PDA Universe of Pre-filled Syringes and Injection Devices in Orlando, FL. Easily adapted to existing label designs, the Autoinjector-Label wraps around the unit, including the cap, and can be read via a smartphone app. Before opening the cap for the first time, the patient can confirm the product is in its original sealed condition. The NFC technology also allows pharmaceutical manufacturers to present interactive product information, demo videos, or special apps to help patients through the self-medication process. Integrated geo-tracking makes it possible to detect gray market activities. The digital Autoinjector-Label adapts to existing label designs and does not affect the normal operation of the device (5).

	One criticism of NFC and RFID tags is the presence of non-recyclable materials. Stora Enso eliminates that objection with its ECO sustainable RFID tag technology. The paper-based RFID tag eliminates plastic and is recyclable along with the paper label (6).

	With e-Fingerprint technology from Systech, any printed barcode can serve as a unique identifier. The winner in the Excellence in Pharma: Supply Chain, Logistics, and Distribution Category at the CPhI Pharma Awards in October 2018, the e-Fingerprint technology relies on microscopic variations in substrate and print and a smartphone app (7). “Systech’s e-Fingerprinting solution changes everything about smart packaging without changing anything at all,” states Tallant. He explains, “Due to the inherent characteristics of the printing process, there are micro-differentiations in printed output.” As a result, the digital e-Fingerprint is completely covert and non-replicable by counterfeiters. The technology relies on Systech’s vision capabilities to look microscopically, at line speed, at the printed output and derive a unique e-Fingerprint for each package. “Then, using a smartphone app, a user is able to authenticate the item [from] anywhere in the world. Because the item is uniquely identified, additional information … like expiry, lot, batch, ingredients, and recall notices can be presented interactively with a user,” says Tallant. 

	He reports, “We have pharmaceutical companies deploying our e-Fingerprint solution globally to fight not just counterfeiting, but diversion of product out of the legitimate supply chain. Because of vastly different price points for medicines globally, it can be very lucrative to divert medicines out of low/no-cost geographies and send them for great profits into high-price geographies. [When products are e-Fingerprinted, manufacturers can] inspect product globally and identify diverted product immediately … and stop the practice. This helps keep medicines in the countries that need them desperately.” 

	Patients and drug makers benefit from trusted authenticity and safety globally. Drug makers gain significant supply-chain protection from diversion and counterfeiting. 

	Smart Packaging prototypes from August Faller Group showcase other potential benefits. “With our Smart Packaging solutions, we have developed three prototypes that take into account the advancing digitalization in the e-health market and the growing interest in interactive packaging solutions,” says Rist. The Counting Device folding carton is equipped with a small e-paper display and electronic controls (buttons) to improve compliance. In use, the patient confirms he/she has taken the tablet by pressing a button on the front of the folding carton. If the supply of tablets starts to get low, the e-paper display shows a warning and reminder to refill the prescription. A tiny microcontroller (storage medium-on-chip) is powered via a battery integrated in the packaging. The flat structure of the electronics was a central requirement for easy integration in a pharmaceutical package and was accomplished via a printed circuit board mounted on the back of the carton and an e-paper display on the front (8).

	The Counting Device is one of three Smart Packaging prototypes developed by Faller in conjunction with MSC Technologies and Pforzheim College. The other two designs include a Level Indicator, which calculates how much liquid remains in an opaque bottle of fluid medication, and the Medical Prescription carton, which counts the tablets, provides an alert when a dose is due, and transmits refill orders via Bluetooth (8).

	The Level Indicator carton also relies on a small e-paper display and electronic controls. The push of a button on the front of the carton shows how much liquid remains without removing the bottle from the carton. Flat electronics with an economical microcontroller, tiny battery, and adhesive e-paper display integrate into the medication packaging without significantly increasing the size of the box (8).

	For flexible packaging and labels, the SecuriLam laminate from TruTag Technologies offers both authentication and traceability functionality. Microscopic, encoded silica particles, or TruTags, are pre-embedded into standard adhesive laminate ï¬lm. The food-grade silica particles are invisible to the naked eye, do not aï¬ect the ï¬nish of the laminate or ï¬nal product, and are readable via proprietary authentication devices. Programmability allows brand owners to segment their packaging. Programmed information can include manufacturing location, product type, or authorized geography to authenticate product and identify diversion (9).

	1. Smithers Pira, “The Future of Smart Packaging to 2021,” www.smitherspira.com/industry-market-reports/packaging/smart-packaging-to-2021, accessed Nov. 14, 2018.  

	2. Chromatic Technologies, “CTI Launches High-Tech Inks to Reduce Product Tampering and Counterfeiting,” Press Release, Nov. 8, 2018.

	3. Closure Systems International, “Closure Systems International & Talkin’ Things Team up to Bring You the Latest in Packaging Technology,” Press Release, Sept. 27, 2018.

	4. Multi-Color, “Multi-Color Corporation and Talkin’ Things Establish a Strategic Partnership to Offer Connected Products,” Press Release, Feb. 27, 2018.

	5. Schreiner MediPharm, “New NFC-Label by Schreiner MediPharm for Digital Authentication of Autoinjectors,” Press Release, Sept. 20, 2018.  

	6. Stora Enso, “Stora Enso Introduces Sustainable RFID Tag Technology ECO for Intelligent Packaging,” Press Release, Nov. 7 2018.

	7. Systech, “Systech Wins Excellence in Pharma Award at CPhI 2018,” Press Release, Oct. 10, 2018.

	8. August Faller Group, “Intelligent Folding Carton with Fill Level Measurement,” Press Release, March 2018.

	9. TruTag Technologies, “TruTag Technologies Launches SecuriLam Intelligent Laminates, Press Release, February 27, 2018.  

	Hallie Forcinio is Pharmaceutical Technology's Packaging Editor, editorhal@sbcglobal.net. 

Articles

Feature

Active and intelligent packaging technologies benefit brand owners, caregivers, and patients.

Smarter Packaging Comes to the Pharma Market

	Merck, known as Merck, Sharp, and Dohme outside the United States and Canada, has started construction on a new, more than $300-million facility in Rahway, NJ that features a flexible design to enable a new, more agile approach to pharmaceutical formulation and process development for both sterile and oral solid-dosage drug products. The new Merck Research Laboratories’ FLEx Center, located within the Rahway research campus and near the corporate headquarters in Kenilworth, NJ, is expected to open in 2021 and will employ approximately 130 people. 

spoke with Allen Templeton, vice-president of Pharmaceutical Sciences at Merck, about the new facility design. 

The need for flexibility in product development and manufacturing to support drugs for smaller patient populations seems to be increasing. Can you comment on this trend and its role in Merck’s decision to build a lab with flexible capabilities?

Merck believes that flexibility is a true enabler of pharmaceutical product development and manufacturing of the future. We are enabling a ‘scale-out’ approach to address the increasing demands to treat diverse patient populations. We have leveraged this flexibility using a combination of ‘modular’ (ability to reconfigure a defined space) and ‘podular’ (fixed space that can be transported intra- and inter- facilities globally) configurations within our new FLEx Center cGMP manufacturing suites. Additionally, we have scoped multiple modalities (small and large molecule, sterile and oral) into the facility to allow for greater modality agnosticism for new chemical entities in our pipeline while integrating both human and animal health capabilities into the facility.

What are some of the flexible technologies used for formulation development?

The laboratory design delivers flexibility through the implementation of an open floor plan layout with mobile case work and ceiling drop utilities. This design will enable easy laboratory reconfiguration to transition the space and technical capabilities to meet new analytical demands of an evolving pipeline. In the new Formulation Center, formulation flexibility will be achieved through a facility design that will enable the cGMP space to be manipulated (expandable, transportable etc.) as required by our pipeline demands. Similarly, designs and user requirements are targeting small scale, portable equipment enabling rapid changeover and movement between products and formulation areas.

What are some of the technologies that allow rapid reconfiguration for manufacturing?  

Our facility design will include both modular and podular construction approaches for the cGMP space within a shell building structure. Modularly built and installed cleanrooms will enable reconfiguration of existing space or creation of new space in expansion areas. Podular built and installed cleanrooms will enable elements within the facility to be portable within the facility or transportable outside of the facility. The application of both concepts will enable the new Formulation Center to have the ability to adapt over time to meet the evolving needs of the business. We will also use the FLEx center to explore a variety of flexible manufacturing approaches, such as continuous manufacturing, as well as install first-in-industry capabilities.

What features will ease scaleup/tech transfer from R&D to manufacturing?

In addition to supporting product development, the vision for the facility is to simultaneously support the development of new manufacturing approaches for future products. The FLEx Center design includes podular manufacturing space that will enable products to be developed and supplied from the Formulation Center and, when necessary, the equipment and space can be moved to a commercial site to support product launch and commercial supply. Benefits of this approach include reduced cost, time, effort, and risk associated with the technology transfer as the same equipment used through product development will be used for commercial supply. We see this approach as being most applicable to small-volume products requiring complex, niche drug-delivery solutions.

What do you see as trends in requirements in the area of containment for worker/product safety?

At Merck, we have seen a significant increase in the number of potent compounds in the pipeline that require increased control and containment for facilities and equipment. Given this, the facility is being designed to support activities associated with highly potent compounds. This capability was included in the project scope as it was deemed critical for the facility to deliver on the future pipeline. Our philosophy and guiding principle for worker safety is containment at source. From an operations perspective, we are evaluating a variety of technologies to deliver on this principle, ranging from the use of contained charging/discharging solutions up to and including the implementation of hard-wall isolators where the highest levels of containment are required. For cleaning, equipment with wet and/or wash-in-place capabilities are being implemented where possible to ensure the necessary containment control is established for those activities.

Digitalization and designing a ‘digital factory’ is another growing trend. Can you comment on what digital approaches you are employing in the new lab and the advantages you think they will bring?

The desire is to adopt Industry 4.0 concepts into the design. The intent is to enable IT [information technology] infrastructure platforms that will adapt to the evolving technologies. The new facility will create a data-rich ecosystem, encompassing integration of all people, product, equipment, and facility data, with simple human interfaces for both use and visualization. Current exploration activities are leveraging video, voice, barcodes, RFID [radio frequency identification], and integrated workflows. Use of AI [artificial intelligence] or VR [virtual reality] technologies for virtual reality standard operating procedure instruction, knowledge management, and job aid/standard work tools are also being explored, so as to create a digitally enhanced work environment.

Will 3D printing be part of your new facility?

3D printing (3DP) is an active research and development area at Merck. We are currently developing 3DP technology for use as an early clinical platform for oral products and have several peer-reviewed publications that detail our technology and approach. There is no immediate plan for inclusion of drug product 3D printing in our new facility, but as we and others develop 3DP and new manufacturing technologies, we will continue to re-evaluate our approaches and integration into our FLEx facility. It is worth noting that we do have an established, state-of-the-art, 3D-printing facility in Rahway, adjacent to the FLEx Center, that we will leverage for prototyping new process engineering concepts.

Modular and podular laboratory and manufacturing allow rapid reconfiguration to support development of drugs for diverse patient populations.

Equipment and Processing Report-01-16-2019

Smarter Packaging Comes to the Pharma Market

Merck’s Flexible Facility Design Reinvents Pharma Formulation and Process Development