Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Biopharmaceutical packaging is changing. As pharmaceutical manufacturers embrace more flexible processes that limit the risk of product contamination, packaging and containment systems are being designed to facilitate manufacturing of smaller product lots and batches. Some fill/finish operations are moving to fully enclosed, automated operation, requiring the use of not only nested syringes and closures, but also nested vials and caps, and manufacturers are working to standardize these components.

	Examples of flexible filling lines may be found at Boehriger Ingelheim’s Fremont, CA facility or Mithra Pharmaceuticals’ line in Belgium. The contract manufacturer, Singota, recently bought contained and fully automated filling technology from Vanrx Pharmasystems.

	But agile manufacturing is only part of the picture. As pharmaceutical manufacturers develop more convenient formulations to improve patient compliance, designers of primary packaging and delivery system components have had to change their approach to product development. West Pharmaceutical Services, for example, teamed up with specialists in ergonomics and human factors to develop components for novel packaging and delivery systems (1).

	Large molecules, which, in the past, could only be taken via infusion or repeated injection, requiring visits to the hospital or clinic, can now be taken with autoinjectors and new delivery systems, but the move to more patient-centered approaches has presented technical challenges.“The monoclonal antibodies and other biologics that are now being produced are highly concentrated and therefore the solutions are more  viscous and may require  higher  dosing volumes,” says Fran DeGrazio, vice-president of scientific affairs and technical services at West.

	These changes in dosing have driven recent improvements in packaging components. Earlier this year, for example, West introduced a 1-3mL plunger for use in 2.25-mL syringes, designed to deliver higher volumes of drug product--especially biopharmaceuticals. The new plunger was developed using the same principles that drive quality-by-design (QbD) practices in drug development. This controlled approach wound up revealing the need for a different design and shape, says DeGrazio. “These differences allowed us to optimize functionality and improve control,” she says.

	Improved component designs come together in West’s SmartDose platform, which uses a cartridge system made from Daikyo Crystal Zenith (CZ) polymer, a  cyclic polyolefin material. When coupled with the Daikyo Flurotec plunger the system is  silicone oil-free. The  West Smartdose delivery device adheres to the patient and can deliver more than 3 mL of drug in several minutes.

	In July 2016, FDA approved Amgen’s monoclonal antibody, Repatha (evolocumab)--not only the drug, but using  the SmartDose delivery system and primary container. Five months earlier, Amgen had opted for CZ vials and a closure system based on West’s FluroTec stoppers, to contain its drug Imlygic (talimogene laherparepvec). The vial was designed to minimize extractables from entering product, says DeGrazio.

	CZ’s ability to withstand lower cold-chain storage and transport temperatures, even down to the dry nitrogen level required for some gene and cell therapies, has been another benefit, says DeGrazio. In addition, when used as part of a syringe system it does not contain silicone oil or tungsten, which has led to particulate contamination. This has been found to cause some proteins to aggregate in prefilled syringes (2). A number of companies are working on alternatives to silicone-treated glass containers, including W.L.Gore, which received a patent in 2014 for a silicone-free syringe stopper.

	Maintaining system integrity and preventing contamination is crucial for product integrity and patient safety, says DeGrazio, and manufacturers accomplish this in different ways, through improved facility and workflow design, use of machine vision inspection and continuous monitoring on the plant floor, and the use of higher quality elastomers and barrier systems. Improved integrity testing is also crucial.

	In August, 2016, the United States Pharmacopeial Convention (USP) released updated its recommendations for container closure integrity testing. The revised USP Chapter <1207> outlines the analytical tests that should be performed to show integral product safety, for instance, leak detection for vial and syringe systems, says DeGrazio. Before the chapter was published, she says, methylene blue dye testing was used in vacuum to find leaks. Now, regulators realize that such methods are more probabilistic than determinant, she says, and subject to error. Among the methods that West uses and offers is helium leak detection, which allows testing and validation down to  -120 °C to  -140 °C.

	A small but growing part of the components and packaging business is pre-sterilized and ready- to-use-nested components.This approach was inspired by the semiconductor industry’s Front Opening Unified Pod, a box of silicon disks that could easily be picked up and manipulated by a robot without operator intervention. These tubs of nested containers and closures allowed for a greater level of automation in fill-finish operations, explains Greg Speakman, vice president of sales and marketing for Vanrx, whose automated approach to fill-and-finish was inspired by the workcells of the electronics industry. Becton-Dickinson came out with the first nested systems nearly 30 years ago, he says.

	Ompi entered the market in 2007 with EZ-fill nested syringes, introducing vials and cartridges two years later, and nested closures for vials, developed together with Daikyo Seiko, in 2015, says product manager Alessandro Massignani.

	Nesting syringes, cartridges, vials and closures in standardized nest or tub packaging allows maximum flexibility from fill/finish equipment, says Gregor Deutschle, business development manager at SCHOTT AG, since fill/finish operations are performed with the containers remaining in the nest. He points to Schott’s adaptiQ vials, which allow all process steps to take place inside the nest, including checkweighing, freeze-drying as well as closure of the vials with press fit caps, as an example.

	The trend to nested systems began with prefilled syringes, so they have been standardized to the highest level so far, says Deutschle. Nested vials and cartridges are just emerging on the market, he says, and are being standardized.Massignani adds that there is a specific work group led by Ompi’s regulatory affairs manager that is entitled to redact the ISO Standard for Ready-To-Use Vials and Ready- To-Use Cartridges.

	Vanrx’s system requires that containers and closures be placed in a nest to allow for robotic handling. Packaging component vendors,including Daikyo Seiko, Datwyler, SCHOTT, SCHOTT KAISHA, Ompi, ARaymond and Vanrx established the Matrix Alliance in 2016, to work on standardization and ensuring interoperability of containers and closures. The key goal is ensuring that a container from one vendor will work with a closure system from another vendor, without requiring extensive retesting and integration by the end-user,” says Speakman.

	Alliance members recently shared test results involving vials and press-fit caps with their shared biopharma customers, and plan to release findings publicly during the first quarter of 2017. But the move to nested vials and caps reflects trends that are not going away any time soon: a shift from blockbusters to smaller niches of high-value drugs; more frequent/fast product changeovers in multi-product facilities, and a move from large facilities in developed markets to smaller facilities in more remote parts of the world, says Speakman.

	Another important shift is that component packaging suppliers are taking over services once handled by pharma companies, says Deutschle. “In using ready-to-use nested components, our customers want to eliminate the need for preparation of the containers prior to filling. Therefore, we take care of depyrogenation, washing, and packaging as well as sterilization.”

	Flexible filling represents a major change from standard fill finish equipment, which is geared toward high-speed, large production volumes, and often dedicated to a single container type or drug, Deutschle explains. Changeover from one container format to the next can take a long time in a bulk filling plant, because all containers must be handled individually and thus require a large number of spare parts. In addition, he notes, classic bulk lines can be very large and require a lot of expensive clean room space.

	Using nested components in a flexible line reduces the need to invest in washing, water for injection, and utilities, and also reduces maintenance and validation costs, says Massignani. “The containers travel in packaging that prevents glass-to-glass contact, reducing rejection rate. This approach adds value, not only by improving product quality but because it shifts responsibility for the sterility and cleanliness of primary packaging from the pharma manufacturer to the packaging components supplier,” he says.

The Critical Role of Human Factors and Usability in Improving medication Adherence

,” IPIMediaWorld.com, June 22, 2016.
	2. A. Siew, BioPharm International, 29 (11), p. 38 (November 2016).

	When referring to this article, please cite it as A. Shanley, "Packaging’s Flexible, Patient-Centered Future,” 

Articles

Primary packaging and container design reflects a move to patient-friendly formulations and delivery systems.

Packaging’s Flexible, Patient-Centered Future

	On December 13, 2016, during a webcast that is now 

, TraceLink released results of its first Global Drug Supply, Safety and Traceability Report, undertaken with the market research firm, Actionable Research.  The study surveyed 331 professionals from pharmaceutical manufacturers, wholesalers, pharmacies, and hospital pharmacies, to better understand issues and compliance trends at the lot level, in order to get a more realistic picture of gaps in readiness, and the challenges that face pharmaceutical companies, distributors and dispensers of all sizes in realizing full product traceability.

	Half of the pharmaceutical companies that responded to the survey expect to comply with electronic data transfer requirements within six months of the November 2017 deadline, and 54% describe themselves as well-prepared for serialization.  However, 19% of companies say they have not begun to address requirement, and only 24% say that their contract manufacturing organization (CMO) partners will be ready. 

	Respondents from pharmaceutical companies say that they underestimated the complexity of implementation, the total cost of IT upgrades required, and the overall impact that implementation can have on business.

	The question of product aggregation, considered the lynchpin to full traceability, shows different levels of sophistication among pharmaceutical manufacturers.  51% expect to have aggregation in place by November 2017, 28% say they haven’t made a decision about aggregation, 13% say they plan to focus on it after November 2017, and 8% don’t have any plans for it at all.    On the customer side, 26% of pharmaceutical distributors say they will require aggregated product, while 23% say they’d prefer to see aggregation, while the balance describe understanding that not all suppliers are ready yet.

	Moving down the supply chain, customers at the dispenser level complain that the documentation required for compliance is often missing from products that they buy directly from pharmaceutical manufacturers. In their dealings with drug distributors, dispensers fear that their electronic data, currently accessible via distributor portals, may not be available if they change distributors.

	In addition to shedding light on gaps in readiness, the survey offered an opportunity to test some common assumptions about the pharmaceutical distribution and supply chain, explained TraceLink CEO Shabbir Dahod.  He began to work in pharmaceutical traceability over 15 years ago, when the terms track and trace, pedigree and e-pedigree were first articulated, leveraging work done at MIT’s Auto ID lab to help the state of Florida improve the safety of its pharmaceutical supply.

	The “normal” linear view of the pharma supply chain so often seen on consultant PowerPoint slides, shows  90% of pharmaceutical products moving neatly from manufacturer to distributors (mainly the “Big Three”  McKesson, AmerisourceBergen Bergen and Cardinal Health) ) to dispensers. This is far from reality, Dahod said.  The true picture should include the practices of small players, and take into account a variety of business relationships and requirements, and models that include such practices as direct shipments, drop shipments and 340B distribution relationships.  Al“Lot-level serialization and traceability is not simple, because there is no ‘normal supply chain’,” Dahod said at the webcast.  These real-world conditions dictate the best way to manage data, in order to achieve compliance.

	A total of 331 people responded to the survey, 31% of them from pharmaceutical companies, where respondents were mainly managers or directors; 14% from wholesalers, 44% from hospital pharmacies, and 11% from retail pharmacies.

	Results showed that 25% of pharmaceutical manufacturers had more than 10,000 customers, while 31% had between 500 and 10,000.  In addition, 29% sell directly to hospitals and pharmacies.

	It’s not all about the “Big Three”

	Assumptions about the dominance of the “Big Three” distributors were also proven wrong by the survey, said Carter Holland, TraceLink’s chief marketing officer, who moderated the webcast.  Although between 80% and 90% of the market’s dollar value may go to the Big Three, that number does not match what happens on the transactional level.  In fact, the survey showed, respondents from pharmaceutical companies said that 43% of sales went to wholesalers other than the Big Three.

	Results suggest a highly fragmented distribution network. Of the distributors who responded to the survey, 58% said they have over 500 customers, and 35% of hospital pharmacies who responded to the survey say that they buy from 16 to 500 suppliers. In addition, 42% of hospital pharmacies and 19% of retail pharmacies resell products to other hospitals and pharmacies, the survey suggests.  

	Using TraceLink’s 2015 pharmaceutical customer base to illustrate the data exchange requirements for full lot-level traceability, Holland described 200 companies requiring 113,000 connections and 51,000 data exchange connections, an average of 143 files exchanged per transaction, 7.3 million files exchanged, over 60 million transaction histories recorded, and 46,000 unique National Ddrug Codes (NDC). Considering that this is only a slice of the full picture, the complexities become clear.

	And some of this complexity may be preventing some pharmaceutical companies, not only from achieving, but even from attempting to achieve compliance.  Although most respondents to the survey said that they found compliance to be “difficult but achievable,” a full 19% of pharmaceutical companies, 11% of wholesalers, and 9% of dispensers were not even addressing lot-level requirements, which took effect in 2016, at all.

	Some other highlights from the research:

		Roughly 37% of pharmaceutical companies bought a solution specifically designed to help with lot-level compliance, while 33% modified an existing third-party business system, 28% have implemented a manual process, and 20% have developed customized solutions.

		12% of T3 data (transaction statements and history as well as product information including lot number) are being handled via a portal, 30% on paper, and 58% electronically. 71% say that customers cannot handle electronic transaction types, but 21% say that they are not prepared to handle them.

		In cases where pharmaceutical manufacturers sell directly to dispensers, 27% of respondents from retail pharmacies and 5% of respondents from hospitals say that they do not receive any compliance documentation when they purchase directly from the manufacturer.

		31% of retail pharmacies and 27% of hospitals have been relying on wholesaler portals to access their “T3” data but they have no idea how long they’ll be able to access that data. They also worry about whether they will be able to access the data should they end their relationship with that distributor at some point in the future.

		54% of pharma company respondents said they were well prepared for the 

 (DSCA) serialization, but 10% said they were not prepared and 37% said they were unsure.

		83% of pharma company respondents say they understand all DSCA requirements, 70% say they can handle the scale and volume of data, and 67% say that responsibilities for serialization have been made clear within their companies.

		Where companies say they are not fully meeting requirements, 50% describe needing more dedicated resources, while 40% are concerned about customer connectivity.

		54% of pharmaceutical companies found that they had to modify systems to accommodate a customer request, but 16% reported being unable to make those changes in response to customer requests

		26% of pharmaceutical companies have experienced an increase in bad or incorrect data exceptions as a result of the compliance requirements. 53% have found that missing data and 47% have found that bad compliance documentation has resulted in product quarantine.

Gaps in Readiness for Serialization

Serialization and traceability have been discussed for so long in the pharma industry that it’s easy to forget the fact that the concepts have been with us for 15 years now. In the early 2000s, efforts to secure the supply chain in Florida first brought the term “e-Pedigree” into pharma’s everyday vocabulary.

	So far, more than 40 countries around the world have set standards and deadlines for item-level pharmaceutical serialization and traceability, and two to three countries join this list each year. By November 2017, the US Drug Supply Chain Safety Act (DSCSA) requires that all pharmaceutical manufacturers serialize products down to the item level, including a product identifier on labels and cases, as well as information on product transactions as the product makes its way through the supply chain. Most larger pharmaceutical companies are well-prepared for the deadline, and successful pilot programs (see 

, p. 76) have shown that manufacturers and distributors can synchronize operations and exchange the data required to make traceability possible.

	Not all companies are ready, however.  In December 2016, a survey of more than 331 industry professionals sponsored by TraceLink and designed to be a snapshot of industry’s efforts (see 

, p. 78) found that 19% of pharma companies, 11% of distributors, and 9% of dispensers still haven’t begun to address requirements, while only 24% of pharmaceutical manufacturers say that their contract manufacturing organizations (CMOs) will be ready for the deadline (1).

	This lagging response is likely due to a combination of factors. Most of the companies that aren’t prepared are small to mid-sized companies, says Bruce Bleiman, Systech International’s global senior vice-president of sales, and many of them were not exposed to serialization concepts in the earliest stages of the industry’s efforts.

	Even if these companies did have some understanding of the concepts involved, many viewed serialization as a limited, packaging project rather than the far-ranging multifunctional effort it is, notes Paul DuPont, vice-president of marketing with Ropack Pharma Solutions, a contract development and manufacturing organization (CDMO) based in Montreal, Canada.  In addition, compliance deadlines for past serialization programs (notably California’s) were extended and some companies may have questioned why they should invest in something that, in the end, might not be required, says Shabbir Dahod, CEO of TraceLink, which offers Life Sciences Cloud, a cloud-based solution for pharmaceutical serialization.

	Even companies that have invested heavily in serialization have been surprised by the level of commitment required. First, there are capital costs, which tend to run approximately $200,000 to $300,000 per packaging line. But beyond that is the complexity of data integration, notes Dahod, especially with CMOs and customers, and the networking and data exchange aspects of serialization.

	Complexity already defines the pharmaceutical supply chain and the relationships within it, he says. This was clear in the TraceLink survey results. Pharmaceutical manufacturers may say that they do most of their business with the “Big Three” pharmaceutical distributors (McKesson, AmerisourceBergen, and Cardinal Health), says Dahod, but, in reality, they have more customers and different relationships, and use different delivery models (e.g., drop ships or special orders) with each one. Pharmaceutical company professionals who responded to the survey said that more than 40% of their business transactions are with customers other than the Big Three; 25% of pharmaceutical manufacturers had more than 10,000 customers, while 31% had between 500 and 10,000. In addition, 29% sell directly to hospitals and pharmacies.

	Not only must companies deal with individual product transaction histories, says Dahod, but, as they bring CMOs and internal packaging lines on board, the number of business and operational processes they must integrate with, both internally and externally, increases dramatically. “Ten to twenty thousand times the amount of information must now be exchanged, and floated forward to wholesalers and hospitals,” he says.

	Companies that have made the effort, however, are seeing results. “Where, in the past, maybe less than 5% of their customers were integrated digitally, they are now connected with all of them. For some companies, that means tens of thousands of connections, promising more efficient information exchange, better systems integration and fewer errors,” says Dahod.

	Making those connections puts companies in a position where they can see the potential for return on investment. “This effort requires end-to-end thinking, from packaging all the way through to our customers,” says Mike Rose, vice-president of supply chain visibility with Johnson & Johnson Supply Chain (JJSC). “The reward is improved visibility that will help ensure that our patients receive genuine product,” he says.

	Some of TraceLink’s original customers are just beginning to see, and leverage, this potential (e.g., with Secure Chain, a product designed to provide closed loop end-to-end traceability for serialized product, within specific supply chain segments). 
	TraceLink has also been working with pharma companies to develop consumer-based authentication solutions, and software that would mine event data to better manage inventory. “In 2018, when large volumes of serialized product are out there, we expect to see more of these types of applications,” says Dahod.

	But, in the meantime, how can unprepared companies be ready by November 2017? “The serialized mandate is approaching fast. Using the conventional approach, not everyone will be able to be ready in time,” says DuPont. “One of the harsh market realities is that there is a limited number of hardware providers out there to help companies who are just starting to put their serialization programs together.”

	DuPont notes that some CMOs, even those who partner with large pharma companies that have advanced serialization programs in place, won’t be ready for the deadline. For pharmaceutical companies and CMOs, he notes, the highest hurdles are buying and installing the hardware, especially given demand for services as the deadline approaches. Others are internal testing (investing in and installing software and data management tools), and managing different requirements at each location.

	To help companies become compliant by the DSCSA deadline, a number of solutions providers are now offering accelerated compliance programs. In late January 2017, Systech International launched “Serialized by November,” a program involving its long-standing equipment partners, which include Omega, LSI by ID Technology, UPAK by Ultimate Solutions, Etipack, and Inno4Life.  The program compresses the process into 90 business days, with the initial phase (kickoff discussion, data collection and software shipment) taking two weeks; the design phase (involving integration drawings, documentation, validation and hardware shipment) taking six weeks; implementation, including factory and site acceptance tests (FAT and SAT) and startup, requiring four weeks; and project closure taking two weeks.

	In late November of 2016, Ropack and TraceLink, together with the equipment specialist Optel, first announced the formation of the International Serialization Hub, which they plan to launch formally in the Spring of 2017, to help pharma companies comply with DSCSA serialization requirements by November 2017 (2). With this program’s operating model, DuPont explains, companies send product to Ropack, which will take it and serialize at the unit of sale (whether item, carton, or pallet), and then send it on to its destination. It’s a simple, fee-for-service approach, he says, and can work with any data management platform. For companies that already use TraceLink’s solution, however, the costs will be much lower and the timeframes, shorter.

	The service would be offered, but not limited to, Ropack’s existing client base. As DuPont explains, the idea for the program came from a large pharma client that had serialized, but still could not get one of its 50-year-old plants ready for DSCSA serialization.

	For Ropack, investment in the program reflects the reality that serialization is no longer ‘nice to have,’ but a mandated regulatory compliance platform. “Serialization has become like validation was 15-20 years ago,” Of course, DSCSA mandates are only one facet of the global serialization requirements that pharma companies now face.  Accelerated programs may not be a long-term solution, but at least they may help resource-strapped companies achieve basic compliance in time for the deadline.

2016 Global Drug Supply, Safety, and Traceability Report

, tracelink.com, December 2016.
	2. Systech, 

Systech Announces 90-Day Rapid Compliance Program for Pharmaceutical Companies

, Press Release, prnewswire.com, Jan. 26, 2017.


	Vol. 41, No. 3
	March 2017
	Pages: 74–78

	When referring to this article, please cite it as A. Shanley, "Serialization Hits the Home Stretch," 

As the November 2017 deadline nears, a surprising number of companies still don’t have a serialization plan in place. New programs aim to get them compliant in time.

Serialization Hits the Home Stretch

	In December 2016, TraceLink and the market research firm Actionable Research released results of the first Global Drug Supply, Safety and Traceability Report (1). The study surveyed 331 professionals from pharmaceutical manufacturers, wholesalers, pharmacies, and hospital pharmacies, to better understand issues and compliance trends at the lot level to get a more realistic picture of gaps in readiness, and the challenges that face pharmaceutical companies, distributors, and dispensers of all sizes in realizing full product traceability. 

	Half of the pharmaceutical companies that responded to the survey expect to comply with electronic data transfer requirements within six months of the November 2017 deadline, and 54% describe themselves as well-prepared for serialization. However, 19% of companies say they have not begun to address requirement, and only 24% say that their contract manufacturing organization (CMO) partners will be ready.  

	Respondents from pharmaceutical companies said that they underestimated the complexity of implementation, the total cost of IT upgrades required, and the overall impact that implementation can have on business. Customers at the dispenser level complain that the documentation needed for compliance is often missing from products that they buy directly from manufacturers. In their dealings with drug distributors, dispensers fear that their electronic data, which are now accessible via distributor portals, may not be available if they change distributors.
	The following highlights from the research emphasize the data integration challenges inherent in serialization:
	Roughly 37% of pharmaceutical companies bought a solution specifically designed to help with lot-level compliance, while 33% modified an existing third-party business system, 28% have implemented a manual process, and 20% have developed customized solutions.

		Twelve percent of T3s (data required for serialization, which include transaction statements and history as well as product information, e.g., lot number) are being handled via a portal, 30% on paper, and 58% electronically. Seventy-one percent say that customers cannot handle electronic transaction types, but 21% say that they are not prepared to handle them. 

		Eighty-three percent of pharma company respondents say they understand the Drug Supply Chain Security Act requirements, 70% say they can handle the scale and volume of data, and 67% say that responsibilities for serialization have been made clear within their companies. 

		Fifty-four percent of pharmaceutical companies found that they had to modify systems to accommodate a customer request, but 16% reported being unable to make those changes.

		Twenty-six percent of pharmaceutical companies experienced an increase in bad or incorrect data exceptions as a result of the requirements. 

	Clearly, serialization challenges remain, but at least more companies “know that they don’t know,” and are networking and learning from their peers from pilot tests and implementations to figure out what to do next. 

	When referring to this article, please cite it as A. Shanley, "Speed Bumps on the Road" sidebar to "Serialization Hits the Home Stretch," 

The author discusses the results from TraceLink and Actionable Research's Global Drug Supply, Safety and Traceability Report.

Speed Bumps on the Road

	In 2016, the pharmaceutical manufacturer Johnson & Johnson Supply Chain (JJSC) and the distributor AmerisourceBergen launched a four-week pilot program to test GS1’s EPCIS standards and to see how effectively data could be transferred between the two partners. JJSC has been working on serialization for some time, and began shipping serialized product back in 2012, so both companies were fully connected, in terms of their IT, and they could try this approach with serialized product. The test simulated the real-world supply chain. 

	A DataMatrix barcode was applied containing a serialized global trade item number (GTIN), batch and lot number, and expiration data for each sellable unit (whether bottle, vial, or blister), and the units were packed into cases and loaded onto pallets, while downstream vision systems and scanners read the barcode to capture all the information. EPCIS recorded events associated with the GTIN, so that AmerisourceBergen could confirm receipt of each item sent by JJSC, automatically. 

	Results showed not only the viability of this approach, but its potential power. “It’s like electronic data interchange (EDI) on steroids,” says Mike Rose, vice-president, supply chain visibility at JJSC. “Over time, supply chain partners will be able to exchange a lot of critical data for additional value,” he says. The pilot ensured that all processes, from plant to warehouse and distribution channel to docks, were tracked. “It forced us to test all processes along with way. We got confirmation from our partner that everything fed back to them, from plant to distribution center, and that they were receiving relevant process data.” Rose expects to see return on investment in terms of improved inventory management and transparency in the future. “But for now, our focus remains on the patient first,” he says. 

	When referring to this article, please cite it as A. Shanley, "Testing GS1’s EPCIS Standards in the Real World" sidebar to "Serialization Hits the Home Stretch," 

Johnson & Johnson Supply Chain (JJSC) and the distributor AmerisourceBergen launched a four-week pilot program to test GS1’s EPCIS standards and to see how effectively data could be transferred between the two partners.

Testing GS1’s EPCIS Standards in the Real World

As manufacturers move into new markets and launch new clinical research programs, including work in the development of cell, gene, and tissue therapies, ensuring the integrity of the cold chain has become more important, and more challenging, than ever.

	Success involves careful partner selection and logistics planning, as well as proactive communication with shippers, freight forwarders, and logistics specialists. It also depends on new temperature-control technologies, a number of which have recently been commercialized (

	In 2016, UPS bought Marken Technologies, which specializes in clinical trial shipments, to strengthen its capabilities in this area.  In this article, Dan Bell, vice-president of quality, compliance and technical affairs at Marken, discusses overall trends, along with Ron Swistock, director of global healthcare strategy at UPS, as well as Mike Sweeney, senior director of global service development, and James Klingelhoefer, regional sales director, both with World Courier, who share insights into some of the challenges posed by cell and gene therapies.

 What recent advances have been made in packaging equipment?

 A few advances we are seeing in packaging equipment include more efficient insulation using nano-technology to improve the thermal resistance, or ‘R’ factors of vacuum-insulated panels, which allow for greater payloads and longer validation times without compromising weight.

	Also, a greater focus is being placed on pallet sized and unit load device (ULD) solutions utilizing passive technology. We’re seeing a push toward lower temperatures as alternatives to dry ice, and competitively priced solutions for controlled room temperature (CRT) (15 °C to 25 °C). Another advancement is integration of technology, especially global positioning system (GPS) tracking and remote reporting from environmental sensors.

 How are the industry’s packaging needs changing?

Pharmaceutical companies are under increased pressure to understand carrier ambient environments in order to develop or justify their transportation methods and risk mitigation plans.

	You’ll see more efforts placed on sustainable materials, and demand will grow for carriers to offer more temperature controls within their networks to minimize packout complexities, costs, and requirements. An increased number of pharmaceutical companies are also innovating and collaborating with reputable third-party logistics companies to create better efficiencies for shipping biopharmaceuticals and clinical trial specimens.

 Reuseable shippers are getting more interest. These may be more expensive up front but they enable a ‘just-in-time’ business model. For the receiving lab, this approach not only offers environmental disposal advantages, but saves floor space because they no longer have to store used shippers.

 What improvements are you seeing in pack-outs?

 We are seeing a shift to universal packout configurations that remove the need for phase change materials at different temperatures and reduce the risk of user error during conditioning and assembly. Another example of packout improvements is the addition of chemical indicators to phase change plates to ensure correct conditioning prior to assembly and deployment.

 Temperature-control technology is improving, and packouts can be much longer than they were in the past. Traditionally, the packout standard has been 24 hours up to 48 hours, but now we are working to bring that up to 96 hours. If shippers can provide this level of protection for a two-day trip, it will ensure safety in case of transportation and weather delays.

	Important capabilities include replenishment of dry ice and ensuring the integrity of shipment. UPS works closely with its business partner, Cryoport, and uses Cryoport’s dewars, and shipments can be initiated from either Cryoport’s or UPS’ websites.

 How is serialization affecting packaging equipment design and features?

 In packaging, we are seeing a greater focus on security around seals and tamper-evident closures along with greater use of GPS tracking and geo-fencing to address Drug Supply Chain Security Act (DSCSA) concerns for drugs in transit. From a technology standpoint, chain of identity solutions--based on the integration of GPS, radiofrequency identification (RFID), and Bluetooth technologies--are being built into packaging and linked to cloud-based tracking software. This becomes especially critical for cell, gene, and immunotherapy products that are patient-specific or derived from patient initially.

 What role are new biological treatments (e.g., cell and gene therapies) playing in the clinical trial logistics business today, and how does planning for trials with these products differ from planning for traditional clinical trial logistics?

 These treatments are still a small part of the clinical trials business, but they require a disproportionate amount of front-end planning. Over the past few years, we’ve seen that sponsors really want to know how integration can play a greater role. These studies require cryogenic shipping, so the question is how many more dewars can be accommodated in our network. This work is also highly specialized.  For example, we need to perform special studies for autologous compounds, which require cryogenic shipment on two legs of the journey. In general, these projects require a very complex and integrated network.

 Cell and gene-therapy products require extensive logistical planning. In the case of autologous cell therapies, the patient’s cells are the active pharmaceutical ingredient used in the manufacturing of the end therapy. Therefore, the patient becomes a part of the supply chain, and he or she can be directly impacted by delays or problems during the logistics process. Additionally, particularly with consideration to the severity of the patient’s illness, the logistics timelines are always extremely tight and any deviation can have a far reaching impact on the clinical team, end-therapy manufacturer, and patient.

	When contrasted with small-molecule or biologics products, we find that there is much less margin for error with the logistics of cell and gene-therapy products. Scoping suitable time, critical routings, and educating airlines on the special nature of these products are all parts of the process.

 How should sponsors and contract partners approach collaboration for these projects? What questions are critical to ask logistics and shipping specialists, and what specific functions should each partner assume?

 Important questions should revolve around service partners’ experience and safety record with dewars, as well as packouts and how long the shipments will remain viable without taking additional steps.

 Sponsors and contract partners should collaborate in early planning stages for both early clinical and commercial development.  Although early clinical-stage development requires careful planning, when the scale is increased to commercial application, it is absolutely imperative that sophisticated scheduling and tracking is put into place.

	It is extremely beneficial for logistical plans for both early clinical-stage development and commercial development to be discussed during the planning phases. Questions can range widely and should include the following, all of which must be addressed at the onset of planning:

		How many sites, countries and cities are involved?

		What is the estimated number of patients?

		What is the nature of the contents--i.e., are they kits, packaging, or apheresis samples?

		Is temperature control management required?

		What is the nature of required chain of custody tracking, or are there special shipment handling requirements (e.g., is x-ray permitted?)

 What issues must be taken into account, and how do they affect the choice of temperature-control and other technology, and overall planning?

 Generally, it will help sponsors to have a basic understanding of the shipping lanes, transit time requirements, and temperature-control parameters to be able to anticipate potential issues and allow solutions to be pre-emptively created.  For example, if the end therapy is going to be transported in a liquid nitrogen dry shipper, then who is going to provide the liquid nitrogen shipper? And, who is going to ensure that the dry shipper unit is properly charged with liquid nitrogen? The answers to these questions will help determine responsibilities, a plan of action, and timeframes.

What are the unique challenges of moving autologous, as compared with non-autologous cell and gene therapies, and other personalized medicines?

 With autologous therapies, the biggest complexity is that, not one, but two really high-performance shipments are involved. There can be challenges, for instance, when the patient visits a facility where blood is collected. Often these trials are run in dispersed locations.  In some cases, there will be fewer labs available to send the blood. In general, with autologous treatments, special planning is particularly important for the journey’s second leg.

 obvious main difference is that an autologous cell-therapy scenario involves a circular supply chain, where the allogeneic model is more of a straight line between two points. With the circular supply chain, there is generally more of a need for careful coordination between apheresis and manufacturing slots. With allogeneic, there is likely more room for maneuvering because it relates to the time between when the therapy is manufactured and the time it is needed for infusion into a patient. The more complex circular supply chain for autologous requires precision planning with no room for error or delays. The straight line supply chain for allogeneic relies on experienced specialists.

 What special temperature-control technologies, storage, and transportation options are required for these advanced therapies?

 This will vary on the product and pharmaceutical sponsor requirements. Sponsors often require temperature-controlled packaging for apheresis samples (typically 2 °C-8 C packaging) and packaging for end-therapy product (typically liquid nitrogen dry shippers). In some cases, customers will ask for GPS tracking devices to help enhance visibility of their shipments.

 Some clinical-trial materials are now delivered direct to patients’ (DTP) homes.  Do you see that approach being used in the future for these types of materials, and how would that complicate the overall process?

 Absolutely. The key with DTP in clinical trials is maintaining thermal integrity over the last mile. This is a critical link in the clinical supply chain and essential to the success of a clinical trial. Regulators are looking now at how to include and enforce standards around the last mile through good distribution practices (GDPs).

	Further, with more pharma companies including both direct-to and direct-from patient homes as options in more of their protocols, we expect to continue to see increased demand. Finding packaging solutions that work well for delivery or collection from a patient at home, along with coordinating this service with in-home nursing care can be very challenging.

 We are seeing a relatively small amount of activity in DTP, but great interest. DTP exists for rare diseases, but the logistics for clinical trials, involving ambient temperatures, are easier. We’ve had success with these studies. Investigational medicinal products must be delivered on a regular basis, typically in one or two doses. In a clinical setting, they may be delivered less frequently. But if people have mobility problems, DTP studies open up potential business.

	So far, there have only been a few DTP studies involving cell and gene therapies, and they have required a lot of upfront work. In one case, the client had little compound available before each shipment, but doses had to be shipped 365 days a year. This required working with special operating places for Sundays and holidays, or when the patient was not home.Not every tudy is a good candidate for this type of approach, but we do expect DTP to become more important in the future.

 At the moment, the majority of shipments would be beyond the scope of home coordination. For many situations, the end-therapy product must be sent at frozen temperatures, including some cryogenically frozen material, which then requires a sophisticated thawing process before infusion. Currently, it is unrealistic to expect a DTP scenario for most cell and gene-therapy products.


	Vol. 41, No. 2
	February 2017
	Pages: 68–71

	When referring to this article, please cite it as A. Shanley, "Cold Chain: Zeroing In on the Last Mile," 

Longer packouts are becoming the rule, as logistics service providers and sponsors gain experience planning logistics for clinical trials involving novel therapies.