Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Shipping temperature-sensitive pharmaceuticals such as biological products, has never been easy. Today, changing global requirements and a more complex supply chain are driving more conservative approaches to temperature control. For products such as cell therapies and tissue culture, cryogenic shipping is now preferred.  Other biopharmaceuticals are being shipped at lower tempertures, and even small-molecule-based pharmaceuticals that might have been shipped at ambient temperatures a few years ago, must now be kept at controlled temperatures.

	Transport has become much more than simply moving product from one place to another.  It’s now being seen as a “mobile form of storage,” says Volker Kirschner, director of temperature control solutions for World Courier Management Co, part of Amerisource Bergen. This is especially true in Europe, he says, where the European Union (EU) began strengthening its good distribution practice (GDP) guidelines three years ago.

	Nothing can be taken for granted.  “From political unrest to pandemic concerns, the possibility of changes in shipping patterns and logistics strategies is quite real,” he says, and developing a global transport strategy has become more complex.

	Specialists in cold-chain shipment are responding to regulatory challenges and uncertainty by investing in new technology and IT, and strengthening partnerships with specialty logistics providers. For their pharmaceutical and biopharm customers, they caution, careful risk-assessment is the only way to avoid costly product shipment problems. Many are adding services and products to help make this task easier.  


	The most pronounced recent change in the cold-chain market has been more complex global regulations, from the EU’s GDP guidelines for pharmaceuticals to the Drug Supply Chain Security Act in the United States. “It can be difficult for companies, especially smaller ones, to know where to begin, and how to revamp compliance processes to stay ahead,” says Wanis Kabbaj, director of global healthcare strategy for UPS.

	Additional requirements (e.g., for controlled room temperature) have increased compliance challenges. Many drugs that were once shipped at ambient emperatures must now be shipped at 15°F to 25°C, increasing costs at a time when most pharmaceutical companies are trying to reduce logistic and supply chain operations budgets, says Ariette Van Strien, chief commercial officer at Marken Global Life Science Supply Chain Solutions, which specializes in cold chain and logistics.  

	Compliance has become especially challenging for clinical trial supply shipments, she says, noting that suppliers must scrutinize their global network, enhance tracking capabilities, and improve quality standards.

	Of utmost importance, says Kirschner, are quality management systems (QMS) and documentation, personnel and training, and risk management, especially regarding standard operating procedures (SOPs); facilities and storage requirements; and transport. “Quality departments within manufacturers’ supply-chain operations are gaining more and more influence,” he says, noting that regulatory agencies expect pharmaceutical manufacturers to take a risk-based approach and enforce audits and quality agreements.


	The most critical aspect to maintaining stability and integrity is choosing the most appropriate temperature conditions for the product and, consequently, the best packaging for maintaining those conditions, says Mark Sawicki, chief commercial officer at the cold chain specialist, Cryoport.

	A perfect example, Sawicki says, is the distribution of critical biomarker samples. Under currently accepted practice, these samples are shipped on dry ice. However, he notes, this shipping method has been connected with a 15-30% product compromise or failure rate. As a result, more companies are opting to use cryogenic temperatures to ship biomarkers, to help eliminate potential risks associated with transit times and temperature excursions.

	PCI Pharma Services, a diversified contract services firm that offers cold-chain expertise, has seen a dramatic increase in demand for storing product at ultra-low temperatures, from -40°C down to -196°C, and has adapted its products and services to focus on supporting these temperatures for storage, packaging and shipments, says Samantha James, associate director of clinical services.

	Pharmaceutical manufacturers need to conduct more critical, comprehensive shipping studies on all materials transported in support of a clinical program, says Sawicki, not only looking at sample failure but the impact of the selected transport medium on assay or product performance.

	“We consult with every client to select the best system and temperature-control solution, whether dry ice, liquid nitrogen, or phase-change materials (PCMs) to ship pharmaceutical products, diagnostic specimens, biotherapeutics, and tissue samples, says Van Strien.  

	Generally, the most crucial factors to consider include therapeutic indication, route, mode of transportation, and product sensitivity, she says. “Because a pharmaceutical’s stability is not always known in early trial phases, additional caution may be necessary, and protection for any changes in environmental conditions.”  

	Van Strien advocates developing a thorough risk assessment to help ensure product stability from origin to destination, including studies of the following:

		Potential risks and mitigation strategy

	For clinical products that are only available in small samples, incorrectly handled shipping and transportation can put millions or even billions of revenue dollars at risk by compromising clinical studies, potentially delaying product commercialization, notes Kirschner. When minimizing risk, it is important for manufacturers to consider the package type and choice of temperature-control mechanisms, environmental concerns, value of the ingredients in the product, temperature requirements and variables, and overall shipping costs.

	Suppliers need to master nontechnical issues as well, including local politics and security issues, especially when conducting clinical trials in new geographic markets. Proactive planning is required, Kirschner says, to help protect the integrity of products and, ultimately, the safety of patients who use those pharmaceuticals.

	Generally, he notes, up-to-date methods should be used to assess risk.  For example, he says, failure mode and effects analysis (FMEA) can be conducted, and risk priority numbers (RPNs) assigned, based on the probabilities and severities of certain adverse events occurring during transport.  These RPNs would help determine whether mitigation is required, and what type would work best for the specific product, market and application.

	Temperature is not the only variable to consider. Many pharmaceuticals and biopharma manufacturers require a great deal of stability protection from temperature, shock, vibration, humidity, and light, explains Kabbaj.  “Healthcare logistics has little room for error, so specialized packaging, advanced temperature and location monitoring leveraging global control towers, and in-transit intervention are all critical.”

	In addition, Kabbaj says, extended time in transit when product is being transported inland may expose the packaging to temperature fluctuations that increase risks. Ocean transportation risk factors include container placement on the vessel, sunlight exposure, container insulation, and dwell time on the dock -- all introducing additional packaging stressors.  

	He suggests that pharmaceutical manufacturing professionals take the following steps to ensure that they are covering all the bases required for risk mitigation:

Test packaging, including seals, for endurance, and put prototypes through compression, impact, vibration, temperature, humidity, and shock tests.

 Package optimization should include validation through design qualification, operational qualification, and performance qualification protocols.

Optimize packaging and transportation together.

 Do not develop a cold-chain solution sequentially with assumptions based on transportation, and then the transportation solution that comes with pack-out expiry. Pairing a lighter and cheaper cold-chain packaging with expedited air transportation, for example, may prove to be more effective than opting for a slower mode of transportation (e.g., ground shipping) with complex, heavy, and bulky packaging.

Innovate continually to create better efficiencies.

 Optimize the shipping carton, minimizing unused space, and select more precise packaging configurations.

	“Pharmaceutical manufacturers that do not continually review, evaluate and update packaging best practices leave themselves open to product risk and cost inefficiencies,” Kabbaj says. “Leave room for new ideas, material innovations, and new packaging manufacturers by engaging cold chain partners in a collaborative mode.”


	Cold-chain service providers have been developing new technologies to help pharmaceutical companies better manage risk and respond to problems.  “New requirements are driving developments in packaging and monitoring technologies,” says Kirschner.  As an example, he points to newer semi-active packaging technologies that allow for longer durations of temperature control with lighter materials that have less environmental impact.

	In addition, he says, passive packaging  solutions have been developed that can provide proven temperature control over long distances. Independent testing has shown these solutions to perform five to seven times more efficiently than semi-active solutions, he says. Kirschner also points to new phase-change materials (PCMs), comprised of paraffin or salt-based solutions, that allow for more precise temperature control to maintain product stability over long distances or through extreme climates.

	Many packaging manufacturers are now developing their own vacuum-insulated panel (VIP) containers, combined with PCM solutions, for easier handling and storage. Additionally, he says, on the monitoring side, developments in global positioning software (GPS) and tracking equipment now include automatic start-up and shutdown mechanisms that can provide a real-time view into a shipment’s status. Many technology providers have invested in real-time, GPS-enabled data loggers. Combined with improved data access, through customer portals and better IT, the technology offers immediate insights into bottlenecks and delays.


	“These data loggers provide the ability to track both condition and chain-of-custody, in real time,” says Sawicki.  They can track, not just temperature, but also monitor the impact of external influences on container integrity including orientation and package damage, he adds, and can also tell whether the container has been opened.

	Examples of new cold-chain data loggers include Sensitech’s TempTale and Nexleaf’s ColdTrace systems. Contract service suppliers are also offering enhanced IT connections. PCI Pharma Services, for instance, has developed a portal to allow clients to access real-time data, 24/7. “They can monitor stock levels, and view and trace all live shipments associated with their project, with direct links to courier tracking,” says James.

	Last year, Marken introduced Sentry, a GPS-enabled sensor platform, designed specifically for pharma with real-time track and trace capability through custom-designed software that monitors, records, and reports on location, temperature, motion, shock, exposure to light (i.e., when the box opens), atmospheric pressure, and remaining battery life. The device transmits in real time and communicates through customized cloud-based software that connects with Marken’s Maestro IT system, says Van Strien.

	Today, major cold-chain trends include increased use of temperature- managed shipping, and an interest in evaluating transport  methods and equipment critically, to maximize sample integrity, says Sawicki. There is also an increased emphasis on protecting the products of cell, gene and immunotherapy, says Van Strien, and the complex supply chain logistics that these products require.


	A growing number of biopharm companies must now ship cell- and gene-based therapies, says Kabbaj.  Such products require cryogenic storage at temperatures -238°F and below. In the past, shippers relied on dry ice (which performs best at approximately  -108.4°C), he explains, but dry ice emits carbon gas, which can damage proteins in biologic shipments, and might be harmful to handlers and to the environment. “Not only is dry ice shipping subject to a wide range of international regulations, it simply does not provide a cold enough temperature for many new specialty therapies” he says.

	Yet another important trend, says Van Strien, is increased demand of remote shipping, for example, of clinical trial dosages to patients’ homes. “We will continue to develop further services to allow patients to participate in clinical trials from home, or remote sites of their choosing,” she says.  

	Marken has also introduced an enhanced online booking app for investigator sites that is pre-programmed by study. It has also integrated enhanced scanning technologies throughout its global network. “More mobile technology will help treat patients at locations of their choosing,” says Van Strien.  

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	When referring to this article, please cite it as A. Shanley, “Cold Chain: Going the Extra Mile," 

Articles

Real-time GPS technology, better IT connections, and more conservative, controlled shipping temperatures are improving the shipment of sensitive pharmaceuticals.

Cold Chain: Going the Extra Mile

Time travelers from the 1980s would not recognize the typical pharmaceutical laboratory of 2016. Large spaces filled with dedicated tabletop instruments have disappeared, as pharmaceutical companies have shut down facilities, downsized, and are outsourcing more analytical laboratory work to contract analytical service providers.  

	As pharmaceutical facilities become modular and more flexible, instruments are shrinking. Portable devices bring more data to the warehouse, plant floor, and the lab, while wireless operation and use of radiofrequency identification (RFID) tags are being used to reduce operator error.  

	Data manipulation has been simplified in more user-friendly chemometrics and statistical analysis software. In addition, procedures such as chromatography have become easier and more powerful, while workhorse methods are gaining ground as “first-pass” alternatives to expensive and complex analytical methods.  

	To wrest value from every procedure and instrument, laboratories are embracing some of the basic concepts of lean manufacturing and optimizing workflow to reduce waste and improve efficiency. “With a move toward outsourcing and greater focus on biotherapeutics, customers are asking for more and better workflow solutions,” says John Rontree, senior director, chromatography and mass spectrometry at Thermo Fisher Scientific. “These solutions simplify tasks for outsourcing vendors, and reduce the complexity that comes with analyzing biologics,” he says.


	A growing number of pharmaceutical companies are outsourcing most, if not all of their analytical work. Today, stability testing, dissolution, and method development are typically outsourced, says Keith Moore, vice-president of analytical services at Metrics Contract Services.

	Standard processes include high-performance liquid chromatography (HPLC) assays, dissolution testing by either HPLC or ultra violet (UV), and Karl Fischer testing procedures, says Moore. Pharmaceutical manufacturers are also outsourcing operations that require specialized equipment and highly trained users, such as mass spectrometry, X-ray powder diffraction (XRPD), and nuclear magnetic resonance (NMR) spectroscopy, he says.

	Pharmaceutical manufacturers either outsource directly to contract laboratory companies or to larger contract manufacturing organizations (CMOs) that have acquired analytical capabilities. Metrics, for example, is a contract development and manufacturing organization (CDMO) with analytical testing capabilities.  

	According to Industry Standard Research’s reports on the state of pharma outsourcing, lab services are the seventh most widely outsourced function for small molecules and the sixth largest for biopharmaceuticals. It’s also an area that is seeing more mergers and acquisitions. Eurofins, for instance, which bought Lancaster Labs in 2011, acquired Sinensis Life Sciences, an analytical services company in the Netherlands, in 2016. At the end of December 2015, AMRI bought Whitehouse Analytical, a major analytical services company.


	Both pharmaceutical sponsors and their contract partners benefit from more powerful analytical methods. The workhorse method, HPLC, still dominates pharma labs, but alternatives such as UHPLC (ultra-high pressure liquid chromatography), offered by leading chromatography vendors, including Waters, Varian, Perkin Elmer, and Thermo Scientific, are gaining users. UHPLC, which uses smaller-diameter resin particles to improve resolution, speed, and sensitivity, allows more samples to be analyzed faster than with other methods. In addition, it reduces solvent requirements and waste for disposal, and requires less space, hood space, and storage.


	UHPLC for analytics has been likened to continuous processing in the manufacturing world. “If continuous processing reduces the cost of goods sold, UHPLC lowers the cost of analysis,” notes Emil Ciurczak, NIR spectroscopist who published the industry’s first papers on the use of process analytical technology (PAT) in pharmaceutical manufacturing when he worked at Sandoz in the 1980s.

	“With UHPLC, less material is required, and less time is needed for preparation,” Ciurczak says. “So, if, for example, you move sampling from 40 mLs to 1-2 mLs per run, you also save the cost of buying, storing, and disposing of materials,” he says. “The throughput increases are especially remarkable, with one instrument capable, in some cases, of doing the work of six conventional HPLCs,” he adds.

	For bioseparations, notoriously difficult to achieve efficiently, vendors such as BIA Separations, Diosynth, Biorad, Agilent, and Merck Millipore have developed monolithic columns that improve mass transfer and reduce purification times.  

	Continuous and simulated moving bed (SMB) chromatography, which allows several columns to be run in parallel, has also been developed by companies that include Novasep, GE Healthcare, Tarpon Biosystems, Knauer, ChromaCon, and Semba Biosciences. Vendors claim that this approach can improve productivity by a factor of up to six, and reduce the use of resin and buffer by 75% (1).


	For dissolution testing, Moore says, UV spectroscopy is often the first choice, even before HPLC, because it provides immediate data for trending and saves solvent, disposal, and other costs. It also uses one value, absorbance, to analyze data, so there is no need to transfer samples to vials. In some situations, Fourier-Transform infrared (FTIR) and Raman spectroscopy are being used to evaluate polymorphism, instead of the more challenging x-ray powder diffraction. In general, chemical imaging is becoming more important, says Ciurczak, and vendors such as Innopharma, which developed a real-time particle size imaging platform with Glatt in 2015, as well as Chemimage, Malvern, Bruker, and Perkin-Elmer, are improving their offerings in this segment.


	Use of ion mobility spectroscopy is also increasing for some applications. “It’s becoming the poor man’s mass spectrometer,” he says. Originally used in airport security applications, the technique, offered by vendors that include Smith’s Detection, Water, SelexION, and SCIEX, found its first pharma applications in cleaning validation back in the late 1990s. Today, it is finding increased use in some lower-end mass spectrometry applications, and is also taking over some HPLC applications. “If you can get the equivalent of HPLC testing in 20 milliseconds without column or solvent, why not?” Ciurczak asks. Although the technique cannot be used for stability studies, he says, it’s becoming a handy quality control (QC) tool.  “In some cases, it can be more specific than Raman or near infrared (NIR), and it’s also convenient for warehouse applications.”

	Use of mass spectroscopy is also increasing, however, and benefitting by improved workflows and features that can streamline processes, eliminate errors, and improve access to data, says Rontree. “The technology may become more sophisticated, but a single system today can provide more information [than was possible in the past] and reduce the potential for errors,” he adds.

Improved access to data and data processing


	Increased outsourcing has changed the equation for laboratory data access and manipulation. Laboratory jnformation management systems (LIMS) have become data storage systems, from which windows can be opened to allow access to and use of data. Some contract labs offer clients access to relevant portions of their LIMS in systems such as Eurofins Lancaster’s LabAccess. In other cases, contractors use a portion of their client’s IT platforms or install required data-access systems.  

	Instrumentation is also being developed so that contract partners can have immediate access to data. “Certainly the cloud is playing an increasingly important role as customers look to personalization and access to private information,” says Rontree.

	“There is also growing demand for more reliable approaches to method transfer,” he adds, which the company aimed to address with its AppsLab product, which allows methods to be accessed online and transferred directly without user intervention.

	Another enhancement has been availability of simplified chemometrics packages. As Ciurczak notes, these can save on training costs, and also mean that every location needn’t invest $10,000 in software licenses. In a typical pharma setup today, he says, software resides at the sponsor company’s home base, but results are cached so that it can be used at a contract partner’s facility or in the field.


	In today’s downsized environment, more pharmaceutical manufacturers are taking lean manufacturing approaches, developed for the plant floor, to the laboratory. The idea is to reduce waste, whether of time, space, or resources, to increase the value of each work step and procedure and improve productivity.  

	All analytical platform vendors are taking these needs into account with equipment and software that improves workflow. Mettler-Toledo has worked with the Swiss Lean consultant Irwin Studer to examine specific problems in the lab. The biggest problems, saysStuder, include time wasted waiting for measurement results, too many working steps, interface problems, where production is held up waiting for lab results, and incorrectly labeled samples. Mettler launched a Lean Labs platform in October 2015, which includes improved sample titration and weighing systems, as well as wireless data transmission and radiofrequency identification (RFID) readers and writers, to allow data to be picked up automatically from RFID tags on sample containers, pipettes, and dosing heads, reducing error (2).


	Portable devices, including handheld Raman and NIR spectrometers, are nothing new in pharma. Spinoffs of technology originally developed for the telecommunications industry, miniaturized spectrometers and imaging devices began to appear more than 10 years ago, but the technology has been steadily improving, Ciurczak says.  

	Today, batteries are much better and hold charge much longer than they did in the early 2000s, and the devices are getting smaller, he says. Some portable imaging systems from leading vendors are beginning to look more like the tricorders made popular by Star Trek, held in holsters, says Ciurczak. He imagines utility belts holding swappable heads for use with different materials, as well as holders for batteries, being worn by the QC technicians and analysts of the future.

	The pharmaceutical industry is already developing new approaches to buildings that would eliminate storage space and maximize flexibility, such as the PCMM (portable, continuous, miniature, and modular) systems developed by GEA Pharma Systems and G-CON Manufacturing, and evaluated by Pfizer and GlaxoSmithKline for oral solid-dosage forms manufacturing. This concept conjures images of the mobile QC technician being deployed throughout the facility, using technology that can move, seamlessly, from lab to process.


	Despite the availability of portable, miniature instruments, this is still far from reality at most pharmaceutical plants. It may be coming closer, however, as portable NIR, Raman, and other imaging systems are used throughout the pharma facility.

	Portability would represent a major change for an industry that has always kept lab and plant staff separate. Ciurczak recalls working for a pharmaceutical company and suggesting that lab technicians go out and insert NIR probes into the material being blended, instead of following the tedious but time-honored approach of sampling, delivering samples to the lab, and analyzing them by Karl Fischer and HPLC. There was no question of sending lab people to the plant, and, as a result, his team had to wait a week for answers, he says. Of course, union rules and restrictions were the first obstacle, Ciurczak says, but mindset might also play some part. “These are not technical problems but rather psychological ones,” says Ciurczak. “The equipment for doing this may exist, but the will to use it doesn’t.”


	However, Ciurczak sees change coming in work underway, for instance, at Rutgers University, which is working to standardize ab initio concepts for continuous manufacturing, focusing on powder flow and behavior.  Instruments used in this research will be calibrated in the lab and used throughout the facility, he says, essentially becoming both process and lab instruments and merging the two worlds.

	There may be other reasons why quality and manufacturing are kept in such different worlds, such as the need to ensure that manufacturing goals do not influence (or potentially weaken) quality standards. However, some of the industry’s strongest programs in lean and continuous quality improvement, at facilities such as Wyeth’s in Pearl River (started before the Pfizer merger) have brought quality and manufacturing professionals closer together (3). Perhaps quality standards could be maintained, or even elevated, in a system where quality staff were closer to those performing the manufacturing work. But, whatever shape the pharmaceutical laboratory takes in the future, instrumentation, methods, and services are clearly changing along with the industry and the pharmaceutical facility.

BioSC Continuous Chromatography for Biologics

,  press release, accessed January 28, 2016.
	2. Pharmaceutical Technology, “

Weighing Equipment Uses Lean Laboratory Principles

,” online, Oct. 13, 2015, accessed Jan. 26, 2016.
	3. A. Shanley and B.Swichtenberg, "

2007 Team of the Year Award: Wyeth’s Pearl River biotech Fill-Finish Optimization Team,

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	When referring to this article, please cite it as A. Shanley, “Exploring New Connections in the Lab of Tomorrow," 

Today’s analytical laboratory equipment reflects the realities of downsizing, outsourcing, and the need for speed.

Exploring New Connections in the Lab of Tomorrow


	Time travelers from the 1980s would not recognize the typical pharmaceutical laboratory of 2016. Large spaces filled with dedicated tabletop instruments have disappeared, as pharmaceutical companies have shut down facilities, downsized, and are outsourcing more analytical laboratory work to contract analytical service providers.  

Advances for Bio/Pharma Analytical Laboratories

As traffic in counterfeit and adulterated pharmaceuticals grows, the idea of a fully traceable pharmaceutical supply chain is taking shape. The concept has changed drastically since the past decade, when the first radio-frequency identification (RFID)-based serialization systems were piloted, and Florida set the first pedigree requirements. 

	Today, 2-D matrix barcoding is the technology of choice, and 40 countries around the world have set requirements for lot- and unit sales-level serialization and traceability, each of which offers specific challenges (Figure 1). 

	In the United States, the Drug Supply Chain Security Act set a deadline of January 2015 for lot-level traceability and verification. Unit serialization requirements will take effect in November 2017, and 2023 will be the deadline for having serialization-based track-and-trace systems in place. In the European Union, the Falsified Medicines Act has set a deadline of the end of 2018 for unit serialization and end-to-end verification and authentication. 

	Pharmaceutical serialization, aggregation, and traceability pose huge technical challenges, requiring the easy transfer of, and access to, massive amounts of data. These data will need to flow from manufacturers--some of whom have merged with or acquired other companies--but also from their contract manufacturing and packaging partners. Data will also have to connect to wholesale distributors, dispensers, pharmacies, and clinics. 

	Over the past few years, the pharmaceutical industry has made progress in developing serialization strategies and investing in the information technology (IT) required. In UPS’ 2015 Pain in the Chain Survey (1), 67% of 421 respondents viewed their investment in serialization IT as successful in improving product security (Figure 2).

	However, challenges remain. Even at the manufacturing level, where IT connections will be required between manufacturers and contract manufacturing and packaging organizations, companies are at different levels of achievement.  Generally, Big Pharma companies were ready for serialization before the deadlines, notes Darryl Brown, vice-president of global strategic marketing at Systech International. For smaller firms and contract manufacturing organizations (CMOs), readiness varies. “Some companies have robust programs in place, but others have been working tactically, to meet the bar set in different parts of the world,” says Shabbir Dahod, CEO of TraceLink, which offers a cloud-based IT solution that won a CPhI Award in 2015 for innovation in supply chain and logistics management.  

	“With less than two years to meet the US deadline, both manufacturers and CMOs realize that they have to move fast,” says Steve Peterson, project manager at CRB Consulting in St. Louis, Mo.  However, he says, over the past six months, lead time for line-level serialization equipment has gone from 12-14 weeks to 10-16 weeks.

If CMOs haven’t started yet, they may already be too late


	Generally, it can take the smallest pharmaceutical CMOs from one to two years to develop a strategy and foundation for serialization, medium-sized CMOs from two to three years, and large CMOs more than three years, Vivian McCain, vice-president of third-party operations, Americas, at Teva Pharmaceuticals, and program owner, CMO Serialization Program, told attendees at the First Serialization Roundtable for CMOs, held in Philadelphia, PA on October 8, 2015 (2). For mid-to-large CMOs that haven’t started laying the groundwork, it may already be too late, McCain said. There are many complex questions to decide, he explained, such as who should “own” labeling artwork issues or IT connectivity projects, or how quality assurance and exception management should be handled.

	Teva Pharmaceuticals began developing its internal serialization strategy four years ago, focusing on its global network of 20 sites. This year, the company began expanding the program, funding a CMO support program to help oversee partner serialization efforts in its external network of more than 700 CMOs. The program focuses on issues that include IT connectivity, quality assurance, tools, and applications. A CMO serialization-management dashboard allows the company to track each CMO’s serialization readiness and progress and assess the risk of noncompliance. Teva is developing risk profiles for each partner to assess the potential business impact of serialization noncompliance.

	To ensure flexibility, it’s important to have an IT solution that’s loosely coupled to the enterprise system, says TraceLink’s Dahod.  However, Dahod sees non-standard data exchange and integration approaches as one of the biggest potential obstacles that the industry faces in meeting upcoming serialization and traceability -regulations.

	Global Standards One (GS-1), the nonprofit organization that maintains standards for supply chains across different industries, and its Electronic Product Code Information Services (EPCIS) standard have played a key role in helping drive a common data exchange framework between packaging sites, enterprise serialization systems, and network trade partners, he says.

	He notes the potential of newer standards as well. “The Open Serialization Communication Standard (Open-SCS) Working Group could extend these data exchange harmonization efforts even deeper in the serialization process,” he says. “Particularly between the packaging line and packaging site level, where the sheer diversity of line-management systems and equipment manufacturers have made readiness for serialization a great challenge.” Jean-Pierre Allard, global serialization program manager for Optel Vision, has called it “the standard that CMOs need” (3).  

	Foundations for the Open-SCS Working Group were laid in February 2015, and executive director Charlie Gifford sees a real need for this work. “With traceability, ultimately, we need to validate the bottle that reaches the patient,” Gifford says, “and the current process--which includes serializing at the bottle level, aggregating and serializing in all forms, and then de-aggregating to the pharmacy level--is still vulnerable to criminal interference.”

	The idea behind Open-SCS is to focus on the three or four data and communication layers (line and equipment, distribution centers and warehouses, plant and warehouse operations management) between the plant and the corporate enterprise resource planning (ERP) system. For serialization, such a standard would help pharmaceutical companies and CMOs improve the aggregation of serialization master data between plants, and optimize plant-floor strategies depending on whether their manufacturing departments assign a serialization number, or whether a government regulatory agency is providing numbers to apply to product.

	Given the number and variety of regulations, and differences between different vendors’ products, the challenges are great. “If you walk into any CMO’s packaging line today, every single piece of equipment there is from a different vendor. Manufacturing Execution System (MES) and ERP vendors sell proprietary systems. By the time you get up to the top level to create a report, it’s a mapping nightmare,” Gifford says. As he explains, line-equipment vendors tend to promote proprietary solutions; at the MES level, they are looking at the batch record, and, at the ERP level, the batch record is different from the master batch record. Also, not all countries are standardized on GS-1, so five different countries may have five different requirements for reporting out of the plant, Gifford says.  

	EPCIS addresses some, but not all of these issues, so many projects become one-offs using custom solutions. “This type of work does not scale. What works in one plant may not be able to accommodate change, and work in five plants around the world five years from now,” says -Gifford.

	Another major problem with one-offs is lack of transparency, says Systech’s Brown. “Temporary solutions will get you through the checkbox for serialization, but if there’s a problem down the line, there will be no way to diagnose it and retain the data, so it will then be very difficult in situations where, say, you need to recall millions of dollars worth of product.” Supply Chain Wizard’s managing partner Burak Tiftikci suggests that manufacturers “design for tomorrow.” As he noted during the October CMO conference, “You can always dumb down the richness of data to meet a specific requirement” (4). He noted, however, that it can be “exponentially more challenging” to work the other way around.

	A prerequisite to successful serialization is having a strong IT system that can handle serial number mapping. Peterson adds, “you need to be able to handle high volumes of data, and to have a disaster recovery and backup situation in place.”

	All of the major ERP vendors have introduced platforms designed to facilitate serialization, although consultants note that some may still be unproven. In September 2015, SAP introduced Advanced Track and Trace for Pharma (ATTP), which replaces its previous Auto-ID Infrastructure (AII) and object event repository (OER) programs as a way to generate serial numbers, send codes to packaging lines, and then track them. That same month, TraceLink introduced an SAP Migration Kit to allow users of SAP serialization products to take that functionality into the cloud.  

Point-of-use connections challenge pharma


	Well beyond the manufacturing and CMO portion of the supply chain, a major challenge is working with pharmacies, clinics, and hospitals at the point of service, Gifford says. “Today, between 20-50% of the cost of serialization is due to paper pushing,” he says. “We’re going into a rudimentary IT world and telling them to put in yet more systems.”

	Concerns that can play out at the point of service were recently seen in Brazil, whose regulatory agency, ANVISA, postponed a December 2015 deadline for its traceability pilot phase. The requirements called for drug license holders to report to the government, and pharmacies feared that access to patient data might give suppliers too much information about stock levels and trends, and allow them to control pricing and supply (5). The government changed its requirements so this information could not be shared with distributors.

	Even so, the challenges of data integration at that level can be formidable, and standards can help. This was shown in Roche’s recent pilot project, which focused on special products and medicines for cancer, and involved collaboration with the systems integrator SPI and TraceLink. The project, which won the 2015 GS-1 Brazil Automation Award, used EPCIS to share information among Roche, its distributors, and clinics. The work was accomplished within three months. Integrating supply-chain links was the biggest challenge, says Rafael Schirmer, SPI’s director, who managed systems integration for the project.  

	The pilot used TraceLink’s cloud-based system, so no installation or local software configuration was required, he says. Connecting with pharmacies and distributors proved difficult initially, Schirmer says, because many of them did not want to invest in the systems required. Roche set up portals for them to meet reporting requirements, and SPI configured web boxes to enable them to access TraceLink’s tool.  

	The project will soon move into its next phase, but Brazil’s mandate is clear, Schirmer says: All supply-chain members will be jointly responsible for the traceability of medicines.  

	Creating a supply chain that is traceable, end to end, may seem like a holy grail, but Open-SCS’ Gifford believes that standards will make it easier.  As he notes, they’ve worked in other industries such as semiconductors, where Sematech, a consortium of the top 10 manufacturers, set a foundation in the 1990s. “Today, at AMD, Intel or Samsung, at any plant anywhere in the world, they’re all using the same interfaces,” he says.

	At this point, pharma is making the connections required for transparency and traceability.  However, as experts caution, only a strategic, long-term approach will yield the best results.

Eighth UPS Pain in the Chain Survey Snapshot

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	2. V. McCain, “Establishing CMO Serialization Support Strategy,” presentation at the First Serialization Roundtable for CMOs (Philadelphia, PA, Oct. 8, 2015).
	3. J-P. Allard, “Serialization Solutions Through Innovations,” presentation at the First Serialization Roundtable for CMOs (Philadelphia, PA, Oct. 8, 2015).
	4. B. Tiftikci, “Serialization: Internal and External IT Connectivity,” presentation at the First Serialization Roundtable for CMOs (Philadelphia, PA, Oct. 8, 2015).
	5. P. Taylor, 

“Brazil’s Drug Traceability Pilot Phase ‘Suspended,’”

:
	When referring to this article, please cite it as A. Shanley, "Serialization: Getting Past the Quick Fix," 

Traceability and transparency will remain elusive if manufacturers continue to approach serialization projects on a case-by-case basis.

Serialization: Getting Past the Quick Fix

Despite the focus on biopharma,  small-molecule drug development has continued to drive pharmaceutical innovation. Between 2005 and 2015, the number of new chemical entities (NCEs) doubled from 3000 to over 6000 says Matthew Moorcroft, director of global marketing at Cambrex Labs, quoting numbers from the market research company, Citeline. Last year, 4711 small-molecule drugs made it into clinical trials, a sharp increase from 2014 (Figures 1 and 2). 

	In biopharma, antibody drug conjugates are an area of increased research activity says Eric Langer, principal of Bioplan Associates. In addition to orphan drugs, there is great interest in oncology, cardiac and diabetes treatments, he says.

	In 2015, pipeline innovation focused mainly on oncology drugs, particularly in targeted therapies such as immunotherapies and specific inhibitors, blocking antibodies and receptor agonists (Tables I and II). According to Moorcroft, oncological drugs are the most prevalent in pharma’s pipeline, with over 3000 candidates currently being evaluated in clinical trials. Pain treatments follow, with 349 NCEs in clinical trials, Alzheimers, with 255 in trials, and diabetes, with 187.

	The top pharma innovators of 2015, based on NCEs now in development were: AstraZeneca with 100, Merck with 97, Novartis with 96, Roche with 88, GSK with 84, Johnson & Johnson (J&J) with 80, Pfizer with 78, BMS with 67, Lilly with 61, Bayer with 58, and Takeda with 54. 


	Another area of focus has been rare or orphan diseases, led by efforts at Genzyme, Shire, and Pfizer. Recent breakthroughs include Alexion Therapeutics’ Kanuma (Sebelipase alfa), the first treatment for lysosomal acid lipase (LAL) deficiency. The drug offers targeted delivery of silent RNA (SiRNA) to allow production of the missing protein in genetically engineered chickens, which produce the protein in their egg whites. The proteins are then extracted and used to treat patients with the disease.

	In addition, The European Medicines Agency (EMA) has recommended the first advanced therapy containing stem cells, a therapy called Holoclar, for approval in the European Union. It is used to treat severe limbal stem cell deficiency, a rare disease that results from physical or chemical burns to the eye.

	Rare diseases affect 1 in 10 people in the United States, and 300 million around the world. Roughly 7000 rare diseases exist but only 30% have cures. The market in the US has grown from $80 billion in 2009 to over $100 billlon, according to research by L.E.K. Consulting (1).

	Encouraged by regulations that offer fast-track review and favor development of drugs for unmet medical needs, rare disease research will benefit from U.S. government funding for precision medicines, which reached $215 million in 2015. Since 1983, $320 million has been awarded to fund studies of rare disease therapies (1). 

	Rare disease patient organizations have become more powerful in developing new medications. The Cystic Fibrosis Foundation, for example, is funding research at Pfizer and has funded work at Vertex. In 2015, the organization sold its rights to future innovation royalties by Vertex to an investment group for over $3 billion, a sum that the group will use to fund more research.


	Immunotherapy continues to dominate recent breakthroughs in oncology drug research. In addition, there is increased use of continuous processing and flow chemistry to make, not only drug substance but drug product, says Jan Ramakers, a consultant based in Edinburgh, Scotland. “It’s not just the small-scale chemistry that is going to continuous processing, but also things like crystallization and formulation.”

	Vertex’s new treatment for cystic fibrosis, a combination product called Orkambi, received FDA approval in June 2015. Vertex is now building a facility that will use continuous processing to manufacture the product. According to the

	Wall Street Journal, the process allows 100,000 tablets to be made in an hour, rather than the four to six weeks required for traditional batch processing (2). J&J, Novartis, and GSK are also working on continuous processing facilities for their products.


	Synthetic biology is emerging as a new way to make drug substances and intermediates, Ramakers says. In a twist on conventional biotechnology, this field applies engineering concepts and approaches to biological systems to design new processes and organisms that aren’t found in nature.  

Editing the human genome by harnessing CRISPR


	Within the past few years, synthetic biology has yielded a platform called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), which is being developed to enable human genome editing. Originally discovered by researchers in the food industry, the platform has enormous potential in medical research and many other applications as well.

	Using the approach, one can geneate an RNA sequence matching the DNA sequence of interest (e.g., within a cell).  This guide RNA can then move into the cell, where it can be used to silence a specific gene, or change its sequence in the genome, effectively editing it.  

	Three different organizations currently own intellectual property for CRISPR. Companies such as Editas Medicine, Intellia Therapeutics, Caribou and Eligo Biosciences are working on therapeutic R&D in this area. Among the pharma companies actively investigating CRISPR’s potential are Vertex, Novartis, and AstraZeneca.

 L.E.K. Executive Insights 2014; Vol XVI, Issue 9.
	2. S. Ayme, S. Lau, L. et al, 

State of Play with Research in the Field of Rare Diseases: 2014-2015

, The International Rare Diseases Research Consortiaum, September 2015, accessed December 28, 2015. 

:
	When referring to this article, please cite it as A. Shanley, "Oncology and Rare Diseases Lead in Innovation," 

Synthetic biology promises to drive tomorrow’s therapies, while continuous processing is already being used in some new drugs.

Oncology and Rare Diseases Lead in Innovation

With less than two years to meet the US deadline, both manufacturers and CMOs have to move quickly to implement serialization practices.