We’ve been covering the topic of pharmaceutical traceability and compliance

 with the Drug Supply Chain Security Act (DSCSA) closely for years, in part because its implications are so fundamental to how drugs will be distributed and dispensed nationally and globally in coming years. There is a lot of DSCSA-related news in this issue—see our 

 (aka “bitcoin”) could solve some looming DSCSA problems; how 

 (a DSCSA requirement for most) can be the spur to modernizing the entire pharma packaging process; and how an 

, is offering serialization services to its pharma clients.

So it’s more than a little disconcerting, in the middle of all this, to hear that FDA has announced a one-year delay (from November 2017 to November 2018) for the next stage in DSCSA compliance. Does this presage an eventual fading away of the entire DSCSA compliance mandate?

 is so invested in the topic. Securing supply chains is a topic of vital interest outside the US (where counterfeiting is more prevalent)—the global initiatives are not going away, even if they’ve been struggling to keep to their own self-imposed schedules. Most of Big Pharma is already well along with the initial steps of installing serialization equipment, and more and more contract packagers are making the investment. And while retail pharmacy has been mostly a reluctant passenger on the DSCSA train, numerous health systems—who are building out their own pharmacy capabilities, particularly in specialty products—are getting more deeply involved (they are obligated to, of course, by the law; but it’s one thing to limp along the process, and another to give it momentum).

We surmise that while industry lobbyists were probably grumbling to FDA about the looming deadline, the main reason for the delay was FDA itself, which is resource-constrained as it tries to deal with a highly complex regulatory process. Newly installed FDA Commissioner Scott Gottlieb made some bold statements about 

patient safety in regard to compounding pharmacies

 in June; recall that that regulatory framework was set up by Part One of the Drug Quality and Security Act (DSCSA is actually Part Two of that Act). It’s difficult to envision FDA tightening drug supply chain security for compounding pharmacies on the one hand, and loosening it for packaged pharmaceuticals on the other, even given all the misdirection and backtracking going on in Washington these days.

It’s also worth noting that while the November 2017 deadline has been pushed off, successive ones for 2018, 2019 and finally 2023, were not delayed.* In Europe, the Falsified Medicines Directive has a February 2019 deadline for serialized products; pharma companies operating globally will have to comply with that mandate, as well as others around the world.

The intriguing aspect of DSCSA compliance is not meeting the requirements of the law, as important as those are, but what this level of supply chain visibility will enable the pharma industry to do in coming years. We’re hearing that some pharma companies are already building use cases for their marketing, patient support and pharmacovigilance efforts. It’s not to wonder how to capture the value of today’s supply chain by DSCSA compliance, but how to stay competitive in the supply chain of 2023 and beyond.

*A timeline of DSCSA compliance deadlines was published in Pharmaceutical Commerce’s annual Product Security Report, accessible at

http://www.pharmaceuticalcommerce.com/supply-chain-logistics/2017-product-security-report/

Articles

FDA’s delay will not alter industry goals

Pharmaceutical traceability stumbles ahead

Pharmaceutical companies are all trying to advance the health

 and well-being of people through their products and services in a way that creates profitable and sustained growth for their organization. However, as these organizations grow and work to achieve these goals, they are faced with ever-increasing layers of complexity within their business. This is especially true with the introduction of new products, technologies, facility expansions, emergence into new markets, and the management of mergers and acquisitions.

Added to this complexity is the challenge of investing in enterprise-wide applications that support an expanding manufacturing process and value chain, as well as a myriad of other issues. This progression creates a diverse set of needs for their employees, suppliers, clinicians, third parties and even customers. These needs include compliance, development and performance across the company.

Companies could greatly benefit from the implementation of a single enterprise-wide earning management system. Unfortunately, what happens more often than not is that each department acquires and implements their own learning management system (LMS), due to the nature of their specific needs and challenges. At that point, the objective to minimize complexity and enhance the success of positive change and growth is handicapped due to disparate LMS programs across the organization. Problems arise with the lack of a cohesive solution in place, including the right mix of technology and knowledge to move people and processes from the current state to a high performing future state.

Determining the reason why a multitude of systems end up in an organization can, at a glance, appear simple. The growing and evolving departments have distinct learning and development goals, and finding a single platform that can be customized to meet these diverse goals has been a challenge.

 build universal competencies across the organization, initiate skill development programs, manage performance reviews, help managers, and have direct reports set goals and career advancement paths.

improve product knowledge, provide medical research training, drive sales performance, increase quality leads, etc.

effective training to meet compliance, proof of competency, Code of Conduct training, anti-bribery training, anti-kickback awareness, HIPAA issues, satisfy all FDA requirements (including 21 CFR Part 11).

Given these very diverse yet mission-critical learning and development goals, the result is various departments acquire their own LMS that they may perceive to be helpful in the short term, but actually adds another layer of complexity that will make solving the real challenge all the more difficult. Having numerous, non-integrated, learning and development technologies in-house is actually symptomatic, in that it exposes the lack of a holistic enterprise-wide strategy for learning development.

This strategy will align not only with the overall learning and development goals, but also with the specific environment, people, processes and process-enabling technologies within the organization. Just as critical, the technology must be sufficiently advanced to adapt to the specific needs of each department.

A significant challenge with pharmaceutical companies often lies with the strict data integrity requirements of US and EU regulations. Companies are required to ensure that anyone involved in the design and production of the products is qualified for their role. In addition, regulatory agencies globally require that the workforce be educated on GxP concepts, as well as SOPs and work instructions based on their specific role in the organization.

Addressing this need is typically outside of the HR auspices and falls under Quality Assurance. It demands an LMS that supports the following five regulatory requirements around GxP training and qualification:

 21 CFR Part 11 requires the "use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify or delete electronic records."

According to 21 CFR Part 11, signed electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised, copied or otherwise transferred to falsify an electronic record by ordinary means.

Life sciences organizations demand extremely tight security roles so that only specific individuals can make itemized system changes, such as modifying system configuration, updating training items, making assignments and much more. The LMS must provide the ability to define very granular security roles based on different functions they will need as managers, trainers and IT personnel, so that managers can only see qualifications of their direct reports.

the LMS must support the creation of role-based groups and assignments to these groups. This greatly reduces the reliance on manual and administrative reviews to determine which personnel are qualified for a specific job function. Role-based functionality also leads to more successful audit answers when job qualifications are raised. And managers also gain visibility into qualifications for resource planning purposes.

The LMS needs to support SOP version control, for example, so that the QA team can successfully “up version” an SOP in the document management system (DMS) so that a new training item is created automatically in the LMS.

FDA has some clear expectations for training. For instance, they require that each employee receives the appropriate education, training and experience (21 CFR 211.25) in the operations the person performs. In order to ensure this is happening, the company should establish procedures for identifying training needs and assuring all personnel are adequately trained to perform responsibilities. The responsibility is not only on the shoulders of the learners, however. The trainers should be qualified. One of the fundamental elements of a training program is that the training not be a once-and-done event, it should be conducted on a continuing basis to ensure employees remained trained and are up to speed on new or revised regulations and procedures. Furthermore, all of this needs to be documented in an air-tight, audit-proof format. That is where a single-enterprise LMS shows its true value. This way, all departments can use one system, regardless of whether they are required to follow the higher-level regulatory requirements or the company’s own guidelines.

To ensure technology adoption and requirements are properly met, companies should have a strategic road-mapping plan in place, establish a governance system, and have a departmental development goal-setting initiative. These will help ensure technology adoption and requirements are met properly across the board. HR will develop goals to measure performance and provide career advancement opportunities to ensure employee retention and employee engagement. At the same time, their goals will capture the department’s need to provide and measure “technical skills,” and to improve an individual’s competency ratings. Quality Assurance will need to track a role-based qualification matrix, as these records are scrutinized by FDA and other global regulatory bodies during inspections.

The enterprise-wide learning system should provide an adaptive user experience that supports “universal” competency programs and performance management programs that HR can deliver to employees.

 that provides a positive learning and development experience for all employees and contractors. Company culture contributes to the identity and pervasive values of and within an organization. For example, if setting and meeting goals is inherent to the culture, both management and employees will have a natural inclination toward setting and meeting goals. Training is something that should qualify as a critical element of company culture and one login to one program that approaches training in the same way across the company will help create a consistent and cohesive vision for the organization.

 the functionality they need to accomplish their goals. People learn in different ways; one popular theory, called the VARK model, identifies four primary types of learners: visual, auditory, reading/writing, and kinesthetic. An LMS that follows best practices will enable each of these principles. Not only will each department have the flexibility to provide the training that is specifically needed to meet their goals, standards and regulations, but it will provide each individual a way to receive training in an effective format.

 executives gain a single, powerful view into an individual's readiness ratings, comparative profiles, potential and overall performance over time. The adage, “What gets measured gets managed” has significant meaning when it comes to learning. By being able to track quantitative and qualitative measurements across the enterprise, the company can better know where the red flags are and where they need to improve.

 their investment in multiple learning management systems, and reduce IT effort to deploy these systems. Companies are seeking to improve efficiency and reduce redundancy. Having a single LMS system brings efficiencies that supporting multiple systems could never provide.

 such as MES, DMS, ERP and HRIS is managed more efficiently. Integrating these other enterprise systems with an LMS multiplies the effectiveness and reporting power of all systems. When a CRM and LMS are used separately in a silo, the reports generated offer only a fractional view of an individual’s performance. By combining the data and information from multiple systems, the outcome and insight is exponential, and far richer data can be leveraged to improve results along the spectrum. Proper integration can also remove redundant manual efforts that can be time-consuming and labor-intensive.

minimized, as employees are tracked across all areas, and “compliance education overlap” is greatly reduced. When a company is reducing risk by aligning with standards and complying with regulations, those responsible for compliance training will push out training focused on changing rules, regulations and policies. If the curriculum is not centralized, then redundancies, and even gaps, can emerge that can threaten the effectiveness of the program and introduce risk.

Timely analysis of the curriculum that is customized by department and realigned when necessary will help ensure that proper training is being given to the right people at the right time.

Perhaps the most important benefit from an enterprise-wide learning system and balanced training system is that managers can conveniently share data across the enterprise, especially in areas of career development and compliance status. What this does is provide decisionmakers with better data and greater insights—within a unified and cohesive system environment. With a single solution, leaders can visualize relationships and patterns between operational and business activities in new and extremely valuable ways. Companies will more effectively see connections to problems and solutions as they are unfolding. In highly regulated business environments, finding these correlations, the single appropriate enterprise-wide learning plan and the ideal LMS solution is more important than ever.

Isabelle Noblanc is vice president and general manager of UL Compliance to Performance.

The case for a single enterprise-wide learning management system

Managing employee training at the enterprise level

 Fig. 1. A serialization program can be the first step toward managing overall packaging line performance. Credit: SCW[/caption]

for supply chains that is used in the “treatment” of counterfeiting or falsifications, while also helping with the quality and integrity of supply chains. Truly a game changer. It is already in the works in more than 40 countries around the world, and more countries are getting ready to adapt this new treatment. However, like every great drug, there are always some side effects, which you might miss, unless you read the fine print (i.e., talk to experts or early adaptors). For serialization, these side effects are not to be underestimated, as it can make parts of your supply chain quite miserable, while trying to improve the others.

Two of the main side effects of serialization compliance is the loss of efficiency in packaging operations and warehouse operations. As manufacturers are getting ready to comply with the US Drug Supply Chain Security Act (DSCSA) and the EU Falsified Medicines Directive (FMD), a few thousand manufacturers will go through this painful journey of installing and validating new serialization (and aggregation) hardware and software on their packaging lines. An estimated 10,000+ lines will eventually be upgraded, and industry surveys suggest that the majority of these implementations have not even started yet. As the deadlines for manufacturers/packagers come before the 3PLs and wholesalers, let us focus on the “side effect #1”: overall equipment effectiveness (OEE) loss in packaging lines.

As one of the early movers in this field, Supply Chain Wizard has helped a variety of manufacturers implement serialization compliance solutions around the world, spanning most of the leading packaging line solution providers. We can conclude that, in almost all cases, there is an inevitable loss of OEE. Key questions that the manufacturers should be asking are:

The efficiency losses happen because there is a set of new equipment being introduced to the line with additional reject bins. New reject bins imply more rejects (i.e., reduction in throughput) and more machines imply more downtime by default. On top of that, the complexity of these systems requires more training, and the human factors added to the equation are causing even more stoppages on the line. Typical loss is around 5–10% of OEE, after the ramp-up and stabilization of the operations. However, early on during ramp-up, losses of more than 30% have been observed. In rare instances, the OEE losses could be mitigated by introducing some level of automation to the line, which require additional investments. The main challenge the industry is facing is that these levels of efficiency losses could mean the difference between profitable and non-profitable businesses, especially in the contract manufacturing/packaging world. For all manufacturers, it means direct negative impact to the bottom line, in terms of higher cost of goods sold.

 Fig. 2. Wireless monitors can gather data for an overall “digital factory” view.[/caption]

Once the manufacturers go through their own initial line implementations and resulting efficiency losses, proactive ones start contemplating pilot projects to improve OEE levels. Measuring OEE baseline before any action is taken is a fundamental first step towards minimizing the losses. The baseline data collection, however, should be “digital” in order to be repeatable and sustainable, instead of being paper based. As the digital data collection on the line activities ramp up, the foundation for a “digital factory transformation” is being put in place. Serialization compliance solutions are only putting verified unique serial numbers on each pack, while an activity we’ll call “digital activity tracking” will start enhancing the serial number data with operational data in such a way that will enable the humble beginnings of a “Digital Factory Transformation.”

Digital Factories are the factories of the future, whereby every process or activity, personnel and product is tracked at granular levels, and such information collected from the operations is used for generating insights (e.g., exceptions, trends, patterns, projections) and for better data-driven decisionmaking (e.g., asset replacement, work order schedules, staffing levels and more). Over time, these systems will turn into learning systems, where more data and insights are used in more automated decisionmaking, creating a virtuous circle of continuous improvement. (Fig. 1)

The digital factory of tomorrow will be in “3D”: Data, Dashboards and Decisions, a three-phased digital transformation process to enable the promise of smart manufacturing (what is coming to be known as Industry 4.0). The 3D journey is from data to dashboards to decisions, from more basic and lower-value drivers to more sophisticated and higher-value drivers. First, let’s better define these three horizons of transformation:

Enriched dataset at the level of unit via unique serial numbers and product visibility along the supply chain is just the beginning of a major data transformation. Internet of Things (IoT) technologies, such as wireless sensors, provide many opportunities to enhance datasets collected by traditional transaction-based systems like ERP, MES and WMS. Unit level product tracking (status, location, environmental factors, duration, carriers, etc.) together with data enrichment processes to associate commercial data (e.g., price, discounts, chargebacks, returns) to the serial numbers will dramatically increase supply chain visibility.

The ability to convert sets of data into meaningful and actionable insights through business and management metrics and visualizations, via role-specific dashboards. For example, a digital factory manager would be able to see a live dashboard of all their production lines with their status (running, down, idle) and the analysis of why the lines are not performing per their target OEE levels for a given time period. Using these dashboards, business patterns could be highlighted, and issues can be addressed faster and more effectively. Similarly, positive outcomes could be measured and input conditions could be replicated at most granular levels (e.g., Operator A runs product X on Line 1 on Mondays more efficiently than any other combination).

 Decisionmaking is the ultimate change in behaviors that impact operations. Therefore, data and dashboards are only useful if the management is changing their actions accordingly. In the ultimate sense, the decisionmaking process could also be digitized by the use of optimization algorithms and machine-learning systems. For example, the scheduling of work orders to the packaging lines with the use of real-time data on line efficiencies, staff schedules and line availabilities could bring significant cost savings due to overtime/waste reduction, while increasing capacity and throughput.

OEE Tracker in Action: A Case Study in Factory Digitization

Late in 2015, one of our clients was faced with the challenge of significant efficiency loss while upgrading their pilot bottle-packaging line with serialization/aggregation technologies—they wanted to optimize their line efficiency despite these challenges, as they were concerned with overall impact to the site after achieving serialization compliance. (Fig. 2) After taking some time to understand the unique nature of the issues, we jointly developed a solution designed to help optimize the way they track their operations—digitally; later we named the solution as “OEE Tracker.”

As the pilot project continued over 12 months, expanding into all the packaging lines at the site, it became clear that the OEE Tracker would be the answer to uncover and remedy many of their issues, highlighting areas of immediate and significant improvement.

By replacing manual and/or paper-based tracking activities with that of digital tracking capabilities, the biggest improvement happened in operational visibility. Our clients started seeing live dashboards of their operations, unexpected stops and delays in production, as well as the root causes of these issues (e.g., specific machines in a line). Once the solution was implemented at multiple lines, it also provided a capability to compare and contrast similar lines, their efficiency levels and emerging problems by consistently measuring and tracking the operations across these lines.

The second biggest source of improvement came with a “moment of revelation” when certain procedure-driven activities showed significant variability in duration during the initial pilot study. Our client started noticing areas of variability, together with the identified sources of variability, which helped improve the tracking capabilities of the solution to clearly identify and capture the root causes of these variabilities. For example, the number of available operators it takes to conduct a certain procedure is an important input to capture, which often correlates significantly with the duration of those procedures.

Once the visibility and newly found capability of variability tracking were put in place, then came the definition of what is regular or acceptable, and what is an exception. Most of the activities tracked could be assigned an expected duration, a possible minimum and a maximum allowed duration (i.e., lower and upper limits). Algorithms automating the reporting of exceptions (i.e., below minimum or above maximum), made it an easy task to get daily or weekly digest emails highlighting just the exceptions for managers to focus on.

Through deep collaboration and data-driven discussions, another important area for troubleshooting was identified as the time it takes to find the right personnel to conduct their duty when required at a given line. For example, bringing the right quality assurance (QA) personnel to release the line after it has been cleaned could sometimes take up to an hour or more of wait time. Similarly, finding the right mechanic and making him come to the line to fix an issue could take significant time, causing additional line stoppage. A simple “call support” function implemented in the OEE Tracker solution, emailing/texting the right person with the right information, significantly reduced this avoidable downtime.

The real improvement in efficiency is not possible until a true change of operational behavior is achieved. Being digitally tracked already contributed to our client’s OEE performance, where without any policy change, an improvement of 10–15% is achieved by the change in behavior of supervisors and operators. More fundamental performance improvement, however, required a new look at the way the work orders are scheduled to the lines to minimize overtime and reduce changeovers. Given a digitally strong foundation of OEE Tracker and digital log book of all shop floor activities, a more robust way of creating the shop floor schedule was created. Early results from the analysis of actual monthly schedule data showed very promising results with a 10–20% reduction in labor cost, primarily due to reduced overtime, and a possible increase in capacity/throughput of 20–40% with better scheduling capabilities using mathematical modeling and machine-learning algorithms to use constantly improving data-sets for decisionmaking.

In all, our work with our client improved the way they manage their packaging operations. After using our OEE Tracker solution, they could quickly highlight areas that impede productivity, as well as calculate and utilize metrics on their line operations for improved efficiency. Having worked extensively with our client, we have concluded that, while data is important, all three aspects of “3D”—including dashboards for operational insights and decisions for actual step change in behavior—must work together to form a complete solution, one that we know is possible with the support of software solutions, IoT sensors, and an open-minded and supportive leadership.

The Digital Factory Transformation journey could be new to many companies and sites, however, with the serialization compliance requirements and side effects on efficiency, more and more companies will embark upon this journey in the near future.

By Evren Ozkaya, Ph.D., is founder and CEO, Supply Chain Wizard, LLC.

Digital factory transformation beyond serialization compliance

 Fig. 1. A part of the traceability problem under current DSCSA guidance: how does a hospital pharmacy (at the far right) know to connect with the manufacturer at the far left to verify a pharma package’s serial number? Credit: C4SCS[/caption]

Not withstanding FDA’s June 30 announcement

 that it was delaying enforcement of the Drug Supply Chain Security Act’s next phase by one year (November 2017 to November 2018), the global pharma industry will have invested several billion dollars in hardware and software to comply with that law and related efforts to secure the pharma supply chain around the world. And while other countries have their own pathway toward providing traceability of pharma shipments, the US’ effort has a small problem: as written, no one knows how the law will work effectively by 2023 when all of its components are to be in place. Oops!

To be sure, there are many, many details keeping IT managers, packaging engineers and logistics specialists up at night, brainstorming ways to address knotty issues like aggregation (the need to identify what serialized numbers are within a carton of many packages of serialized product), product returns (which need to be re-verified before being re-entered into trade) and the millisecond-level response time a traceability system will call for. Smart, collaborative efforts going on now will address many of these details. But the bigger problem (see box) is: how to determine the chain of custody of a pharma package that might show up on a pharmacy shelf, when no one authority or source has all the information about the product transfers that brought the package to the shelf? (Fig. 1) In other words, how to verify the integrity and authenticity of an individual pharma package—which is the original goal of the entire DSCSA framework?

Enter the blockchain topic. By essentially making the storage of transaction data (such as the sale of a pharmaceutical product from a manufacturer to a wholesaler) a secure, unalterable yet sharable message, blockchain has the potential to streamline the data-storage and -access problem. It also has the potential to make this data process relatively inexpensive to set up (cloud-based data storage being one of the main operating expenses). But the technology is relatively unproven in commercial transactions, and executives involved with current DSCSA implementation difficulties will be loath to take on yet more burdens. However, blockchain is advancing fairly rapidly; developers are attracting venture capital, and it’s conceivable that the technology could be ready to use by the time the 2023 DSCSA deadline arrives.

Blockchain has major developmental commitments at IT systems houses such as IBM, Unisys, Deloitte, Accenture and others. In March, two San Francisco, CA companies—a blockchain startup called Chronicled, and a pharma supply-chain consultancy, the LinkLab, announced a DSCSA-oriented pilot program (they say they have the support of a major pharma company). iSolve, an East Norriton, PA consultancy, is exploring blockchain applications in various life sciences tasks, including supply chain traceability. Rubix, a Toronto, Canada blockchain development company supported by Deloitte, is exploring a variety of supply-chain-related applications.

A number of these efforts come together at the Center for Supply Chain Studies (C4SCS), a nonprofit group set up by Robert Celeste, a former executive with the GS1 organization (GS1 has a number of standards specific to healthcare data tracking, notably the EPCIS standard, which is fundamental to DSCSA compliance.) C4SCS is currently running a workgroup that meets monthly to explore blockchain applications to DSCSA compliance.

The vendors of DSCSA-enabling software currently being installed at pharma companies and their trading partners appear to be keeping a wait-and-see attitude toward blockchain. One exception is TraceLink, the industry leader in DSCSA compliance implementations, which is a member of C4SCS, and recently announced a service to help its customers transfer compliance data among themselves (the catch here is that at least one of the parties needs to be a TraceLink client, so non-TraceLink transactions will remain outside its system).

The comparison has been frequently made that blockchain technology today is very much like the internet was 

 1990: Something important was going on, led by a disorganized mass of self-proclaimed experts; substantially different methods to effect communication were competing for attention and market share; and there was enormous potential but no clear way of achieving it.

Most people associate blockchain with what they’ve heard about bitcoin—a nongovernmental currency that somehow retains value simply because the people using it (or having it) agree on that value. Bitcoin’s driving force as external to government also gives blockchain an outlaw air, which doesn’t help matters. But the reality is that there is much more to blockchain than bitcoin and that problems of verifying transactions of many types besides bitcoin “cryptocurrency” are attracting intense interest from IT developers. In this broader context, the “blockchain” concept itself is losing out to “distributed ledger” technology (iSolve, for one, prefers to speak about “advanced digital ledger technology,” or ADLT, rather than blockchain.)

A distributed ledger is simply a list of records (such as transactions) that is stored on multiple, separate IT systems in a network. Each new record—and each query or interaction with a record—becomes a recordable event itself in the ledger. When this is combined with powerful identity management tools (which can either be a distributed-ledger process itself, or some variation of identity-security methods) a “non-repudiatable” record is created, and thus, trust between two parties to

Another cross-cutting concept in distributed ledgers is the “smart contract”—a set of code that automatically takes an action (such as authorizing a payment) when preprogrammed steps have been followed. In theory, a smart contract could become the equivalent of the Transaction History (TH) document specified by DSCSA—the set of records that establishes that Party A sold Product X to Party B, with the identity of the two parties and the product verified (i.e., is non-repudiatable).

An example of how far blockchain or distributed-ledger technology has to go is that the concept of a smart contract, as opposed to a piece of paper with two signatures on it, is yet to be accepted in courts of law or international trade agreements.

Like the early days of the internet, when IT developers were grappling with Ethernet, the TCP/IP protocol, the World Wide Web and other concepts, today’s blockchain developers have created a growing list of data-exchange platforms or protocols (or protocols that are platforms). Ethereum, a relatively new cryptocurrency platform, is being promoted by, among others, IBM and Microsoft. Others include such systems as Blockstream, Everledger, Bloq, Fabric, Lightning Network—the list is long and growing. A parallel effort has been going on to establish a reliable identity-management protocol; in this context, the efforts of the SAFE-Biopharma organization is notable, since its processes are tailored to the needs of the life sciences industries.

Another foundational component of blockchain networks is how they are administered—who makes and enforces rules about members and permissible actions within the network? Some platforms are designed intentionally so that no one is the administrator—the system itself ensures that all parties are legitimate and carrying out legitimate activities. Others call for a centralized administrative function. These concepts, in turn, define a “public” blockchain network—where anyone can participate—from a private network, where only trusted parties can engage.

The DSCSA compliance endpoint, for all this technology, is a system where each sale of a specific package of pharmaceuticals can be traced back to the point of origin, and each party involved in the chain of custody is verified. It is possible to limit how much data is exposed during a track-and-trace process by limits imposed either by the network itself or by specific trading partners (for example, no one is interested in sharing the price information of a transaction)—but the details of this remain to be worked out.

Bob Celeste at C4SCS has identified five obstacles to implementing blockchain for DSCSA today:

connection between non-adjacent trading partners, i.e., a connection between, say, a wholesaler who bought product from a manufacturer directly, then sold it to a second wholesaler. The second wholesaler is “non-adjacent” to the manufacturer.

between these trading partners, that is, to verify the identity of the parties.

 without inadvertently exposing proprietary information.

 activity required of trading partners—for example, attempting to manually account for the transaction records of a returned product.

C4SCS has created a simulator to run analyses of blockchain-based supply-chain activities, such as handling a product return, or matching a product’s transaction with discounts such as copay cards. There can be various ways to record and share the information, with pluses and minuses for each setup.

 Fig. 2. Various data-communication methods have limitations to meet expected DSCSA requirements. Key: Dark green—sufficient; light green—some limitations; red—fails. Credit: J. Stollman[/caption]

At a June meeting organized by the IEEE Society (which could have a hand in creating an industry standard for blockchain, as it has for a wide variety of electronic or digital technologies), Jeff Stollman, an industry consultant, assessed the potential advantages and disadvantages of current concepts for DSCSA traceability. (Fig. 2) The simplest, a conventional relational database managed by each manufacturer for its products, falls down because each database owner is responsible for the accuracy, reliability and security of its own database.

The “breadcrumb” approach—where transaction records are shared between each pair of trading partners (“one up and one down”) but no one else—is appealing for its practicality, but falls down on many aspects of data security, and is probably more costly if implemented, since each trading partner must maintain its own database and data-access system. A public blockchain has problems with access security. A private blockchain, which Stollman specifies as having decentralized administration, has questionable access and confidentiality issues, while only a closed blockchain, distinguished by having centralized control, meets all the potential criteria he has called out.

There is both a potential downside to current plans for DSCSA compliance (which are basically to have individual databases and let FDA, or other regulator, figure out how to access information when an investigation needs to occur), and a potential upside to use of blockchain technology, says Stollman. “The discovery of ‘suspect’ product will occur only when there is a public health crisis. The likelihood that the thousands of repositories holding each firm’s data in its own silo will all be available and operationally compatible when a crisis does arise is statistically unlikely.” On the other hand, “The potential offered by blockchain is to proactively discover suspect product in the supply chain before a bad drug gets into the hands of the public and creates a public health crisis. The technology is available to do this.” However, there are “significant” governance issues to be resolved over how the blockchain would be managed.

 Fig. 3. As blockchain technology is generally understood, it is well suited to meeting

 operational requirements of DSCSA compliance. Credit: Prof. Tim Mackey, UC San Diego[/caption]

Getting a handle on those governance issues is a large part of what Celeste’s Center for Supply Chain Studies is focused on, at least when it comes to blockchain. Celeste says that the simulation software the group uses has been set up with the typical parameters of various trading partners in the supply chain—manufacturer, wholesaler, retailer and the like—and then scenarios can be played out based on various criteria, such as the appearance of an unaccounted-for serial number in the supply chain, or a product recall with expired product.

“The concept of ‘smart contracts,’ which is built into the Ethereum platform, looks promising,” he says, based on the fact that the code could be set up to answer a product-authentication question (does this serial number exist?) without necessarily revealing every piece of information about the serial number. And it can be done very quickly—valuable in a scenario, for example, where a wholesaler is trying to verify returned product that is still saleable.

Celeste’s work group has attracted a cross-section of industry players—and that has value all by itself since each player has a different perspective on needs and capabilities. Participants include Pfizer and Merck, Cardinal Health and AmerisourceBergen, the Geisinger health system, the Healthcare Distribution Alliance, Rx-360 (an industry consortium), and industry software developers iSolve, TraceLink, Unisys and Verify Brand. Mention of longtime traceability vendors like TraceLink and Verify Brand brings up the interesting question whether blockchain will replace part of what these vendors have been doing—creating the mechanism by which stored data can be made available to trading partners. (Fig. 3) The consensus, at the moment, is that blockchain technology is complementary and not competitive to the software that collects serial numbers from packaging lines and stores them.

At iSolve, CEO Gordon Tampol emphasizes that his company provides blockchain consulting services and code that “sits on top of” a blockchain platform (such as Ethereum or HyperLedger), and is therefore platform-agnostic. The company is working on multiple blockchain applications besides DSCSA compliance, but for that application in particular, it is preparing to launch a pilot, using its distributed-ledger software (which has been branded as Advanced Digital Ledger Technology, or ADLT) and—hold your breath—a cryptocurrency it is branding as PharmaCoin. (Side note: it has become common, among blockchain startups, to hold an “initial coin offering,” or ICO, rather than the conventional IPO of startups. Investors pay dollars for coin, and then the coin becomes the medium of transactions within the network, with participants earning coins by virtue of hosting data or providing network support. If the network proves useful, the coin will rise in value, benefitting the initial investors and creating a way for new participants to join in.)

“Given that we did not see the industry coming together around a single solution, we implemented a revenue model using the ADLT PharmaCoin as a way to offset the implementation cost and to incentivize trade partners for data acquisition or providing consensus,” says Tampol. “To ensure a more predictable cost to the life sciences and healthcare industries, we will alter the transaction cost to place/retrieve information from the Blockchain to account for external market forces.”

Efforts like C4SCS, iSolve and the other developers in this field have a ways to go before there will be an industry consensus around addressing DSCSA compliance; most industry observers feel that it’s still early days for commercial application. On the other hand, the energy around blockchain in other industries, such as financial services and banking, is truly intense. It could be that, by 2023, enough commercial activity will have occurred that a transition to a blockchain-enabled traceability network will become a matter of course.

The 2023 DSCSA all-digital transaction statement mandates the following of manufacturers and their trading partners, who shall have:

The systems and processes necessary to promptly facilitate gathering the information necessary to produce the transaction information for each transaction going back to the manufacturer, as applicable, shall be required—

(i) in the event of a request by the Secretary (or other appropriate Federal or State official), on account of a recall or for the purposes of investigating a suspect product or an illegitimate product; or

(ii) in the event of a request by an authorized trading partner, in a secure manner that ensures the protection of confidential commercial information and trade secrets, for purposes of investigating a suspect product or assisting the Secretary (or other appropriate Federal or State official) with a request described in clause (i)

Industry experts are grappling with the eventual requirement to provide accurate supply-chain traceability

Blockchain: the technology to make DSCSA work after 2023?

 of AmerisourceBergen, is adding Physician Office Drug Inventory System (Podis), a provider of cloud-based inventory and billing reconciliation. Purchase price was not disclosed.

The Podis system uses barcoding to track inventory, and provides an “integrated order-to-reimbursement” capability to physician offices. Product enhancements are planned. Besse Medical will continue to offer and invest in its CubixxMD product, a cloud-based solution that allows practices to manage inventory from multiple locations including desktop computers, mobile devices or medical-grade, RFID-enable

Besse Medical acquires Podis

growing business as a third-party logistics provider (3PL) for pharma manufacturers, operating out of an expanded distribution center in Boca Raton, FL. Now, in what it says is a first for the pharma industry, the facility can also provide serialization services to meet the November 2017 deadline for compliance with the Drug Supply Chain Security Act (DSCSA), which, among many other things, requires a unique serial code on each package of commercially distributed product after that date. While most major manufacturers are well along with their serialization programs, smaller manufacturers with either a limited number of products, or a product volume too small to economically justify installing a DSCSA-compliant packaging line, now have another option.

Many of these smaller manufacturers typically work with a contract manufacturing organization (CMO) to handle packaging and serialization, but that can present operational problems, says Larry Hotz, marketing manager at Woodfield. “The brand owner is ultimately responsible for the disposition of the serial codes, and to convey those codes to trading partners,” he says. “Unless the CMO and brand owner have worked this out carefully, DSCSA compliance will be a multistep, overly complicated process.” Hotz says that Woodfield has chosen TraceLink as its serialization-management solution, and will set up a cloud-based data repository under the control of the brand owner. In effect, Woodfield is not only providing serialization, but also managing the trading-partner data transfers that will be part of later DSCSA compliance requirements.

Woodfield Distribution has a sister company, Woodfield Pharmaceutical, that is a full-blown CMO, and has an installed serialization system in place. That CMO competes with many other CMOs in providing packaging and serialization services; the company can package plastic and glass bottles; nasal spray devices and tubes; and provide secondary cartoning, tray and shrink-wrap packaging. By incorporating a serialization service in the 3PL part of the company, Woodfield hopes to provide a more flexible option for its distribution clients. Most of Woodfield’s current business is in US 3PL services, but Hotz says that the company is looking ahead to providing its service to exporters from the US as well.

More serialization options, especially for low-volume pharma manufacturers struggling with the November 2017 deadline

Woodfield Distribution offers 3PL-based DSCSA compliance services

 in which DHL has opened what it calls its Life Sciences Centers of Excellence, essentially warehousing and logistics facilities, along with the necessary training and documentation of good distribution practices (GDPs) for handling pharmaceutical shipments. The all-new facility has 3,700 sq. m. (40,000 sq. ft.) of capacity, segregated into different temperature regimes: ambient (15–25°); chilled (2–8°) and a blast & holding freezer capable of temperatures of -20°C. Service capabilities include storage, pick & pack, and inventory control. Plans are in place to extend the service across the temperature regimes and provide value-added repack and postponement services. The new DHL logistics center is expected to create up to 50 jobs over the coming months. Through its proximity to the Dublin Airport, it will have “full access and integration with DHL’s temperature-controlled transport services by Road, Air, Ocean and Express,” according to the company.

40,000-sq. ft. facility is near Dublin Airport

DHL opens a cold-chain center of excellence in Ireland

Biologics (including biosimilars), vaccines, and gene therapy

 scale-up and manufacturing processes will be the goals of the BioTherapeutics Pharmaceutical Sciences facility, with groundbreaking having occurred at a location in Chesterfield, MO. The 295,000-sq. ft. facility will include state-of-the-art analytical capabilities, says the company; therapeutic targets include oncology, rare diseases, internal medicine, inflammation and immunology.

While far from the biotech centers on the US coasts, Pfizer notes that it has a 15-year history of working in the St. Louis, MO area. About 450 Pfizer employees working in various locations in the area will come together at the new site, and an additional 80 are expected to be hired “in coming years.”

The capital investment figure was not included in the news release; however, Pfizer noted that as part of a “strategic incentives” program of financial support from the state and St. Louis County, Pfizer is donating $20,000 to a local school district.

Construction starts on a Pfizer biopharma plant near St. Louis

While R&D scientists and medical researchers are blazing new trails into areas like cellular therapy and genomics, the folks managing life sciences and healthcare supply chains are dealing with their own revolutions in patient care, new forms of drug delivery and new regulatory systems. Some of this thinking shows up in a new report from DHL, whose Life Sciences and Healthcare unit is the leading provider of global logistics services to the sector. There are six trends it highlights, and while the data behind the trend reporting is somewhat subjective, these trends should give pharma supply chain managers some guidance on what to expect from their logistics functions. The six are:

By linking patient data across a spectrum of services, healthcare providers will be better able to predict demand and manage inventories. Big data tools are also helping to de-risk logistics processes.

Increasing visibility through connectivity (Internet of Things).

 IoT technology is impacting materials management within health systems, and to monitor pharma shipments in transit and either respond to temperature and other environmental factors, or to minimize the introduction of counterfeit products.

Healthcare on demand (On-Demand Delivery).

 “On demand,” by DHL’s thinking, includes the trend toward home-based patient care, with online pharmacies, point-of-care diagnostics and remote monitoring impacting healthcare delivery.

Automating for speed and accuracy (Robotics and Automation). 

One effect of better and cheaper robotics is their increased use in logistics processes, such as packing shipments or managing warehouse inventories. DHL itself is investing in robotics at a variety of locations; in one intriguing instance, a robot handles a packaging and labeling function for tailoring injection pens to local markets, where demand is unpredictable. The result: lower inventories throughout the supply chain, and better demand management.

Increasing efficiency with Augmented Reality.

 Another technology that, for DHL, could impact warehouse operations: DHL is experimenting with using augmented reality (data viewed through a small screen) to improve pick-and-pack operations.

Additive manufacturing scored one key breakthrough in 2016 when a 3D-printed drug was approved by FDA. In the near future, additive manufacturing will streamline production and inventory of medical devices (constructed to meet ongoing demand); it could also impact traditional batch manufacturing of pharma products.

In announcing the report, Scott Allison, president, life sciences and healthcare, DHL Customer Solutions & Innovation, said, “We are only just beginning to understand the huge changes the Life Sciences sector is facing in terms of how patients are diagnosed and treated, what new care challenges it faces, and the technology-driven tools to address them. DHL’s new report focuses on the transformation in the way medical products and services are produced, distributed and consumed. It is clear that logistic providers have a key role to play in this transformation to deliver healthcare to the world with cost-effective, agile and highly responsive supply chains.”

 The Future of Life Sciences and Healthcare Logistics

New DHL report sees transformational trends

Looking ahead in life sciences and healthcare logistics

There is true excitement in the rapid pace of advances in cellular and genetic therapies—Kite Pharma, for example, one of the leaders in developing this science, has gone from concept to Phase III trials in 27 months, and an FDA approval is possible this year for one of its products. Dozens of other companies are pursuing targets in immuno-oncology, autoimmune disorders and a variety of rare diseases. Still with the wind at their back are a variety of stem cell therapies that continue to advance.

While all of this is generating high enthusiasm in R&D circles, logistics service providers are scrambling to revise their processes to meet the new demands of these therapies. A “new paradigm” is evolving, in the words of Bruce McCormick, president of Savsu, a logistics equipment and services provider, replacing what he calls “cold chain 1.0,” the traditional practices associated with shipping refrigerated (2–8°C) products.

This new paradigm is driven by two radical changes:

The prevalence of cryogenic temperatures to ship and store living cells

The need to make cell collection (often from individual patients) part of the drug-approval process, which in turn taxes parts of the healthcare system—hospitals, blood collection networks, infusion centers—with GMP responsibilities that are new to them.

A third factor—not unique to subzero pharma logistics, but arguably more consequential—is that there is no turning back once a frozen cell or biospecimen has improperly thawed. A point of reference: in April, Arctic ice cores stored at the University of Alberta thawed due to a freezer malfunction, ruining some part of the specimens representing millions of dollars of work and constituting an invaluable record of climatic history. More to the point: in 2012, 150 autopsied brains of autism patients stored at a Harvard biorepository thawed and were ruined; the director called the collection “priceless.” Potentially, a process upset like these at any point in cells going to or from patients undergoing cellular therapy could be a last chance at life.

“A reliable cell therapy development strategy is imperative to ensuring [the industry’s] biopharmaceutical products, therapeutic materials and patient biological samples remain viable from the point of collection to the final clinical site delivery,” reads a statement from Fisher BioServices, one of a number of service organizations preparing for the new technology.

It’s not industry vendors alone who are paying attention to the growing challenges. In Europe, the European Medicines Agency is struggling to develop a tailored regulatory system for what it calls “advanced therapy medicinal products” (ATMPs). There is pushback from the PIC/S organization, a non-governmental body focused on GMP policies and practices; it sees problems in a potential “loss of harmonization” between the conventional GMP policies it follows, and new ATMP regulatory scheme.

A research-oriented EU project is CARAT—Chimeric Antigen Receptors (CARs) for Advanced Therapies, which kicked off in January 2016 with a goal of integrating “novel cell manufacturing tools and enabling technologies into a new, comprehensive platform that will facilitate the safe, automated and cost-efficient manufacture” of CAR-T cells. The project has €6 million in EU funding, will last until 2020, and is being project-managed by Miltenyi Biotec (Bergisch Gladbach, Germany).

 Fig. 3. Logistics-specific elements of the NCMC roadmap, and their developmental timelines. Credit: NCMC[/caption]

In the US, besides ongoing efforts at FDA Office of Cellular, Tissue and Gene Therapy within the Center for Biologics Evaluation and Research, a collaboration between the Georgia Institute of Technology and the Georgia Research Alliance, with support from the National Institute of Standards and Technology (NIST) has established a National Cell Manufacturing Consortium (NCMC). NCMC, in turn, has published “A Technology Roadmap to 2025,” to define manufacturing and supply chain needs. (Fig. 3) NCMC has a distinctly American slant: “The cell manufacturing community can facilitate the advancement and market penetration of next-generation cell-based medical products, and support the long-term growth and global competitiveness of the US cell manufacturing industry.”

In a like manner, the UK government, through its Innovate UK program, has supported the creation of a center of excellence, the Cell and Gene Therapy Catapult. Interestingly, it is headquartered inside a London, England hospital; there is also a manufacturing center currently under construction in Stevenage, just north of London. Its vision “is for the UK to be a global leader in the development, delivery and commercialization of cell and gene therapy.” In March, Fisher BioServices announced that it would locate units of its CryoHub setup there. CryoHub is a combination of storage and logistics handling systems, modularized so that it can be expanded from clinical through to commercial operations.

Meanwhile, the field is getting another momentum boost from a handful of IT vendors, such as the UK’s TrakCel and a GE-Mayo Clinic partnership, Vineti, both of whom are offering IT platforms not only to manage logistics processes, but also the internal manufacturing steps (customized to manufacturer requirements), and even the reimbursement and patient follow-up steps desirable for commercial viability of the technology.

Cryogenic (technically, under -180°C; we’ll use “subzero” to cover the entire range) processing is not new to pharma research labs and some healthcare processes: Biorepositories have been using liquid nitrogen (LN2, at -179°C) for decades, and there are various low-temperature refrigeration processes and equipment for subzero storage and shipping. Companies like Fisher BioServices, Chart Industries, Taylor-Wharton (now part of Worthington Industries) and Brooks Instrument, have been providing dewars (generally, a metal, double-walled container), freezers and related equipment for many years, used in biobanks, at in-vitro fertilization clinics and in research labs. (There is also a substantial industry around cryogenic air separation, liquefied natural gas, and cryogenic application in aerospace and electronics). Thermo Scientific, Panasonic and others sell mechanical refrigerator/freezers, which can reach temperatures as low as -86°C. When products or research materials need to be transported, a dewar containing liquid nitrogen or dry ice is customary.

Those dewars present two problems for routine, commercial-scale distribution of cellular therapy products: they can be big and bulky (the transportable units are generally more than 50 lbs.); and they are prone to tipping over, which can cause LN2 vapor to leak out more rapidly, cutting into the stable temperature range of the device. Savsu, which has been providing reusable containers for 2–8°C shipping for years, is addressing both of these concerns with the just-introduced “evo DV” line (Fig. 2), which has redesigned dewars equipped with what it calls a Smart Cap top (to make the device relatively immune to tipping complications), and in a range of sizes that are manageable. “If you think about a cellular therapy provided to a patient at a hospital, you need to consider where and how the drug is going to be warmed prior to administration,” notes Savsu’s McCormick. “If it’s at bedside, you’d need a forklift to deliver a conventional dewar and that’s not going to happen.”

Another logistics problem with conventional dewars is that it takes upwards of 24 hours to load them with LN2 and stabilize the container’s temperature. The DV device is said to cut this to less than an hour. The unit can be specified for -196, -80, and 2–8°C operating temperatures.

Another player that has targeted cellular therapies specifically is Cryoport, which has offered a tailored LN2 shipping container for a number of years. The company has expanded its offerings to include the SmartPak II condition-monitoring system. Smartpak starts with a communications-enabled (Wi-Fi or cellular) datalogger, which transmits data through the Cryoportal, a website where Cryoport or its clients can monitor a shipment. Cryoport works with a variety of carriers, but also has arrangements at multiple airports to replenish LN2 if necessary, with dedicated depots at Rotterdam, Singapore and Irvine, CA, its headquarters.

Mark Sawicki, chief commercial officer at the company, says that a number of clients are now requesting Cryoport to collocate a shipping center at their sites; the service would entail preparing containers for shipment, packaging the product and managing the logistics processes to ensure safe delivery. He also touts the company’s customized shipping containers: “In some cases, we take a commercial package and make as many as 50 modifications to it, providing better locking mechanisms, our datalogging and condition-monitoring technology, and other improvements,”

The company’s most recent announcement is CryoStork Next Flight Out, a branded service specifically for IVF centers (Cryoport says that as many as 400 IVF clinics make use of Cryoport services). CryoStork will handle sperm, eggs, embryos and reproductive health tissues, according to the company, with global delivery.

Another service, about to be announced, expands Cryoport’s offerings to the 2–8°C refrigerative world. Sawicki says that it is typical, in applications such as CAR-T therapy with autologous T-cells from individual patients, to collect the T-cells via apheresis, and to ship that blood component under 2–8°C conditions. The return trip of the treated cells is performed cryogenically. “Adding the 2–8°C service enables us to provide a closed-loop service to clients,” he says. Cryoport has partnered with Pelican BioThermal to make use of the latter’s Credo line of cold-chain containers, which feature vacuum insulated panels and specialized gels as a source of cold.

Pelican BioThermal has developed a range of phase-change materials (PCMs) that can be effective in ranges as low as -40C. There are products, such as vials with rubber stoppers, that need to be kept within a lower and upper limit, even in the subzero range; Pelican’s PCM expertise enables them to meet this need. The main goal is to sidestep the use of dry ice, which has limitations in air freight (since it’s regulated as a “dangerous good”). Bill Mayer, director of research there, also makes the point that better insulation (such as the vacuum panels that Pelican uses) can also make PCMs viable in subzero regimes relative to dry ice.

Sawicki and others in the field point out the extraordinary demands cellular and related therapies put on traditional pharma logistics practices. Autologous therapies (using the patient’s own cells) must, of course, be tracked precisely to and from the patient; on the other hand, allogeneic therapies (which includes a number of stem cell approaches) are a “one to many” process where one source of cells might treat multiple patients—but the same tracking details need to be preserved. Some proposed cancer treatments require both the patient’s T-cells and biopsied tumor tissue. A further complication is that the re-infusion of the cells in the patient is dependent, in part, on the health and well-being of the patient; while the extraction and initial processing might proceed rapidly, once the treated cells are cryogenically stored, the re-infusion can be scheduled at an appropriate time.

There is considerable variation in the sub-zero temperatures called for in clinical protocols: -40, -60, -79 (the transition point of dry ice) and -196° all show up in cellular therapy literature. Much of this appears to come simply from traditional lab practices to the preferred, modern modality—LN2 at -196°C, where nearly all cellular activity ceases. Most logistics processes depend on maintaining one set of standard conditions; the variety of temperatures involved here is one of the reasons that specialized life sciences logistics services are desirable.

“There’s considerable debate about suitable temperature ranges,” says Savsu’s McCormick. “A big part of this is the transition from clinical practices to commercial-level activity,” he says.

Cryogenic freezing and thawing are performed gradually to prevent shocks to the living cells; but whether slow or fast, cryogenics usually calls for use of a cryopreservative to minimize freeze-thaw damage. BioLife Solutions is one company that has taken a proprietary position on cryopreservation, with two products, CryoStor (for the -70 to -196°C regime) and HypoThermosol (for 2–8°C). The products contain (among other components, some of which are trade secrets) dimethyl sulfoxide (DMSO), which has been a common cryopreservation agent for many years. Many researchers have “home brew” preservatives with little in the way of rigorous analysis or consistency—problems that BioLife is seeking to address with its products.

“Cryopreservatives minimize damage from ice crystals forming during the freezing phase; when these cells are thawed, they have near immediate need for pH buffering, free radical scavenging and providing a source of energy for the cells,” explains Mike Rice, CEO of BioLife. BioLife’s products are regulated essentially as excipients, he says; and because they have been written into more than 100 clinical protocols they could eventually become part of formal drug applications. From that, BioLife expects to generate revenue as it supplies the preservatives as essential ingredients.

Rice says that cell viability, a critical measure of a therapy’s potential efficacy, varies all over the lot in clinical trials being conducted currently; a rough measure is that 20–50% of cells lose viability during freeze-thaw transitions. Using cryopreservatives like BioLife’s can cut that to below 20%.

BioLife and Savsu formed a joint venture in 2015, biologistex, to handle the courier-based or freight-forwarding operations of their clients. The service makes use of Savsu’s evo Cold Chain 2.0 platform for data collection, monitoring and quality control.

Arguably, the clearest indication of how different cellular therapies are shaping up, relative to conventional drug development, is that there wasn’t a ready-made IT platform to manage production and distribution processes. Researchers are accustomed to working with clinical trial management systems (CTMS) and laboratory information management systems (LIMS); plant managers have used manufacturing execution systems (MES) or extensions of enterprise resource planning (ERP) for years. But the scope of cellular therapy, involving steps at a healthcare facility (apheresis or other cell extraction), advanced genetic manipulation of cells (and cell proliferation), re-infusion, and all the logistical steps in between, don’t fit any of these IT platforms. Business managers looking at eventual commercialization have realized that the need for monitoring outcomes of individual patients—and how that could become an integral part of a value-based reimbursement for the therapy—should also be digitized.

TrakCel, which has been operating since 2012, has coined the term “Cellular Orchestration Platform” (COP) to characterize this broad foundation. “There are many stakeholders to bring together in a cellular therapy project; and some of those stakeholders follow lab-based protocols, others, good manufacturing practices (GMPs), and yet others in health-related procedures,” notes Martin Lamb, EVP at the Cardiff, Wales firm. “All of this has to come together in a tight scheduling framework.”

TrakCel’s product is cloud-based, and while it encompasses a variety of specific functions (such as data collection during logistics processes), it is also built with interfaces to enable data transfer from lab, manufacturing and other IT systems. For a client, the company maps out a customized flowchart of necessary processes, combined with the necessary interfaces. Some risk-based contingency planning is also enabled; for example, a patient might require preparatory treatments before a cell-extraction process is carried out; ensuring that these steps are carried out is accounted for in the system.

TrakCel looks like it’s about to get some head-to-head competition from a joint venture between General Electric Healthcare and the Mayo Clinic, Vineti (which changed its name from Vitruvian at the beginning of the year). Like TrakCel’s approach, Vineti also encompasses healthcare-facility steps, manufacturing and reimbursement (see Fig. 4). In some yet-to-be-determined fashion, Vineti will also tap into GE’s storehouse of manufacturing knowledge, as well as resources tied to other parts of GE Healthcare, and Mayo Clinic’s experience in biomarker development, cell therapy processes and outcomes.

Cellular and genetic therapies drive a ‘new paradigm’ for logistics

Pharma’s cold chain is going below zero

 the healthcare ecosystem, pharmaceutical organizations find themselves in the unique position of balancing volume and value. The era of massive blockbuster drugs has now faded away and most pharma companies are endeavoring to engage smaller pools of high-value patients. This shift comes at a time when the healthcare industry has begun a steady transition to value-based care. The pursuit of better outcomes at lower costs implies the need for certain efficiencies in the care delivery system: where unnecessary tests and trial-and-error treatments are reduced to a minimum, if not eliminated. Enter precision medicine, with companies like Prognos utilizing specific lab test results to more effectively identify and help treat patients at the earliest opportunity.

Pharma has traditionally focused on large-volume patient pools with chronic conditions as a focal point for many of their programs. Pivoting to diverse initiatives focused on rare and niche diseases requires a different approach. Patients with these diseases have an atypical patient journey, which starts with symptoms and, in many cases, biomarker testing to determine a correct diagnosis and subsequent treatment regimen.

In the aftermath of the Affordable Care Act, a larger portion of household budgets now goes toward healthcare-related expenses. Growing premiums, higher deductibles and skyrocketing care costs cause consumers to take a more active part in their treatment decisions. These decisions, such as testing regimens, treatments and ongoing adherence, have traditionally been unilaterally made by medical professionals. This phenomenon is referred to as “patient as payer,” implying that the patient is making the ultimate treatment decision, not the physician or the insurance company.

This trend doesn’t eliminate the need for a competent physician. Providers are encouraged to become highly attuned to the specific needs of individual patients as the value-based care payment model ties their incomes directly to patient outcomes. Physicians are incentivized to help patients get tested appropriately for both new conditions and ongoing treatment regimens. A key success factor in the new outcomes-based world is the timeliness of diagnosis, particularly in the case of malignancies or rare diseases that may go unidentified for years.

Many drug brands have recognized this shift and are adapting their business models to suit the new environment. An average company’s focus on understanding the complete patient journey has evolved to entertain pre-symptomatic, symptomatic and diagnosis stages, as well as post-treatment issues like persistence and compliance. This expanded focus requires a deep understanding of both testing patterns and diagnosis decisions in early stages, as well as monitoring biomarkers and access to medicines in later stages. Biomarker test results are among a group of triggers for determining a treatment regimen early in a patient’s journey, and biomarker monitoring can help identify patients who are not getting optimal care and aid them in selecting the next line of therapy.

This more comprehensive approach to the patient presents a perfect opportunity for pharmaceutical organizations to proactively educate healthcare professionals on the benefits of their therapies at the right time: either earlier in the process before a patient receives a first-line therapy or when a first-line therapy fails to meet the patient’s need and a subsequent second-line therapy is evaluated.

At Prognos, for example, we have partnered with more than 200 labs to build the largest repository of diagnostics results. These results are captured in real-time: we receive them at the same time that the ordering physician does. The timing and periodicity of these data empower brands to engage healthcare professionals before treatment decisions are made, so that physicians are armed with the best knowledge to prescribe. We leverage healthcare AI, which uses techniques like machine learning and natural language processing on reams of clinical diagnostic data to determine specific and complex patient journeys. AI empowers us to “see” what patient trajectories look like and compare them to historical data to predict where these patients are in their disease progression.

The result of these technological advances enables pharmaceutical firms to find providers with patients who may benefit from a specific therapy or need an alternative or additional therapy earlier in the care process—before treatment decisions are made. Earlier diagnosis and treatment, in many cases, prolong life and improve outcomes for patients. We believe that early identification holds the potential to flatten the disease curve and decrease other unnecessary spending as a result of misdiagnosis or treatment. This is an exciting opportunity to be a part of the rapidly changing healthcare environment and to help pharma brands eradicate disease.

Artificial intelligence’s value in influencing treatment decisions

customers—payers, PBM managers and others—remains the No. 1 priority of Pricing and Contract Management leaders, according to 

Future Issues in Contract Management: 2016–2019

, a landscape study conducted by TGaS Advisors. Calls for outcomes-based or risk-based contracting was the No. 2 priority. Changing legislation, access restrictions, new types of customers and calls for pricing transparency are among other high-level concerns.

By comparison, the top issue two years ago was “maintaining optimal/profitable access,” which indicates that the pendulum has swung to a point where manufacturers have much less leverage now with payers than in the past. This is primarily because manufacturers are still in the process of figuring out how to address the multiple demands. A second priority from two years ago was “increasing analytical capabilities.”

The landscape analysis is based on data and information from interviews with 17 leaders of PCM organizations. They report taking a number of key steps to address these priorities. After customer demands, the most critical action items for the next few years include (in order of number of mentions):

 legislative developments; monitoring market changes; and attending training, seminars, webinars and conferences

 and exploring innovating contracting offerings (outcomes-based or risk-based contracting)

Integrating pricing and contracting strategies

 to create alignment; working with internal stakeholders to assess pricing change impact and transparency

(both pre-deal and post-deal) to assess the marketplace and target/segment customers

by exploring outsourcing or alternative resourcing models to handle increases in contract volume and complexity

with account teams and internal stakeholders to help them understand the marketplace

Regarding outsourcing, a recent TGaS study indicates that 16 of 25 responding companies (large-, mid-tier and small) have outsourced at least one contracting function. The most common include data validation, rebate processing, chargeback processing, coverage gap/donut hole processing and Medicaid rebate processing. The pre-signature contract functions of pricing/contract strategy and proposal development, however, are rarely outsourced.

Respondents to the landscape analysis were asked to force-rank 15 pre-determined internal PCM functions in terms of their importance. The top seven include 1) creating innovative contracting strategies; 2) preparing for product launches; 3) ensuring compliance for government price (GP) calculations and reporting; 4) upgrading current systems; 5) successfully completing required audits and SOP creation; 6) reducing revenue leakage; and 7) predicting contract value.

Pharmaceutical Commerce - July/August 2017

Pharmaceutical traceability stumbles ahead

Managing employee training at the enterprise level

Digital factory transformation beyond serialization compliance

Blockchain: the technology to make DSCSA work after 2023?

Besse Medical acquires Podis

Woodfield Distribution offers 3PL-based DSCSA compliance services

DHL opens a cold-chain center of excellence in Ireland

Construction starts on a Pfizer biopharma plant near St. Louis

Looking ahead in life sciences and healthcare logistics

Pharma’s cold chain is going below zero

Artificial intelligence’s value in influencing treatment decisions

How Pricing & Contract Management looks—from the inside

A conversation with Bijay Singh, DKSH

Digital opinion leaders (DOLs) and their role in pharma markets

Walgreens-Rite Aid merger falls away, replaced by sale of some stores

URAC plans a specialty-pharmacy workshop in conjunction with the NASP annual meeting

HDA honors 2017 DIANA winners, Lifetime Achievement Nexus winner

EvaluatePharma’s look ahead: 2022 global pharma sales will hit $1.06 trillion

Arxium promotes a ‘Pharmacy 4.0’ perspective on automated compounding

At BIO, San Diego touts its genomics breadth

Woodfield Distribution offers 3PL-based DSCSA compliance services