Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	Alan Kennedy, executive director of TEAM UP, shared perspectives on Poseidon and ocean transport with 

: Why was Poseidon established and what do you hope to achieve with the program?

: Like-minded individuals at the 2017 European Temperature Controlled Logistics Conference agreed that, in order for any degree of wholesale, across-the-board improvement in the pharma-cold chain, there would need to [be] more alignment between supply-chain stakeholders. Poseidon’s model is built around some of the principles of supply-chain collaboration and integration that are being successfully applied in other industries. Instead of a supply chain, Poseidon is a supply network that involves all of the stakeholders that are responsible for transporting pharmaceutical products. Currently, 19 companies are involved in the Poseidon project, including eight pharmaceutical manufacturers.

	Driven by pharmaceutical companies, the program is designed so that each pharma firm and its shippers, logistics companies, and suppliers sit around the same table as equal partners. A network partner agreement governs the relationships between all these parties, and they work together as a single team with common goals, rules, and performance incentives.

	Poseidon is putting together an end-to-end integrated network for pharma logistics. We hope that the model will serve as a template for pharmaceutical companies in their quest for more efficient, more competitive, and more concerted supply chains that are fit for purpose in today’s rapidly changing environment.

: How are you connecting the many stakeholders who would be involved in ocean transport? 

: A cloud-based Poseidon Collaboration Hub enables members to communicate in real time or whenever needed. Stakeholders around the world facilitate network communications, exchange ideas, disseminate news, share information, access up-to-date documentation, and manage projects. The Hub is also used for non-transactional network communications, for meetings, and to store documentation.

: What types of technology (e.g., temperature and condition monitoring) are being refined for ocean transport, and how would they differ from solutions that were developed for air transport?

: The challenges of sea freight broadly mirror those of air, although some of the protection and monitoring equipment had to be adapted to the different time parameters and operating conditions. For example, one of our participants, DuPont, is currently exploring new cargo-cover materials for ocean freight use.

	One of the advantages of sea freight is that it offers better shipment visibility so that shippers can monitor the geographical position and physical condition of freight in real-time. At this point, Poseidon is only using Maersk ‘smart’ reefers and US-built Klinge ‘redundancy’ reefers.

	For air freight, the US Federal Communications Commission requires transmitting devices such as data-loggers to be auto-switched off during flight for safety reasons. Although the loggers continue to capture data during the flight, this information can only be retrieved later. As a result, there is reduced opportunity to receive alerts or to intervene quickly, to fix a problem that has been reported while it is happening, such as an unexpected temperature excursion that might compromise product quality.

: Are insurance costs more of an issue for sea than air freight?

: Ocean transport insurance can sometimes be perceived as a black hole by shippers, who are often more comfortable with the comprehensible and comprehensive insurance provisions associated with air freight.  Shipping lines, for instance, tend to apply inconsistent liability limits, which, in any case, are invariably much lower than the typical value of a full container consignment of pharma products.  It’s a problem that currently prevents many otherwise suitable products from being shipped by water.

	Poseidon is actively addressing this issue and has brought the insurance industry into negotiations from the project’s start. As a result, Poseidon can now offer a wide-ranging insurance framework specially devised to provide satisfactory cover for all pharma shipment risks and values. Poseidon insurance will provide significantly improved coverage while demystifying the marine protection process.

: Have there been any regulatory changes regarding ocean shipment or position pronouncements by the World Health Organization (WHO) or other global authorities on ocean transport of pharmaceuticals?

: GDP legislation is indiscriminate, non-prescriptive and applies universally to all transport modes. So, the same standards must be met by all (The IATA CEIV program is a translation of these regulations to make them more air-freight-friendly).

	Although a high proportion of vaccines are currently transported by sea, the use of ocean freight has not yet been officially endorsed by WHO due to concerns surrounding the perceived implications of a ‘total’ loss situation (i.e., where a huge volume of urgent vaccines or drugs might be lost in a single event). WHO is expected to review this position, however.

: Have there been any detailed risk benefit analyses of ocean transport performed recently?

: Different pharmaceutical companies have launched proprietary pilot studies to ascertain savings and quantify results. 

	However, Poseidon is working with several pharma manufacturers to design and implement the largest ocean freight transport validation exercise to date. This study will involve multi-container intercontinental shipments of different pharmaceutical dosage forms (oral solid dosage forms, vial parenterals, and topical creams), which will be rigorously monitored and documented. This exercise will be completed by June 2018.

: Are there types of pharma companies that tend to rely more on ocean transportation?  What interest are you seeing in the industry?

: For the first time, the 2017 IQPC Temperature Controlled Logistics conference in London included a Sea Freight Focus Day. This event was sold out, and 70% of those attending worked at pharmaceutical manufacturers, almost all seeking to enter sea freight or to upgrade their sea freight usage.Most of Big Pharma is already shipping some of its products by sea. However, these companies typically deal in huge volumes that lend themselves well to full container load (FCL) shipments. 

	Small- and mid-sized pharma companies, which contribute half the industry’s output, do not currently have access to a GDP-compliant less than container load (LCL) service, also known as ‘groupage’ or shared container service. Therefore, they are forced to send materials by air. We expect this restriction to be lifted once Poseidon introduces its GDP-compliant LCL service later this year.

	When referring to this article, please cite it as A. Shanley, "From Supply Chains to Supply Networks: Poseidon Aims to Redefine Pharma Cold-Chain Logistics," 

Articles

Alan Kennedy, executive director of TEAM UP, shared perspectives on Poseidon and ocean transport with Pharmaceutical Technology.

From Supply Chains to Supply Networks: Poseidon Aims to Redefine Pharma Cold-Chain Logistics

Transporting sensitive pharmaceuticals is a risky and complex business. “The lower deck conditions within a Boeing plane or a typical intermodal freight container are a long way from the GMP-validated cleanrooms and controlled laminar-flow environments of the pharma production environment,” says Alan Kennedy, founder and executive director of TEAM UP, an organization that focuses on pharma supply chain issues. 

	According to the International Air Transport Association (IATA), the global pharmaceuticals logistics market is valued at $64 billion and is one of the most regulated, expensive, and fragile cargo markets in the world today (1), says Kennedy.

	Pharmaceutical transport typically combines different modes, explains Kennedy. Air transport, prized for its speed and flexibility, is used mainly for long distance, intercontinental distribution of the most valuable therapeutics, he says, while road is the most widespread method and is also used to connect with both air and sea freight.

	Rail remains an insignificant factor, but this may change, Kennedy says, as new “silk route” connections between Asia and Europe are established (2).

	Ocean transport may conjure 1940’s images of the days when most people still crossed the ocean by ship. It has historically been the Cinderella of pharma distribution, says Kennedy, but, IATA notes that 3.5 million metric tons of pharmaceuticals are still shipped by ocean each year, compared with 0.5 million metric tons by air (3).

	Over the past five years, ocean transport has taken on much greater visibility in the pharma industry. Cost competitiveness is one factor driving acceptance, he says, since it is up to 80% less expensive than air transport.  In addition, Kennedy notes, although it takes much longer than air travel it is often more reliable, because there are far fewer product handoffs. According to some studies, air freight accounts for 80% of all reported temperature excursions, compared with 1% for sea journeys (4,5).

	With ocean freight, customs clearances and other time-consuming paperwork procedures can often be arranged during transit. “The fact that ocean freight entails a greater stock tie-up can also be mitigated through use of ‘floating warehouse’ principles whereby goods in transit are recognized as inventory,” he says.

	In addition, ocean transport has a carbon footprint that is 1/25th the size of air travel’s (i.e., 1000 grams per m.t./km of CO

 are released during air transport, compared with less than 40 grams by ocean transport (6), says Kennedy.

	A 2013 report by analysts from The Seabury Group (7) found significant quality-control problems with air freight.  As a result, Kennedy says, air cargo carriers began to set higher standards, establishing the IATA Center of Excellence for Independent Validators (CEIV) Pharma program to interpret general European Union and other good distribution practices (GDPs)  for air cargo (8). 

	That same year, the EU extended GDP regulations to cover controlled room temperature (CRT) products, which must nominally be kept from 15-25 °C, which only accelerated a switch from air to ocean transport, Kennedy says. 

	So far, most of the growth in pharma ocean transport has been around relatively low value, high-volume products such as solid-dose tablets, generic pharmaceuticals, APIs, and excipients. However, advocates see that it also has potential to handle more sensitive large-molecule biologics as well as personalized medicine therapies.

	Among ocean transport’s strongest pharma advocates is AstraZeneca, which has increased the percentage of products it ships by sea from 5% in 2012 to nearly 70% in 2017 (9). Eli Lilly, which has been conducting studies of ocean transport of biologicals, has found that transporting products by sea saves 80% in costs, reduces carbon footprint, reduces staffing requirement, packing, and storage needs, and also reduces vibration and shock to materials during transport (10).  

	Lilly has partnered with Modality Solutions for protocols and reports, with Q Products for thermal covers, and with Sensitech, using TempTales, monitors that allow for simultaneous tracking of both temperature and location.

	One test involved simulating worst-case scenarios for a 40-foot reefer transporting 18 pallets of placebo, evaluating temperatures ranging from 0 -115 °F.  The studies used Locus Traxx GPS and Lansmont’s Saver to monitor product shock and vibration.  Other tests compared results of trucking product to Long Beach, CA, a two-to-three-day trip, with shipping product to Australia, a 45-day trip one way.

	A Bayer study (11), meanwhile, showed ocean transport plus trucking to be an efficient way to transport pharmaceuticals inland in Brazil. Logistics efforts in that country can be challenging, because they involve driving long distances overland and, in some areas, facing potential security issues. 

	In 2016, at the European Temperature Control Logistics Conference, a number of stakeholders in pharma cold-chain shipping joined forces to form TEAM UP. Their aim was to explore ways to improve the shipping of pharmaceuticals. In January 2018, TEAM UP established Poseidon, a network involving the different types of companies involved in the ocean transport of pharmaceuticals (see 

	Led by pharmaceutical manufacturers, but involving shippers, logistics companies, and suppliers as full partners, the group is focusing on applying best collaborative and integration practices. Its goal is to leverage the latest technology to address any performance gaps that might still separate ocean from other transport modes. Technology vendor members currently include Maersk, H. Essers, Marsh, DowDuPont, Pelican Biothermal, Klinge Corp., Logtag Recorders, and Controlant. Members are collaborating on new projects, including a major validation study that will be completed in June 2018, as well as new insurance and container options for sea freight.

Pharmaceutical Transportation: How to Increase Air Cargo’s Share

,” aircargopedia.com, 2017.
	2. J. Webb, “

The New Silk Road: China Launches Beijing-London Freight Train Route

,” forbes.com,  January 3, 2017.
	3. IATA, “

Astra-Zeneca Eyes Major Shift from Air Freight to Ocean: A More-Controlled Environment for Drugs

,” theloadstar.co.uk, December 15, 2015.
	5. 

, fluglaerm.de, 2015.
	6. Opinion Editorial, “

Unreliable Air Cargo Industry Loses Pharma Traffic to Sea While IATA Sleeps

, coolchain.org, May 14, 2013.
	8. IATA, 

Centers of Excellence for Independent Validators

, iata.org.
	9. A. Guisbert-Wiliams, “Eli Lilly and Company NALO Logistics Paradigm Shift Air to Ocean (A2O),” 15th Cold Chain GDP and Temperature Management Logistics Summit, Canada, 2017.
	10. J. Wann, “Air, Ocean, Road Strategy at AstraZeneca,” Logipharma, April 2017.  
	11. R. Velazquez Trevino, “Modal Shifts: Where Are We Going?”  TCL London 2017, January 31, 2016.


	Vol. 42, No. 3
	March 2018
	Pages: 60â63

	When referring to this article, please cite it as A. Shanley, "Poseidon Takes on the Pharma Supply Chain," 

Lower costs, fewer opportunities for temperature excursions, and a smaller carbon footprint are making ocean transport more attractive for pharmaceuticals. Poseidon, a new collaborative pharma initiative, seeks to leverage benefits.

Poseidon Takes on the Pharma Supply Chain

Based in Dublin, Innopharma Labs was launched in 2009 during the heady days of FDA’s Process Analytical Technology (PAT) initiative, when advocates of modern process control and industrial engineering predicted a major shift in the industry’s approach to quality control and manufacturing. 

	Years later, a full-scale shift may not have yet occurred, but concepts such as continuous manufacturing and pharmaceutical quality by design (QbD), and a redefinition of process validation, have begun to drive new, more modern approaches to drug development and manufacturing with an increasing number of approvals implementing these principles.  Moving beyond its foundation in PAT and particle size imaging, Innopharma has responded by branching out into new areas that include automated process control, services, and education.

	In January 2018, the company formally launched a new advanced manufacturing program based on the concept of predictive control, permitting “self-guided” granulation and sophisticated control of modified-release oral solid dosage forms. Enabling this move was a  €13-million investment in Smart FB, a suite of technologies that include a data historian and cloud-based data repository, to allow manufacturers to achieve the benefits of more advanced process control for batch processes.  The technology can be test driven at the company’s new dedicated process R&D facility in Dublin.

	Company founder and CEO Ian Jones discussed these initiatives and industry trends with 

	While Innopharma is focused on the pharmaceutical industry, particularly formulation and manufacturing, it also serves the chemical, food processing, and solids processing sectors, and this knowledge informs the company’s technology platform. Jones will be discussing Manufacturing 4.0 at INTERPHEX 2018 in April.

	Exploring self-guided granulation and coating

: When did you launch your advanced manufacturing pilot program and are you currently working with any industry partners?

: We officially launched the pilot program in January 2018, after testing it with pharmaceutical companies during 2017.  This work builds on the application development and sensor system integration with partners Glatt, a specialist in fluidized bed drying, and Colorcon, which focuses on formulation materials including coating.

: Are you working with any academic partners?

: Over the past seven years, we have collaborated broadly with academia for PAT, but decided to invest in hiring process scientists, engineers, and chemometricians and bring this expertise inhouse. Based on input from pharmaceutical manufacturers, we have also developed our own Smart FBX advanced development and manufacturing modular platform incorporating PAT sensors, data integration engine, secure data storage, analytics and automated control components.

: Why did you feel this was necessary?  After all, can’t companies currently source the individual technologies (e.g., data historians and process control platforms) separately, themselves?

:  We felt that it was important to bring everything together. As mergers and acquisitions have become the norm in pharma, companies are managing a more diverse and global network of manufacturing sites than ever before, and contract manufacturing organizations (CMOs) are becoming a more prominent part of these networks. Our goal is to provide process data visibility, and to enable global access to development and manufacturing data so that we can support process development projects, wherever in the world they are based. Where companies lack in-house resources, our staff can step in and help with development and control problems.

: Why do you see advanced control as being so important to pharma’s future?

: Just consider a car or cell phone from 15 years ago and compare them to what exists today. They are almost completely unrecognizable. A high level of advanced analytics and diagnostics has been built into these devices which has become standard in these industries, but this is not yet the case for pharma.

	If the pharmaceutical industry wants to develop and manufacture safer and more affordable medicines faster, improved automation and process control will be key enablers.  That’s why we’ve gone down this road. At this point, the goal is not to pioneer, but merely to start to catch up to what other industries are doing with automation and analytics.

	Smarter control will be especially crucial for scaleup and tech transfer.  More, and better, technology is needed to support this work in the pharma industry.

:  What do you see as being responsible for pharma’s conservatism?

:  The main reasons are financial and regulatory. Today, the basic focus is on doing more with what you have, rather than investing in new technology. There is also an understandable conservatism to moving away from the traditionally accepted regulatory path in case of delay to approval or a request for significant additional data for a variation submission. As a result, it has been a major challenge for tech providers and the industry to get to a stage where advanced manufacturing is even possible.

	Continuous manufacturing has been a great eye opener for many pharma companies, because it has helped them understand the potential role that feedforward and feedback process control might play in their operations.  Quality experts at pharmaceutical companies often see moving from batch to continuous as being too risky, so the groups leading continuous manufacturing projects are typically those charged with starting a new process for a new product. Nevertheless, as more companies support the continuous concept, even at a very limited level, it is opening the door for them to accept more innovation, especially in automation.

:  Are you currently working on continuous projects with clients?

: We’ve worked on continuous since 2009. Advocates for continuous processing predict that 2% of all pharmaceutical products will be made that way by 2020.  Companies are moving ahead with continuous, and all the major equipment suppliers are offering platforms but the industry isn’t jumping as quickly as many people expected it to at first.

: Is Smart Batch a response to these issues?

:  Yes, in a sense we have stepped back. We still see continuous as pharma’s future, but for the present, why not retrofit existing batch processes, using the algorithms and controls that are needed to make them smarter?

:  How would Smart Batch fit in to process development, or is it mainly for manufacturing?

:  There is no standard approach to control for process development. Everyone is trying to figure out how to optimize development to get to market as quickly as possible and meet QbD requirements with a risk-based approach to design of experiments (DoE). Fluidized bed processes tend to have a higher regulatory risk profile for chemical, manufacturing and control (CMC) strategy, so we are working on a systematic approach. 

	But automated control is much more relevant during product commercialization. Algorithms can react to various permutations in the process to bring automated dynamic process control, but nobody has gone on that journey yet, and we’re trying to figure it out. Customers clearly need to make batches smarter, however.

	Getting closer to ‘hands off’ manufacturing

:  How do self-guided coating and granulation  processes work?

:  They bring ‘hands off’ manufacturing closer to reality, using PAT to track critical process parameters and the product’s critical quality attributes during processing. Then, they use a model to control the process phase changes, including endpoints, automatically.

	In addition, the technology is being developed so that these processes can be monitored remotely in real time from anywhere in the world, even, potentially, from a smart phone.  In time, advanced manufacturing will facilitate real-time release and continuous processes.

	Manufacturers around the world are supporting more automation and greater visibility of data, with many pharmaceutical companies developing and evolving plans for Pharma 4.0. There are considerable opportunities to increase manufacturing efficiency and regulatory compliance by implementing elements of Manufacturing 4.0. Improved control coupled with real-time process analytics provides process operators and supervisors with critical real-time information and reduces the risk of data transcription errors or deliberate falsification.

	Primary focus on fluid bed coating and drying

: Why did you choose to focus on fluidized-bed (Wurster) coating and drying first, and why is control important to these unit operations?
	Jones: First, fluidized bed coating is a multi-step process with potential for considerable variability,  for example, due to raw material variation. Even where product is within specifications, bead size can change from batch to batch.  Microcrystalline cellulose, for instance, is a natural material, so measurable qualities will vary, leading to varying process results. These variations impact product quality.  Fluidized bed drying can also be difficult to control, which can have a big impact on the final product quality if the optimal level of moisture content is not achieved

:  How does that variability affect the quality of finished product?

:  Let’s consider Wurster coating. A typical pharma manufacturer will use a fixed amount of coating material, assuming that the beads are all the same size. But if you add the same amount of coating material each time, even a 20- to 30-micron difference in the size of individual bead diameters will result in different coating levels on the beads which will impact the product performance as measured by dissolution profile.

	So we are applying PAT concepts to coating to help ensure fixed particle size change so that users can get the same coating characteristics every time, despite variability in raw materials and other factors. This approach uses advanced manufacturing principles.  

	First, the Eyecon analyzer is used to measure the initial particle size at the start of processing.  The initial size data is automatically fed to a dynamic process-control algorithm that we’ve developed inhouse. That algorithm defines the trajectory needed to add the correct amount of material per minute to achieve to required coating thickness and stops the process once it has reached a predefined growth level.

	The platform will be useful for developmental work, because it complements DoE software and allows product development teams to program and schedule development batches and access time aligned process and PAT sensor data such as PSD, moisture, spray rate, atomization pressure, air flow, temperature etc. on demand. Operators can then run the experiments, collate data, and run a sequential experiments. After each batch, users can access data to see how that batch did, and, after all runs are complete, they will be able to compare data and transfer key data to the DoE analysis tool. The platform makes definition of a design space and development of a process control strategy more efficient and makes data required for technical justification more accessible.

	Jumping forward to controlling a commercial-scale batch, this setup would allow users to determine the optimal bead growth rate and terminate underperforming batches to ensure that rate is achieved.

	Dissolution prediction would also be a crucial capability, but we will have to partner closely with each customer to determine the best approach, since every formulation will involve unique challenges (e.g., whether using water based or solvent based coatings, or different levels of API).

	We will be focusing on fluidized bed coating for the next two years, and haven’t yet decided what the next step will be.

	As the industry becomes more comfortable with remote data access, users would be able to view data via smartphone, laptop, or tablet using a 21 

: How does this platform embrace the concept of the Internet of Things?

:  Through its use of process equipment sensors and additional PAT sensors for critical process parameter and quality attribute measurements, cloud-based architecture and artificial intelligence, in the form of dynamic process control and the use of algorithms, and, ultimately through remote data access. We have talked with nine out of the 10 Big Pharma companies that use PAT extensively, and their feedback was very positive.  We’ve also had positive feedback from equipment vendors, and the regulators are open to facilitate the adoption of new technologies. FDA appears to be leading the field with its most recent Pharmaceutical CMC Guidelines, “

Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry

: Are you focusing on one single equipment vendor or a limited number?

: We will continue our long standing collaborationwith one vendor (Glatt), but expect to be able to retrofit to any customer’s or vendor’s equipment.

:  You had recently launched training and educational programs.  What are your plans in that area?

: As well as up-skilling thousands of students each year, we are in the process of launching our new online education program.  It will first be available only in the European Union, but by the third quarter of this year, will be accessible from anywhere in the world.

	This program fits in with our contract services in validation and scale-up support, which we introduced 18 months ago. Pharmaceutical manufacturers often have difficulty filling positions in these areas because there aren’t enough people with the right skills and experience to handle formulation development, scaleup, and manufacturing. With FDA’s new process validation guidance, there is a need for continuous process verification and the skills and technology required to support that effort.

	Another focus for us, in both training and services, is project management. We have taken people without any pharma experience (e.g., professionals who have worked in the electronics industry) and given them 500 hours of validation and project management training and experience and found that they perform very well when placed into (bio)pharma environments.

: At this point, we are focused on small molecules.  In addition to our work in pharmaceuticals, we are also very active in the food and chemical industries, where we have worked on processes for infant formula and industrial solids materials. The experience is extremely applicable to oral solid-dosage form manufacturing, where there has been a real uptake in interest in automated control over the past three to four years.

:  What impact is outsourcing having on the way that pharmaceutical monitoring and automation solutions are being developed?

: It’s hard to impose technology on a service provider.  A contract manufacturer will generall make product with whatever tools the sponsor provides and supplement with support for process critical gaps identified during tech transfer planning. But the virtual company, Vertex Pharmaceuticals, has given the industry a great example of what is possible when the right tools are provided, in particular, for analytics and control.

	Remote data visibility in real time has huge potential to improve outsourcing.  One of the industry’s greatest challenges is the fact that, due to restructuring, the repositories of manufacturing knowledge aren’t there anymore.  As a result, gaining real-time data visibility is very powerful. If a batch isn’t performing properly, this visibility allows you to react and intervene right away. As a result, we are getting some very positive responses from CMOs.  Meanwhile, sponsors are using analytical technologies to profile processes at old sites and replicate them in new ones.

:  Your company came into being during the years following FDA’s PAT initiative.  How fully has the industry adopted PAT? 

: I prefer to take a 20-year perspective on PAT.  Back in the earliest days, before the FDA initiative, some people were using the concept and spending a lot on it, but they didn’t fully understand what they wanted it to do and how it would help them develop and control a process.

	In addition, the technologies they were using had come from other industries and were not as fit for purpose as they might have been for pharma. For example, an analyzer might have been good for measuring cement but not the particle size diameters found in pharma excipients.  In addition, much of the early equipment lacked compliance capability for pharma applications. Then along came the FDA guidance, which may have brought too much rigor to the implementation approach. The whole initiative seemed to go quiet for about 10 years.

	Over the past five years, however, we have seen a renaissance in process analytical technologies.  People understand the guidelines better and are more comfortable with them, and the industry is more mature in its approach to buying the technology that is required.  At the same time, technology providers have invested a considerable amount of money in making their equipment fit for purpose in pharma, in particular, developing better, more user-friendly interfaces for pharma. We’re seeing much greater use of PAT for measuring moisture content and particle size for powder processes, and it is finding greater use in tech transfer.  More generic-drug manufacturers are also using it.

:  Where do you see advanced manufacturing going in pharma in the short term?

:  It’s too early to tell, but there are already many initiatives in development to implement QbD principles to develop more defined, better understood processes. Efforts are increasing to apply automation, at least for end point control of critical process steps, often by combining process equipment sensors and PAT sensors to develop more sophisticated control. These are important early steps on the journey toward fuller automated process control.

	One wonders what Elon Musk might do if he were to explore pharma. How would he get the molecule to the patient?  The question is whether disruptive technologies will allow pharma to reach true patient-centered care and circumvent the 

. Only time will tell, but we hope that our efforts will stimulate new thinking and help answer some fundamental questions.


	Supplement: Solid Dosage Drug Development and Manufacturing
	March 2018
	Pages: s25–s28

	When referring to this article, please cite it as A. Shanley, “Innopharma Bets on Manufacturing 4.0," 

Pharmaceutical Technology Solid Dosage Drug Development and Manufacturing

Can an Irish analytics company and its CEO bring pharma closer to 21st-century practice?

Innopharma Bets on Manufacturing 4.0

Counterfeit pharmaceuticals continue to threaten public health and safety.  The International Criminal Police Organization (Interpol) estimates that counterfeit drugs cause more than one million deaths per year (1). While governments explore fundamental solutions to the problem, pharmaceutical manufacturers are fighting this threat to their customers and brands through serialization and the use of anticounterfeiting technology.

	Several years ago, for example, Eli Lilly invested $110 million on serialization and anticounterfeiting measures such as color-shifting inks and distinctive tablet shapes and colors, for its widely copied Cialis, Cymbalta, and Zyprexa brands (2,3).

	Merck KGaA is using pigments in its Security-M labels, which are added to product packaging, allowing products to be identified and authenticated. It also offers CheckMyMeds, an app for patients that lets them verify barcodes on medications before taking them (4).

	Counterfeiters, however, continue to improve their packaging and “manufacturing,” too, so the fight against them shows no signs of abating. The search is on for technologies that counterfeiters cannot hack. This article describes the scope of the problem and highlights some research in areas that could be applied to personalized medicines as well as analytic testing and forensics. In 2017, the Pharmaceutical Security Institute (PSI) documented a rise in drug diversion incidents around the world, including diversion of medicines provided under compassionate use or “named patient” programs and purportedly from trusted countries, says PSI director Tom Kubic. In addition, in 2017 more counterfeit pharmaceuticals were able to reach the legitimate supply chain in Europe, Kubic says. Tablets and capsules remain the most widely imitated dosage form.

	Policing efforts claimed some victories, most notably Operation Pangea VIII in 2017, which involved Interpol, the World Customs Organization (WCO) and customs and security forces in more than 115 countries, and FDA. The effort resulted in the seizure of more than $81-million-worth of counterfeit medicines and medical devices and the shutdown of 2400 illegal websites in 2017 (5).

	A final, formal report on Pangea VII is still being drafted, Kubic says, noting that Pangea included counterfeit medical devices for the first time in 2017. “Interpol’s successful coordination of the global enforcement effort against illicit medicines, such as the Pangea operations, illustrates its ability to overcome significant challenges. Its partnership with WCO serves as an exemplary model of cooperation, and they deserve credit for helping to protect the safety and well-being of patients around the world,” says Kubic.

	According to PSI data from 2016, posted directly on the organization’s website, www.psi-inc.org, 3147 cases of pharmaceutical counterfeiting, theft, and diversion were reported, up 5% from 3002 in 2015, and 2177 in 2014. Of these incidents, 520 resulted in either raids or customs seizures.  However, seizures fell by 45% between 2015 and 2016, according to PSI data. In 2016, 38% of seizures occurred at commercial facilities, but 46% were noncommercial.

	The five most frequently counterfeited therapies were genito-urinary medications, anti-infectives, central nervous system treatments, hormones, and cytostatic drugs, according to PSI.  In addition, 1258 people were arrested for counterfeiting and diversion, down 9% from 2015, according to PSI data.

	In the United States, meanwhile, the opioid addiction crisis has brought increased levels of counterfeit opioids, especially fentanyl, into the supply chain, blurring distinctions between illegal street drugs and counterfeit pharmaceuticals. Fentanyl follows the historical tradition of a legitimate therapeutic eventually becoming a street drug. This first happened with Merck’s morphine, then with heroin, which Bayer introduced as a synthetic and (so the company thought) non-addictive treatment for opium addicts.

	The pattern was later seen with Purdue Pharma’s oxycodone, and has repeated with fentanyl, a synthetic pain reliever originally developed under a Janssen patent, that is 50 to 100 times more potent than morphine (6).

	The PSI has noted a shift in counterfeit fentanyl manufacturing to the US, and an increase in illicit imports of equipment such as tablet presses as well as other formulating ingredients into the US. In 2016, customs officers seized 440 pounds of fentanyl, up from two pounds in 2013, also seizing increased volumes of its precursors 

-Phenethyl-4-piperidinone (NPP) and N-phenyl-1-(2-phenylethyl)-4-piperidinamine (ANPP).

	In addition, customs confiscated 58 pill pressing and tableting machines in 2016, up from 24 in 2014 (7).But, on the government level, some believe that light penalties fail to deter counterfeiters, and argue that too much of the responsibility for preventing product diversion and counterfeiting has shifted to the manufacturer.

	Legislation such as the EU Falsified Medicines Directive (FMD) and the US Drug Supply Chain Security Act (DSCSA) require that manufacturers identify pharmaceuticals at the unit package level, as a first step to establishing full product traceability within the supply chain, to prevent pharmaceutical counterfeiting. However, the cost and effort required is considerable.

	As Price Waterhouse Cooper (PwC) analysts have noted, compliance with the FMD alone has already cost manufacturers 500 million euros (2). A PwC survey of 38 senior pharma executives in 2017 found that most were satisfied with their companies’ supply chain integrity protection methods, yet acknowledged that extra steps would be needed to protect product from counterfeiting (2), suggesting the need for more incentives to invest in the required technologies.

	Today, one year before the FMD deadline and nearing the extended DSCSA deadline, a number of manufacturers and their contract partners have not even begun serialization efforts. Efforts such as the Open SCS working group are underway to simplify and reduce the IT costs for serialization and traceability efforts (8).

	In the end, more collaboration will be needed between governments, law enforcement agencies, and manufacturers. Some governments don’t treat counterfeiting as a national healthcare issue but instead believe that the industry needs to solve and pay for the solution, notes Charlie Gifford, technical director of the Open-SCS working group. “Merely implementing a data-collection system will not be enough.  The data must be used and organizations set up to follow up on counterfeiting incidents. In addition, laws need to reduce the incentive for counterfeiting by exacting harsher penalties,” he says.

	Anticounterfeiting is challenging because it needs to be approached from three different perspectives and lines of attack--from the point of view of the manufacturer, distributors and healthcare providers, and the patient, says Jay Kennedy, assistant professor with the University of Michigan’s Center for Anticounterfeiting and Product Protection (CAPP).

	More education is needed for healthcare providers, Kennedy says, to ensure that they do not buy medications from unauthorized sources. But education is most crucial for consumers, and the lure of lower costs is hard to counter when addressing online pharmaceuticals. In addition, quick response (QR) codes and the other technologies that are being used for anticounterfeiting can be daunting for some consumer groups, including senior citizens.

	Technology already exists to improve manufacturers’ response to counterfeiters.  Taggants, packaging and bottle designs, inks, and labeling are all being improved. In the taggants area, TruTag’s platform was selected for use in nutraceuticals and health products by the Daily Wellness Company. Products will be tagged to enable their detection and authentication throughout the supply chain. The company has also partnered with Sumitomo Corp. of America, which is investing in its technology, to develop its platform for various applications, including those in pharmaceutical manufacturing (9).

	Applied DNA Technologies, meanwhile, has expanded its global operations with a new test lab in India. The company has also been selected by TheraCann International Benchmarks to develop its SigNature molecular tracking system for use in the tracking and tracing of legal cannabis for medical use (10).

	In 2017, the plastics manufacturer Clariant introduced Plastiward, a system that uses covert taggants developed by SICPA SA, to provide an integrated plastic-based anticounterfeiting technology that can be used in pharmaceutical packaging or placed within a medical device. The taggant is incorporated either as a masterbatch form or as a finished polymer compound. Through the supply chain, the tagged product could be detected and authenticated using a monitoring system developed by SIPCA (11).

	New approaches are also in the works that will be nearly impossible to duplicate, says Kennedy. Many of these will be especially useful for personalized medicine. He points to a new DNA tagging system (12) now in the early conceptual stage, which is being developed by University of Michigan professor Evangelyn Alocilja. In this approach, a strand of DNA would be attached to a product and a sequence would be coated with a material that would allow it to be seen with a light emitting diode.

	The strand would allow users to identify product information, manufacturing data, and chain-of-custody information on that product, and would cost less than a penny per item.

	At the University of Copenhagen and Finland’s Abo Akedemi University, researchers are looking into the use of ink jet printing to make edible dosage forms in a QR code that the patient would simply ingest. APIs would be placed in the ink in the pattern of the code, and dosage form would look like a code on a substrate. Not only could this approach lend itself to point-of-use manufacturing, but it could prevent product diversion, tampering, and counterfeiting (13).

	Other advances are focusing on analytical measurements to aid in the forensic detection of counterfeit pharmaceuticals within the supply chain. One effort is focusing specifically on measuring surface gloss, using diffractive optical element-based sensors to inspect the surface porosity of flat, two-phase tablets.

	Researchers used lab-based and handheld gloss meters as well as an optical profilometer to study the surfaces of commercially available tablets, contrasting measurements from authentic and counterfeit antimalarial tablets. Gloss values and surface roughness measurements between the two groups were substantially different, suggesting that the method could be used for quick inspection and field screening of fake tablets (14).

	At Sao Paulo State University in Brazil, researchers are evaluating the use of matrix-assisted laser desorption and ionization (MALDI) mass spectrometry to detect counterfeit dosage forms of all types. Researchers report that the technique simplifies analysis, speeds detection, and minimizes sample preparation (15).

Counterfeit Drugs Kill 1 Million People Annually: Interpol

,” insightcime.org, October 4, 2013.
	2. PriceWaterhouse Cooper, “

Fighting Counterfeit Pharmaceuticals: New Defenses for an Understated and Growing Menace

, pwc.com, June 29, 2017.
	3. J. Swiatek, “

Eli Lilly Intensifies Efforts to Stop Fake Pharmaceuticals

,” indystar.com, April 6, 2014.
	4. Merck KGaA website, 

A Global Fight Against Dangerous Counterfeits and Unapproved Medical Products

,” FDAvoice.com, June 30, 2015.
	6. S. Bhatia and D. Turock, “

Chemical Engineers Respond to the Addiction Crisis

,” Chemical Engineering Progress,” November 2017.
	7. Dept. of Homeland Security, “

Stopping the Shipment of Synthetic Opioids: Written Testimony of CBP Acting Executive Assistant Commissioner for Operations Support

,” dhs.gov,  May 25, 2017.
	8. A. Shanley, 

, 31(1), 2018, 48-59, 51.
	9. Press Release, “

Trutag Technologies and Sumitomo Corp. of America Form Global Strategic Partnership

,” December 4, 2017.
	10. Press Release, “

Applied DNA Sciences Awarded Multi-Year Contract

,” adnas.com, January 25, 2018.
	11. Clariant, “

Clariant and SIPCA Plastiward Anticounterfeiting System Featured at Pharmapack Europe 2017

,” Press Release, January 2017, clariant.com.
	12. C. Graminich and J. Wilson, “Emerging Challenges and Progress: A Report on the ACAPP Center Brand Protection Summit,” University of Michigan, 2017.
	13. M. Edinger et al., International Journal of Pharmaceutics, 536(2018), 138-145.
	14. P. Bawuah et al., Journal of the European Optical Society, Rapid Publications, 13(18), June 2017.
	15. J. Bronzel et al., Journal of Mass Spectrometry, 52 (6), 752-758 (2017).


	Vol. 42, No. 2
	February 2018
	Page: 56–58

	When referring to this article, please cite as A. Shanley, “Anticounterfeiting: In Search of the Unhackable,” 

While more companies are embracing taggants, researchers are developing new technologies that will be extremely difficult to reproduce.

Anticounterfeiting: In Search of the Unhackable

In API development, a clear strategy is crucial to ensure that a new compound doesn’t end up with the 90% of new molecules that fail during clinical testing. Process development and scaleup are extremely challenging, drawing upon the complementary skills of chemists and chemical engineers, and employing methods advanced by pharmaceutical quality by design (QbD).

	The end goal is a safe and scaleable process that is rugged (i.e., reproducible on scale, while ensuring quality and the right level of process control), says San Kiang, research professor at Rutgers University’s chemical engineering department. The process must be able to provide enough material for clinical trials, even though it has not been finalized or commercialized.

, along with Shyam Vispute, general manager, technology transfer, at Neuland Labs, which opened a new process development and optimization center in India in March 2017. Here is some of what they had to say.

	Measuring the efficiency of process development

: What are the different goals at each phase of process development?

): At the earliest stages, you’re in a hurry.  You want the process to be expedient and to produce the material quickly. You really do not have time to look at efficiency and cost. You just want to make the product to get to the end of Phase I. In Phase II, you want to emphasize practicality so that the process will scale up reasonably well.  At this point, efficiency and cost start to enter the picture, but process optimization isn’t really needed until Phase III.

: How do you measure the efficiency of pharmaceutical process development?

): The chemical route is very important, and engineers seek to reduce the number of chemical steps required. ‘Process intensity’ indicates how many resources are used to product a given quantity of product.

	Other key questions are whether the product can be made using existing equipment and whether it will require exotic starting materials that might be difficult to source. Minimizing waste is also crucial to reducing the environmental impact, and the cost of that impact, and, thus, to minimizing overall manufacturing costs. The key disciplines required are reaction engineering; pharmaceutical engineering, which operates at the point where engineering, pharmacy, and chemistry connect; and safety engineering. In a reaction lab, you look at reaction kinetics and try to derive the reaction mechanism, or diagnose and troubleshoot problems with a reaction that you’re working on. Catalyst screening is also important, as are separation and purification, notably through process chromatography, which is used to make materials in early-stage development.

:  How do chemists and engineers collaborate on process development?

): Chemical engineers are involved in process development right from the beginning, with route selection and finalization. More interactions with chemists occur, however, once the process’ feasibility has been confirmed. Once the process has been shown to be able to manufacture compound that meets quality specifications, engineers must evaluate the process from the safety, health, and environmental standpoint.  Their contribution is crucial, since they have studied the unit and process operations involved and have a clear understanding of critical utility and hardware requirements.

	They also generate process safety data, using software to screen relevant examples from the literature, and performing thermal and hazard studies in order to develop an inherently safer process. 

	In addition, they generate data on material balances, perform energy balances to evaluate the utility requirements for plant scale, and select equipment for commercial-scale production, whether for retrofits or new facilities.

	They also scout for new technology and see its potential to improve results, given the specifics of the process (i.e., the volume of products, safety threats, troubleshooting activities related to the commercial products, and the need for capacity enhancement).

	Chemical engineers also lead quality and safety risk assessment efforts, including hazard and operability studies (HAZOPs), hazard identification and risk analysis (HIRA), and powder safety characterization studies.

	They are also involved in particle engineering, which requires the evaluation of particle size, bulk density, surface area, and any polymorphs and their effects. This area is extremely important, and is typically done before scaling up in order to ensure that the product achieves the desired physicochemical properties.

	Chemists, meanwhile, select the best synthesis route, and determine the feasibility of that route. They are also involved in optimizing and validating the process to meet the predefined quality and yield levels.

	Both chemical engineers and chemists work collaboratively and must understand the critical process parameters (CPPs) and critical quality attributes (CQAs) of the process during development phases.

	Chemists are experts in various types of synthetic reactions, based on the literature search and experience. They identify and characterize process impurities that could have an impact on product quality.

	In addition, chemists are involved in ensuring that the process achieves the desired quality and performance specifications. They generate and qualify reference and working standards, and must interact continuously with the business and legal departments to guard against any potential patent infringements.

Chemical engineers and chemists each bring unique skills to API process development and optimization. Success depends on their close collaboration, at both sponsor and CDMO facilities.