Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

For the past few years, it has been no secret that many small to mid-sized pharmaceutical companies in the United States, the European Union, and beyond have not yet begun to prepare for serialization deadlines set by the US Drug Supply Chain Security Act (DSCSA), the EU False Medications Directive (FMD), and other traceability directives around the world (1).

	In the US, this compliance gap led FDA to postpone by one year the implementation deadline, moving it to November 2018 (2). The FMD’s deadline still stands at February 2019. 

	However, in the second quarter of 2018, Tracelink’s 2018 Drug Supply, Safety, and Traceability Report found that only one-third of 660 pharmaceutical manufacturers, contract manufacturing organizations (CMOs), wholesale distributors, hospitals, and pharmacies were confident that they were ready to meet requirements, and only half had prepared their internal packaging lines of serialization or projected the number of units that would need to be serialized each year.  The survey found that, at that time, only 8% of pharmaceutical manufacturers had integrated serialization processes with their CMOs and only 11% said their CMOs were ready to ship serialized product (3). Where executives from half of CMOs in the US felt ready, only a third of their counterparts in Europe did.

	Manufacturers and CMOs in Europe are well behind schedule, according to recent reports (4). Second quarter 2018 data from the European Medicines Verification Organization (EMVO) suggested that 50% of countries whose manufacturers sell pharmaceuticals in the EU will be too late to meet the FMD deadline. Even for all European suppliers to comply would require equipping some 10,000 packaging lines at 1500 pharmaceutical sites in a matter of months (5). Getting EMVO approval is itself a process that can take several weeks. First, a series of transactions must be submitted and reviewed before the company is allowed to submit relevant production and other data to the EU Hub.

	At the Serialization Innovation Summit, held on June 20, 2018 in Philadelphia and sponsored by the serialization IT supplier Adents, Maarten Van Baelen, market access director for Medicines for Europe, a generic-drug trade association, revealed the scope of the challenge. As of May 2018, he said, out of the 2200 pharmaceutical companies that will need to submit serialization data to EMVO for FMD, only 749 had done so. Meanwhile, further along the supply chain, only 10% of wholesalers were connected to the EMVO system, although they were working very hard to solve the “considerable technical challenges” involved, he told attendees at the June Summit.

	Solution providers have responded to these issues with a number of “quick compliance” tools-modular, template-driven approaches designed to help companies meet serialization requirements quickly. In May 2018, TraceLink, a cloud-based IT serialization solutions provider, introduced the EU FMD Express platform, designed to help smaller manufacturers and CMOs in Europe meet requirements and send serialization data to EMVO (6).

	As of June 2018, TraceLink reported that 34 companies had completed conformance testing using TraceLink’s kit. Of these, 11 companies received EMVO approval to submit data to the EU Hub and 14 companies were awaiting review. Biosyn is one company that reported good results from the program, while, in June, IBI Lorenizini, an Italian CMO and supplier, signed up.

	Adents, another cloud-based IT vendor, is approaching the serialization readiness gap with programs of its own. Started up in 2007 in France by specialists with experience handling provenance and serialization issues in the fine perfumes and champagne markets, the company introduced Serisa, a line-level serialization solution supported by Siemens, in 2010. In 2014, Adents released Prodigi, a cloud-based system designed to facilitate serialization data exchange. 

	In 2017, the company established a collaboration with Microsoft, and the two partners introduced NovaTrack to the US market in June 2018 (7). The approach, utilizing Microsoft’s Azure Cloud technology, is designed to incorporate blockchain and artificial intelligence, and to bring Internet of Things (IoT) technology to bear on cold-chain and other supply chain issues. Julien Faury, vice-president of operations for Adents Americas, says that the program features open architecture and works both at the centralized IT level and at the line level, using a “top down” approach and a cloud-native, vendor agnostic approach. 

	The company offers users a certified gateway to enable faster transmission of data to EMVS. It has integrated with the Origin database in the US, operated by the Healthcare Distributors Association, and is developing a gateway to Russia’s serialization database.

	The company is working with Microsoft to develop and optimize blockchain solutions using Microsoft’s Cocoframework, which offers 20,000–50,000 transactions per second. This speed is considerably faster than solutions based on Ethereum, according to Tianna Umann, cross-domain solution architect with Microsoft, who spoke at the June summit. 

	Both partners have assembled an industry workgroup lead by the Healthcare Distributors Association to evaluate different approaches to blockchain.  In addition, Adents and Microsoft are working on systems that would use Microsoft’s Hololens technology to train operators on serialization and make relevant documents accessible to them in their workspace via a wearable device. Hololens is based on the concept of Mixed Reality, which incorporates some of the digital elements of virtual reality, but operates in real space (8). Adents’ operations manager, William Minaeff, senior project director, shared some insights into pharmaceutical serialization with 

: What changes have you seen in the industry’s approach to serialization in 2018, as the DSCSA and FMD deadlines draw near? 

: We have seen several changes since FDA offered a year-long extension in 2017. FDA recognized that solution providers were finding it difficult to scale up to service the number of production lines required by the various pharmaceutical companies. As a result, many serialization service providers have had to hire hundreds of employees in a short time frame to meet demand. 

	The major hubs in the United States are in the San Francisco Bay Area, the Northeast, and of course, Research Triangle Park. Additionally, we see a large opportunity for external manufacturing in the Midwestern US. The beauty of cloud solutions is that they have unlimited scalability, so we are able to work with companies of all sizes and customize our solutions according to the size of the business. Further, Colombia and Brazil are emerging markets, while Canada will adopt serialization within the next five years due to changes in regulations. 

: Just a few months ago, many small to mid-sized manufacturers and CMOs had not even started formal serialization programs. Where are you seeing the greatest challenges?

: Serialization implementation faces the following challenges:

		Collaboration between thousands of parties

		Management’s view that serialization is a cost, not a benefit

		The need to share billions of terabytes of data.

: There are already a number of cloud-based data management systems available for serialization.  How is Adents’ different?

: Adents was established to explore the new generation of serialization software. The major challenge with serialization is not the actual marking or reading of serial numbers but rather the data management expertise that backs up the serialization. Over the past few years, Adents has created a new software suite, with an open architecture. 

	The first part of this software was released in 2010. This software-driven serialization solution took off very quickly in the European market. The solution is not only used in the pharmaceutical sector but also in the wine and spirits, and health and beauty sectors. 

	In 2012, pharmaceutical companies in the United States and Europe started to implement these processes and began to look into cloud-level solutions. Adents partnered with Microsoft in 2014 to codevelop Adents Prodigi, which was released in 2017. Adents has since grown to nearly 100 employees and more than half of its customer base consists of life-science companies. 

: What is needed to help more companies leverage the work that they have done to enable serialization to achieve broader business benefits?  

: As a serialization project progresses, there are many challenges that need to be faced and many sources of complexity. Serialization failures most frequently come from a failure to understand the scope of a serialization project, for example, failing to identify all stakeholders and their requirements (e.g., packaging, label change, supply chain, IT, and Enterprise Resource Planning [ERP]).

	Essentially, five key elements are required for a successful track-and-trace serialization solution for the pharmaceutical sector:

		Configurability, so that no specific software development is needed, in a platform that can be easily updated and upgraded, reducing human error.

		Scalability, so that after initial rollout, additional lines can be deployed seamlessly without having to duplicate the entire process.

		Interoperability (i.e., increased flexibility) so that users can choose the hardware that fits the best with their objectives, use existing equipment when possible, and minimize costs and delays in delivery.

		Site-level management capabilities to cope with change management. One centralized point from which configuration and processes can be managed can help to facilitate configuration management, data exchange, reporting, change management, and validation support as well as IT governance. Site-level management capability minimizes risks and help users prepare for future track-and-trace challenges.

: How is the industry moving beyond serialization to the larger goal of traceability?  

: Modern software companies rarely look past three-to-five-year planning cycles, due to the rapid change of technology and business requirements. However, if we look at the current pace of change in automation, robotics, regulatory requirements, consumer demands (from both customers and manufacturers), we begin to see the increasing role that software must play in manufacturing, to provide lifecycle management and support ‘right first time’ production goals.

Pharma Serialization Nears a Tipping Point

,” pharmtech.com, January 2, 2018
	2. PharmTech Editors, “

FDA Pushes DSCSA Serialization Enforcement Deadline Back to 2018

,” pharmtech.com, July 5, 2017
	3. A. Shanley, “

,” pharmtech.com,  April 5, 2018.  
	4. S. Milmo, “

,” pharmtech.com, June 1, 2018. 
	5. Press Release, “

TraceLink Customers Receive EMVO Approval for Data Submission to the EU Hub

Concern Voiced About Pharma’s Serialization Readiness

,” April 12, 2018, pharmalogisticsiq.com
	7. Press Release, “

Adents and Microsoft Introduce Blockchain Serialization Solution

Serialization Innovation: Latest Technologies for the Pharmaceutical Industry

	When referring to this article, please cite it as A. Shanley, “Serialization: Scaling Down for the Final Stretch" 

Articles

Vendors are offering template-based models and direct data-filing services to help smaller companies meet imminent deadlines.

Serialization: Scaling Down for the Final Stretch

Several years ago, groundbreaking studies revealed the losses that pharmaceutical companies incur each year as a result of temperature excursions or transportation delays. In 2014, analysts at IMS Health found that the top 10 pharmaceutical companies lost $16 billion worth of product each year, 20 times the average pharma company’s price-to-earnings ratio, due to transportation problems and resulting temperature excursions and other delays. For the entire pharmaceutical industry, losses exceeded $35 billion (1). 

	International shipments have proven the riskiest. The product is out of the pharmaceutical manufacturer’s control, and manufacturers need to rely more on subcontractors, third-party logistics companies, and other partners whose primary focus may not be pharma, said Rafael Palma, regional logistics manager for Latin America for AbbVie, during a webcast at the Temperature-Controlled Logistics online conference in March 2018 (2).

	Of all the modes of global pharma transportation, air transport has been deemed the most potentially risky, accounting for 80% of all reported temperature excursions (3). Within a plane, turbines can generate heat, leading to potential temperature exposure problems, but the challenges only intensify once the product moves outside the plane. Delays during which pharma cargo is left waiting on the airport tarmac can leave product vulnerable to temperatures that can be 50 °F higher than ambient levels (1).

	Delays caused by product transfers are also part of the problem. In Brazil, for example, Palma said on the webcast, it can take 10 to 20 days just to get the permits required to move product from the airport to ground transportation.  “End-to-end risks and lead times must be considered closely,” he said.

	Regulators and standard setting groups, notably the European Commission, have promoted current good distribution practice (cGDP) guidelines to ensure that best practices for temperature control and optimal risk assessment and management practices are used (4). More countries have set requirements for temperature traceability, and new regulations have been established, not only in the European Union but in Canada, Israel, Saudi Arabia, and Peru, Palma told attendees at the webcast (2).

	At the same time, all stakeholders, from pharmaceutical manufacturers to third-party logistics companies, shippers, airlines, airports, freight handlers, and packaging companies, have been working to reduce opportunities for temperature excursions. One of the most significant achievements to date has been the establishment of the International Air Transport Association’s (IATA’s) Center of Excellence for Independent Validators (CEIV) Pharma Logistics program in 2014 (5).

	CEIV’s goal is to amalgamate local regulations and standards to set global air transportation standards for pharmaceuticals, to certify stakeholders that use best practices, and to encourage collaboration and communication between different stakeholders. The effort was a practical response to the fact that air transportation had lost ground to ocean transportation, and fell from 17% in 2000 to 11% of all transportation in 2013.  According to recent estimates, 3.5 million metric tons (m.t.) of pharmaceuticals were shipped by ocean in 2016, compared with 0.5 million m.t. by air (3). However, IATA saw demand for pharmaceutical air cargo shipments growing 9% in 2017 (6).

	Since it was established, CEIV’s effort has been making progress in reducing the number of temperature excursions. At the 2018 Temperature Controlled Logistics Conference, Francisco Rizzuto, cargo specialist and manager at IATA noted that 221 organizations are currently CEIV-certified, and over 75 more companies are in the process of becoming certified. CEIV has also launched a bulletin board, designed to help pharmaceutical and biopharmaceutical companies locate business partners that have been certified (7). 

	As Rizzuto noted, global GDP regulations assign shippers with the responsibility of securing the transportation chain, from the manufacturing plant to the patient.  As the pharma and biopharma markets grow, he said, lane validation based on clear risk assessment is especially important in emerging markets and unknown territories.  

	It has become imperative that freight forwarders help and support shippers in these efforts. However, Rizzuto said it is crucial for pharmaceutical companies to learn how the air cargo industries, and particularly, how airports work, in order to improve communication. There should be some understanding of capabilities at sourcing airports says Palma. “A lot of truck transportation is used in Europe, but a key question is how much product can be kept waiting in a truck safely?  Based on each shipping lane, companies need to understand specific issues,” he said at the webcast (2).

	Meanwhile, pharma companies should also communicate more clearly with cargo firms, noted Rizzuto.“Air cargo companies need to be made aware of the consequences of temperature excursions,” he said.

	One important step that more companies must learn, Rizzuto said, is that pharmaceuticals should not be shipped as “perishables” with the PER label, but as pharmaceuticals, with the PIL label, in order to be handled properly. Some companies have attempted to reduce costs by going with the more basic label, and that has often led to service and quality problems. 

	Generally, choice of transportation mode will impact cost. Controlled room temperature requirements will raise shipping costs, noted Palma on the webcast (2), with air transport in active or passive shippers leading to a 70–80% cost increase, compared to reefer trucks and containers, which would increase costs by 15–25%. However, air transport offers enhanced security, he said, which can be particularly important for high value products. 

	As Rizzuto noted, IATA is working to update certification requirements, continuously, to reflect changes in regulations (6). In the meantime, individual airports are reporting significant improvements, such as Brussels Airport’s BruCargo arm, which is collaborating with Johnson & Johnson, Pfizer, and Merck, as its strategic pharma advisors. 

	The airport invested 68% more in its pharma services in 2017, and saw temperature and other nonconformances drop 45% that year, according to Nathan De Valck, Cargo and Product Development Manager at the Brussels Airport Company, who spoke at IATA’s annual meeting in March 2018 (8). Milan Airport, which is CEIV certified, found irregularities decreased 77% between 2016 and 2017 (6).

	The CEIV initiative is stimulating the use of new technologies, such as thermal blankets and cabinets designed to keep temperature-sensitive pharmaceuticals at stable temperatures for 26–32 hours on any airport tarmac. However, Rizzuto said, the right packaging is crucial, and manufacturers need to devote time to ensuring that product leaves the facility in the best possible packaging designed for the specific conditions of that particular destination and shipping lane. 

	While collaborative efforts with CEIV are leading to improved shipping solutions, they may also result in some new technologies. Two CEIV-certified airlines, Air Bridge Cargo in Russia and Cargo Logic in the United Kingdom, are currently working with SITAOnAir to use its Internet of Things technology to allow the two carriers to monitor the movement of pharmaceuticals in real time (9). 


	2. Webcast, “How to Safeguard Controlled Room Temperature Medicines on the Move,” 

, March 13-14, 2018, PharmaIQ.com
	3. A. Shanley, 

, 42(3), pp. 60-63, 2018.
	4. European Commission, 

Guidelines on Good Distribution Practice of Medicinal Products for Human Use

, 2013/C 343/01, November 2013.
	5. A Shanley, 

, 40(8), p. 56-57, 2016.
	6. C. Henry, “

IATA Hopeful for the Future of Pharma Air Freight


	Vol. 42, No. 8
	August 2018
	Page: 54–55

	When referring to this article, please cite it as A. Shanley, “Reducing the Risk of Pharma Air Transport," 

Air transport continues to be the most secure way to ship valuable therapies, but it is also the riskiest. Standards are helping to improve service quality.

Reducing the Risk of Pharma Air Transport

Studying how a drug dissolves and disintegrates is crucial to understanding how it will perform in the body. The US Pharmacopeial Convention (USP) has established guidelines for testing dissolution in most commercial dosage forms.

	However, especially for pharmaceutical tablets and capsules, the seven traditional test methods and equipment recognized by USP (1) are variations on a single theme: tablet holder, bath, and paddles. They can seem worlds away from the complexities of the human body. 

	As William E. Brown, senior scientific liaison for general chapters with USP explains, the dissolution test distills all the information that is known about the performance of a pharmaceutical in a laboratory setting. “It is highly simplified and intentionally so,” he says. “For manufacturing, you want a test that passes or fails.” 

	To delve deeper into studying bioavailability, complex systems are available that mimic closely the digestive systems in a mammal or a human (2,3). Ishai Nir, small-molecule product manager at Distek, a manufacturer of dissolution test equipment and ancillary products, recalls the TNO gastro Intestinal Model (TIM), a simulator developed by researchers at the Netherlands-based Organization for Applied Scientific Research (abbreviated TNO in Dutch) in the early 1990s. 

	As Nir explains, TIM includes a stomach model with simulated contractions, as well as simulated mouths and intestine, all modeled with the correct pH, flow time of materials, and simulated gastric fluids. Other advanced models include the Institute for Food Research’s dynamic gastric model (DGM), France’s National Institute for Agricultural Research’s (INRA in French) In-Vitro, and Canada’s Laval and Guelph. 

	These models, however, are costly, complicated, and take a long time to use because they involve so many variables, says Nir. “Of necessity, the industry has replaced bioavailability testing with dissolution testing as a simpler QC test for manufacturing,” he says. Companies pick the formulation that showed efficacy in clinical trials and put it through conventional dissolution testing so that it becomes a benchmark for future manufacturing QC. 

	“It’s like goodness by association. We know that this formulation with this property performed well in the clinic trials, so if we keep making tab- lets that have the same dissolution and disintegration characteristics, we can assume they will continue to work well 

	“In fact, in many ways dissolution is largely a reproducibility test that asks whether the last batch is the same as the current one, and whether or not it behaves the same 

as it did in the clinical study where the formulation was shown to work,” he elaborates. 

	But, as formulations become more complex, will that be enough for the future? Researchers are working to improve the correlation between 

testing and to come up with better methods that are more representative of bioavailability and give more information about functionality, says Nir. “For some,” he says, “this effort has become a holy grail.” 

	It began, he says, with using simulated gastric media instead of running tests using simple media such as water or 0.1 Normal hydrochloric acid. Tests would emulate the stomach when full or fasted, and simulate a much broader array of variables than simply pH, he adds. In addition, Nir notes, some innovator companies are examining the properties of compression and its impact on dissolution more closely. Because the stomach works based on muscular contraction, researchers are simulating that (although, perhaps, not to the extent seen in TNO’s TIM), to identify key parameters. 

	A 2016 article (4) coauthored by experts from Bristol-Myers Squibb and AstraZeneca discussed some of the ways that dissolution testing could be made more biorelevant. At this point, however, the industry isn’t exactly clamoring for more biorelevance in dissolution testing. “The test is well understood and well constrained, and makes it easy to compare between batches and between facilities, and to do scaleup without a tremendous amount of work,” says Nir. 

	Dissolution testing has remained largely unchanged for the past few years, says Nir. However, USP continues to update its information. The organization recently drafted a new general chapter on performance testing for mucosal routes, has a new chapter on testing for topical routes, and plans to re-evaluate testing for injectable pharmaceuticals, says Brown. 

	At the same time, draft guidance from FDA may bring some changes. For readily soluble biopharmaceuticals in the biopharmaceutics classification system (BCS) 1 and 3, says Brown, regulators have said that traditional basket/paddle test methods should suffice. “New products in BCS 1 and 3 won’t need new exotic dissolution test methods,” he says. 

	In the recent past, FDA guidance had focused on validation, with the agency advocating the use of mechanical validation alone in validating dissolution test apparatus, without USP’s prednisone “tester tablets.” The argument against using the tablets was that they themselves could be subject to variability, and thus inject more variability into a process that can already be affected by environmental and equipment factors and technician training and experience.

	As Nir says, FDA’s guidance led some companies, particularly some of the larger name-brand companies, to change their approach, and to move to mechanical calibration for validation. However, many manufacturers, and particularly those in developing nations, continue to use the tablet testers for validation, he says.

	“If a manufacturer looks at its own dissolution numbers quite frequently, its products are much more likely to be consistent and to have tighter dissolution profiles, but that doesn’t make a very good diagnostic. The USP intentionally makes its calibrator tablets sensitive to multiple parameters. This way, if there is too much vibration, if component concentricity is off, or problems with other parameters, then this will be indicated by the testing” says Nir.

	Sometimes product batches will fail because of other factors. “From what we have seen, the single biggest parameter that people tend to get wrong is degassing. Not only are the tester tab- lets sensitive to physical factors, such as vibration, concentricity, and centration, they are also very sensitive to degassing,” says Nir. This can cause perfectly good batches of product tablets to fail dissolution tests.

	“When we respond to calls about test failures, and measure dissolved oxygen in the vessel, we often find that the level is too high. Even if the manufacturer has degassed properly, by the time they get the material into the vessel, they may have inadvertently re-aerated it, and there will be problems with the batch test,” says Nir.

	To get around this problem, Distek offers EZFill, a degasser that degasses and dispenses the media at the same time, providing better uniformity of degassing in the vessel itself to help prevent false alarms.

	Despite FDA’s guidance, USP’s position on calibration is that enhanced mechanical calibration alone is not enough to ensure quality. “Our standards already incorporate mechanical calibration, but we do not agree with the use of mechanical calibration alone,” says William (Jay) Pearson, project director, portfolio and program management at USP.

Mechanical calibration or tester tablets?

	“We suggest use of performance verification tablets because mechanical calibration alone may not be able to address some things that might be intrinsic to the setup of a given dissolution test in a given lab. The tester tablets have been designed to speak to these issues,” he says.

	Brown agrees: “It’s not sufficient to just look at speed and operation of the stirring element and the dimensions of vessel. If we really want to control performance, and variability due to the testing apparatus, we need to put a probe right where the apparatus is working. That is difficult to do by any means, but using a tester tablet is a good way to evaluate performance.”

	Dissolution test methods have been adapted for new formulations such as slow-release tablets. One technology that is becoming more prominent for longer dissolution tests (i.e., those lasting 24 hours or longer) is fiber optics, which, Nir says, can address problems such as evaporation and the need to replace media for sampling.

	The biggest problem with dissolution testing for extended release is that, if you’re running a fairly large number of sample points, you have to control evaporation but still have a way to get liquid in and out. “It’s very difficult to have a sealed environment because you need to run probes and have access points,” says Nir. “Fiber optics is a completely sealed measurement tool and lets you take as many measurements as you want without having to extract and replace media,” he adds.

	Distek purchased fiber optic testing technology from Leap Technologies in 2012. Use of the technology was first published by AstraZeneca in Sweden in 1988 (5), Nir notes.

	A number of companies are also work- ing with process analytical technologies (PAT) for dissolution testing (6). “There have always been projects that use fluorescence, near-infrared (NIR), and Raman spectroscopy. But NIR tends to be very sensitive to physical parameters, which is one of the challenges in implementing NIR for content uniformity. The models work very well until people change the manufacturing site, the compaction, physical parameters, or excipients. Then they have to develop a new model,” says Nir. Raman is great for selectivity, but that’s not a problem with dissolution, he says.

	Between ultraviolet (UV) and high-performance liquid chromatography (HPLC), virtually all bases are covered for dissolution testing, says Nir. One notable exception, however, is in processing nanoparticles, whether they are encapsulated or deposited on nanospheres. “These exotic dosage forms are giving people fits, not because HPLC or UV don’t work but because filters stop working, so the question then becomes: how do you arrest dissolution after you’ve pulled a sample if you cannot filter out all the existing remnant particles in that sample? That’s another area where fiber optics has become the go-to technique because it allows measurements in-situ in real time, eliminating the need for filtration,” he says.

	The use of spectroscopy, however, points to the potential to use principles of PAT and quality by design (QbD) for real-time release (RTR) testing. Recently, notes Nir, the industry has been abuzz since news came that Vertex Pharmaceuticals received approval to release an existing product using a model, rather than traditional dissolution testing (6). “It’s a very specific case, but points out what might be possible in the future,” Nir says. Vertex is doing online monitoring, he says, and applying PAT/QbD, instead of doing dissolution testing. However, Nir notes, the company did a tremendous amount of dissolution testing using fiber optics to get the data needed to develop the models.

	“Of course, one can correlate NIR to dissolution, but part of the reason the company could do this is because the product had been manufactured for many years so there was a tremendous amount of data to work with. It’s not like attempting RTR testing with a brand-new product,” says Nir.

	Innopharma Labs is developing predictive methods that model dissolution to optimize tablet coating for real-time release, as a way to ensure consistent coating despite variability in raw materials and other factors (7). In this approach, an NIR analyzer measures initial particle size at the start of processing. Initial size data are automatically fed to a dynamic process-control algorithm, which defines what is needed to add the correct amount of material per minute to achieve the coating thickness for optimal dissolution, and stops the process once it has reached a predefined growth level.

	USP is evaluating the use of PAT and predictive dissolution methods, although nothing has been incorporated into any specific standards or guidance yet. Nir sees the idea of doing this as very promising. “It’s nondestructive, and allows manufacturers to modify and improve the process. Someday it may even be possible, for example, that if a given formulation develops a problem that it could be fixed in real-time by adjusting some parameter like the compaction, allowing the manufacturer to save the batch,” he says. The question is how sensitive the models will be to future changes and differences in the excipients or manufacturing equipment used.

	Recently, multiple component analysis (MCA), a chemometric technique, was used with UV fiber optics to allow UV dissolution testing to be done on formulations containing two active ingredients (8). Normally, UV spectrophotometry would not be able to provide clear results for formulations that contain more than one active.

	The benefits of this particular form of MCA stem from the fact that it is a closed, rather than an iterative technique, says Nir. “You solve a series of equations and develop the model. Because these are well defined, it makes it easy to validate,” he explains.

	While efforts continue to improve the way the industry approaches dissolution testing, many pharmaceutical manufacturers take an ‘if it ain’t broke don’t fix it’ approach. “Those in the industry who are focused on making product are very happy with the dissolution test as it is,” says Nir.

.
	3. M. McAllister, Pharmaceutics, 7(5), pp 1374-1381, 2010.
	4. X. Lu et al., 

, September 2017
	5. M.Josefson,E.Johansson,A.Torstensson, 

.60 (1988) 2666–2671.
	6. I. Colon and J. Medendorp, “

Novel Approaches and Challenges in Dissolution Testing of Pharmaceutical Solid Oral Dosage Beyond Commercialization

Innopharma Labs Bets on Manufacturing 4.0

,” PharmTech.com, March 21, 2018.
	8. A. Kielt, I. Nir, et al., “Analysis of Two APIs...Using UV Spectrophotometry with Multiple Component Analysis with a Fiber Optic Dissolution Analyzer,” white paper, 

When it comes to dissolution testing, research is focusing on ways to extend its reach, improve in-vitro and in-vivo correlation, and make real-time release testing a reality.

Dissolution Testing: Keeping It Simple

Since the early days of biopharmaceutical manufacturing, upstream and downstream primary processing have been considered separate worlds. There was no profound reason for this separation, explains Charles Cooney, professor emeritus of chemical engineering at the Massachusetts Institute of Technology (MIT). “It goes back to the pre-biotech days of industrial bioprocessing, when the people involved upstream were mainly biologists, microbiologists, biochemists, and chemists, and the downstream people were usually chemical engineers, because they were engineering unit processes for product recovery,” he says.

	Still, these historic disciplinary roots have continued to organize and define the industry for decades, and the result has often been isolation, rather than integration, Cooney says. More recently, however, as financial pressures intensify and interest in continuous biopharmaceutical processing increases, distinctions between up- and downstream are starting to disappear. “The conversation is no longer split by differences in vocabulary and has become much more integrated,” he says. 

	Greater integration is also seen, he says, in the move to fed batch processes (now standard for monoclonal antibodies [MAbs]), perfusion processes (standard for therapeutic enzymes and more unstable products), and continuous chromatography, enabling, for instance, a continuous capture step using a perfusion culture. The industry may still be years away from adopting integrated, end-to-end biopharmaceutical process control, but it is getting closer. Enabling this move has been greater acceptance of approaches that had already been in use for years in other industries. such as food and chemicals. 

	FDA’s support of process analytical technologies (PAT) helped drive this change, says Bob Lenich, life-science business director at Emerson Automation Solutions, but economic pressures also play a role. “In the past, pharmaceutical manufacturers didn’t have to optimize manufacturing, but now they do, and they are applying more advanced analytics and control to help reduce costs,” Lenich says.

	Now that automation standards such as the International Society of Automation (ISA’s) S-88 and S-95 (1) have been adopted by the pharmaceutical industry, the current focus is on “plug-and-play” solutions that will reduce the cost of automation, says Christie Deitz, engineering manager at Emerson Automation Solutions. “Equipment vendors are looking at unit operations that can run continuously, and skids on wheels, whether for chromatography, filtration, or bioreactors, that they can reconfigure to get to the next run,” says Deitz.  Emerson, meanwhile, is extending use of its flagship DeltaV product, through the Discovery platform, into the R&D lab, secondary manufacturing, and packaging, and automation standards are moving from the plant floor to the lab and to secondary manufacturing. 

	Enabling this change has been greater adoption of PAT, the use of which is now widespread in biopharmaceutical manufacturing, both upstream and downstream. “Even though downstream processing is still practiced as individual batch processes, the use of PAT with those batches is quite standard,” Cooney says.

	Initially, use of PAT was limited to monitoring specific culture attributes upstream with near-infrared (NIR) spectroscopy, or performing transition analysis and performance studies with ultraviolet (UV) and NIR spectroscopies downstream, but there were challenges with sensitivity and specificity (2), explains José C. Menezes, CEO of 4Tune Engineering, Ltd.

	An important evolutionary step for PAT in biopharma came when companies moved from simply monitoring parameters to using PAT for process state estimation and to explore control opportunities. As Menezes explains, multivariate analysis was used to provide a complete estimation of the bioprocess state over time (e.g., a process trajectory during upstream cultivation, creating the opportunity to define guided sampling and endpoint determination strategies). NIR, mid-infrared (MIR), and Raman spectroscopy are all being used in this type of approach (2,3).

	Recently, Menezes says, some manufacturers have begun to use in-situ mass spectrometry in multiple attribute methods (MAM), a term coined by FDA’s Emerging Technologies Team to describe a method that aims to connect process condition-monitoring to accurate product quality-control during processing. “The ability to use mass spectrometry (MS) as a PAT [tool], and to aggregate the multiple attributes that it can very specifically measure, is a real breakthrough,” he says.  

	Using new approaches such as MAM to monitor product quality attributes, end-to-end, both upstream and downstream, will open up new uses for PAT in biopharma, Menezes predicts. “Not only will it be used earlier in biopharmaceutical development to build very fast process and product understanding, but to support process performance qualification (PPQ, Stage 2) and the entire commercial lifecycle (Stage 3),” he says.

	Most biopharmaceutical manufacturers are now at a stage where they are integrating quality measurements (typically spectral measurements) inline, so that they know they’re producing what they expected to produce, and connecting those measurements to closed-loop control, says Lenich.  “That approach is everywhere,” he says, “but the question has now become: Where can you take a new measurement that you didn’t have inline before, and how can you apply that measurement in a model to show that the process is working better?”

	Biopharma is also relying more on model predictive control (MPC), says Deitz, and a number of presentations at the International Forum on Process Analytical Chemistry (IFPAC) 2018 focused on this area, which is still relatively new for biopharma. 

	“Today, many of our biotech customers are using MPC to look at an individual unit operation (e.g., a chromatography column or a bioreactor process),” says Deitz, “and some are also using it to synch connected operations downstream, for example, when a chromatography column and a tangential flow filtration (TFF) skid are connected, and a specific liquid level must be maintained in the feed tank to the filter skid. MPC can help prevent disturbances (e.g., a tank overflow or insufficient liquid level) from impacting unit ops down the line,” she says. 

	At this point, MPC is being used more widely in secondary than in primary biopharmaceutical manufacturing to control more straightforward processes such as filling and powder management, says Lenich. Modeling is also being applied to optimize facility operations. Rather than focusing on yield, companies are using MPC to examine throughput more closely and improve manufacturing, he says.

	Modeling downstream biopharmaceutical processes remains challenging, however. “It’s not an easy thing to do. You need to know what’s going on in the process and you need a good understanding of the technology. You have to have the right people involved, and they need to be taking the right kinds of measurements,” says Lenich.At this point, he says, some crucial measurements exist offline in the lab, and it may take hours or days to get this information. “These data need to be moved inline or at line so that things can be done in real time,” he says, noting that Emerson is collaborating in a BioPhorum Operations Group study that is determining what kinds of measurements are needed to optimize manufacturing and improve quality in biologics. 

	Having a digital strategy is the key to fast, successful biopharmaceutical process development, says Cooney, who notes that analytics and good data are fundamental. “Analytics is the vocabulary with which process development people communicate with each other and regulators, and the chemistry, manufacturing, and control (CMC) filing is all about this,” he says. “What is new is the ability to use those analytics more effectively to learn what is important and to improve the quality of control. We are beginning to see the use of machine control techniques that will be the hallmark of process development strategies in the future.” 

	The final obstacle to increased use of MPC is regulatory. “Everyone appreciates that these approaches work. But FDA and industry are not sure how to validate what is essentially a black box approach,” says Lenich. “Guidance is starting to come but no definitive ruling, so, for many companies, the question is: when you are using MPC, how can you be sure you’re using the best approach and that it can be validated?” 

	Increased uptake of PAT has also led to more use of soft sensors in bioprocessing, not only within unit operations, to provide real-time estimates of hard-to-measure parameters or end-point predictions, but across operations, says Menezes. “As data-management becomes sophisticated at most companies, the possibility to retrieve and aggregate data from critical process parameters (CPPs) and critical quality attributes (CQAs) in real-time will allow CQA estimates during processing for subsequent operations. That opens many possibilities for end-to-end optimization and feedforward control that will make pharmaceutical quality by design a reality in bioprocessing,” he says. Examples already exist in areas such as media, relating quality attributes to upstream yields or stability (4).

	Although the use of continuous manufacturing is much more evident in small-molecule oral solid dosage form manufacturing, all major biopharmaceutical companies are evaluating continuous, at least at the unit operations level. Some companies, such as Merck, Bayer, and Sanofi, have begun to explore the potential for continuous end-to-end primary biopharmaceutical manufacturing.

	End-to-end continuous biopharmaceutical manufacturing will require global integrated control. At this point in biopharmaceutical manufacturing, control is typically handled locally, says Cooney. However, growing interest in end-to-end continuous manufacturing is stimulating development of global control strategies. One prototype employing this approach has been developed by Chris Love, associate professor of chemical engineering at MIT. It involves a fully-integrated biologics process done at a very small scale, in an installation that is roughly the size of a refrigerator (5), says Cooney. 

	Love’s project, part of MIT’s Biomanufacturing Research Program (BioMan), was originally sponsored by the US Defense Advanced Research Projects Agency (DARPA), with the goal of developing a process to make biologics on demand to manufacture small lots of material in response to emergencies. It uses a continuous, highly integrated process that can deliver doses of biologics, says Cooney, and would enable highly distributed biopharmaceutical manufacturing strategies. All of the major biopharmaceutical manufacturers with continuous manufacturing research in progress are paying very close attention to the control strategy, says Cooney. “If you’re going to run an integrated process, you have to have an integrated control strategy in place. The systems control industry is prepared to deliver the technologies (e.g., DeltaV) that are needed for this approach.” 

	“Bottlenecks often come when a biopharmaceutical manufacturer tries to put a business case together for moving to continuous or integrated processes,” says Cooney. “The right business case must be in place, and that case is typically based on one or more of four metrics: cost, quality, speed, and flexibility,” he says. “If you own a big stainless-steel manufacturing plant and are making a good product, you’d be hard pressed to throw that all away and start over again with continuous, but if you’re expanding capacity and you want to be able to respond with greater agility to market trends and forecasts, then continuous becomes very attractive,” he explains.

	Batch processes do pretty well, Cooney says, but if one or more of the four business-case criteria are of concern, then continuous processing can offer an effective solution. Improved quality can be one incentive, he notes. Reduced capital expenditure and operating costs can be another. 

	Other issues make the move to continuous manufacturing and integrated process control more challenging. For example, Cooney says, continuous process requires adaption and use of different unit operations, and different integration and interfaces are required between them. The biopharmaceutical industry is just starting to learn how to handle these interfaces,” he says.  

	The third challenge is operating existing, successful batch processes if the batch unit operation is different from what would be done continuously. The emergence of single-pass TFF has been somewhat enabling to the adoption of membrane filtration to continuous manufacturing, says Cooney, as has the use of multicolumn or continuous chromatography, or replacing batch acidification for viral inactivation with a continuous reactor. Menezes sees the following as the top challenges to integrated control:

		Operations stability over long periods of time

		The integration of upstream and downstream processes with very different unit operations, in terms of dynamics and duration

		Insufficient data aggregation capabilities and a dearth of IT platforms that can extract information automatically to support effective decisions and control actions

		Insufficient end-to-end lifecycle risk and knowledge management

		Limited ability to provide regulatory reviewers and inspectors with evidence and rationale for risk-based change management.  

	Menezes predicts that plant modularization and new designs will be a major driver in reshaping the industry, and process control, for the next decade.

,” isa.org
	2. J. Menezes, “Process Analytical Technology and Quality by Design in Bioprocess Development and Manufacturing,” Industrial Biotechnology, Volume 3, Ed. A Moreira, in Comprehensive Biotechnology (2nd Edition), Moo-Young Ed., Elsevier, pp 501-509 (2011).
	3. “NIR Spectroscopy in Laboratory and Process Analysis,” 

(Wiley, 2012), DOI:10.1002/9780470027318.a9361
	4. “Method and System for Preparing Synthetic Multicomponent Biotechnological and Chemical Process Samples,” Hoffmann-La Roche AG, WO/2015/097217
	5. MIT, “

MIT Team Receives $10.4 Million Biomanufacturing Grant from DARPA

,” mit.edu, Press Release Sept. 18, 2013


	Vol. 42, No. 7
	July 2018
	Pages: 42–45

	When referring to this article, please cite it as A. Shanley, “Moving Toward Unified Process Control for Biopharma " 

Traditional barriers between upstream and downstream bioprocessing are slowly starting to break down, as biopharma embraces more advanced analytics and process control.

Moving Toward Unified Process Control for Biopharma


	Vol. 42, No. 7
	July 2018
	Page: 52–54, 61

Clinical trials are the proving ground for any new pharmaceutical. On average, these trials take approximately seven and a half years to complete (1). For manufacturers, who can spend anywhere from $161 million to $2 billion to bring a new drug to market, the returns from investing in this important work have been diminishing. Patient recruitment and retention, which cost $2.3 billion per year (1), have become a major challenge. Typically, one out of every four patients drops out of the average clinical trial. In addition, problems with recruitment and retention can often result in longer and more expensive trials, less statistically valid results, and poor morale among clinical staff, healthcare providers, and patients (2). 

	As the population continues to age and pharmaceutical manufacturers shift their focus to chronic and degenerative disease research (1), resolving patient recruitment and retention problems has become a key priority. Seven years ago, armed with online technology, advances in cloud computing, and wireless communication tools, pharmaceutical companies that include Pfizer and Sanofi turned the traditional clinical trial model on its head, bringing the trial direct to the patient (3). 

	In this direct-to-patient (DTP) approach, trials follow the same blinded protocols, but patients receive medication in their homes, so they do not have to travel to medical facilities or wait for services. For pediatric patients and the elderly, the convenience of DTP trials can determine whether they choose to remain in the clinical study or not. 

	The DTP approach has also been shown to reduce overall costs. Research suggests that it can help reduce costs by up to 16% in Phase I trials, by up to 22% in Phase II, 17% in Phase III, and by up to 13% in Phase IV (1). 

	According to a 2017 survey by Arena International, DTP clinical trials are growing rapidly, and should increase from 24% of all clinical trials in 2017 to 33% by the middle of 2019 (4). 

shows one logistics services provider’s top DTP destinations globally, while 

shows its volume of DTP shipments from March 2017 to 2018. 
	

Coordinating drug and lab sample deliveries 

	For cold-chain logistics specialists, the DTP model poses many additional challenges, especially since precision medicine also requires regular patient laboratory tests. Scheduling lab sample drop-offs and pickups adds to the challenges of delivering patient doses.  

	Other new changes stem from going “off the grid,” with drivers leaving the main highways and navigating local streets and residential locations, and learning how to interface most effectively with healthcare providers and patients, without compromising patient privacy. 

	The most basic challenge, ensuring that treatments remain safe and viable, has also become more pronounced, since today’s clinical trials increasingly involve novel therapies such as immunogenic, cell, and gene therapies. 

	Today, a typical pharmaceutical manufacturer may take a variety of approaches to clinical trials. Some companies are working on developing end-to-end DTP clinical trials. In May 2018, exemplifying this trend, Science 37 and UCB Parma launched a partnership to use Science 37’s MetaSite approach and cloud-based Network Oriented Research Assistant (NORA) network to develop site-less clinical trials (5). 

	In other cases, within the same trial, different approaches may be used with different portions or phases, with some being run traditionally, and others using the DTP model. However, as the DTP approach becomes more important to the industry, logistics companies are stepping up their services to support this growing business. 

	In March 2018, Marken, now part of UPS, launched a service that will allow nurses to drop off clinical trial samples from patients at any UPS store location. The company already offers DTP services in 51 countries. 

	World Courier, part of AmerisourceBergen, began to expand its involvement in DTP clinical trials back in 2012, and established a partnership with the Medical Research Network (MRN) in 2015. The alliance aims to create a more highly integrated model for community-based clinical trials that increases patient recruitment and retention. 

	The company is currently revamping its global transportation management system worldwide, a process that has involved a lot of localized DTP work, explains Michael Sweeney, senior director of patient-centric logistics at World Courier. Sweeney was formerly director of global service development, with a broader concentration on high touch personalized supply chain services, including cell and gene therapy. His role shifted to a steady focus on DTP a few months ago, reflecting the increased importance of the model in the industry and World Courier’s business plans. Sweeney shared some insights into the overall market, and World Courier’s activities, with 

: How long and how extensively have you been working with DTP clinical trials? 

: We’ve been supporting these types of trials for a number of years, but demand for DTP has dramatically increased since 2014. In fact, it more than doubled between 2015 and 2016 alone.  

	Since 2012, we have handled DTP shipping for 424 customers in 52 countries involving 386 different trial protocols. We also ship DTP for expanded access and compassionate use products. This means that we handle hundreds of DTP shipments weekly. 

	There is no ‘typical’ client for DTP work. Customers include traditional Big Pharma companies, as well as contract research organizations (CROs), clinical trial home care nursing firms, contract development and manufacturing organizations (CDMOs), clinical packaging service companies, central laboratories, and small innovator biotech companies. 

: How does the relationship work with home care nursing providers such as MRN? 

: Collaborations, like ours with MRN, are designed to simplify patient participation in clinical trials. A qualified nurse visits the patient in his or her home and performs all medically necessary procedures required by the clinical trial, which may include infusion and collecting blood or urine samples. World Courier delivers or picks up related materials to and from the patient’s home and the clinical trial site. We have created detailed standard operating procedures to ensure compliance with the regulations, patient confidentiality, and protocol support. 

: What are some new technologies that can enable the DTP approach to operate most effectively? 

: One innovation that we offer through a collaboration with our sister company, Cubixx Solutions, is CubixxCT, a small access-controlled refrigerator that stores drug products at an optimal 2–8 °C temperature in the patient’s home. It tracks usage, provides reports to researchers, and enables real-time temperature monitoring and PIN-controlled access. Plus, it eliminates the need for frequent deliveries where relevant and ensures the product is available when medical staff arrive to administer it. 

	In addition, World Courier’s Bio-STAR system provides real-time access to protocols and special handling instructions, helping to anticipate and prevent costly shipping issues problems that can come up during any clinical trial. 

: Does your new job title reflect any change within the company and the industry? 

	Sweeney: As healthcare moves towards a patient-centric approach and clinical trials expand in growing markets, the DTP model is becoming increasingly popular. In March, World Courier launched international personalized supply chain teams that support three specialty areas, all of which experienced double-digit growth, that include DTP. The technical experts work directly with our customers, offering a combination of project management and customer service to deliver a service tailored to specific requirements and, ultimately, connect patients with the vital treatments they need. 

: What are the most important aspects of planning a DTP clinical trial logistics program? 

: The most important part is getting the initial plan right, and making sure that it is broad enough. The planning process, and the plan, should involve everyone who will be involved in the project. It should spell out clearly the scope of work, the resources that will be needed, when the project is expected to be completed, and, generally, ensure that everything within the plan ties back into (and works in) the real world. 

	Planning is extremely important in dealing with complexities. In some cases, patients are just receiving medications. In other cases, their drawn specimens will need to be delivered to labs. This requires careful coordination and timing. 

	Quality control and assurance are also paramount, particularly temperature monitoring. Basics need to be established very early on (e.g., in case of an emergency, who must be informed, and is there a contingency plan in place if drug safety is compromised?) 

	There is also the challenge of randomizing the supply, interfacing with nurses, and handling the logistics of specimen testing at the central lab. All of these factors must be taken into account in the original plan. 

: How has the timeframe required for clinical trial logistics changed under this new DTP model? 

: We’re interfacing directly with patients at home in some cases, and also often with nursing companies. And we’re working on just-in-time delivery. In the past, we were used to a broader timeframe. Now, nurses are often prepping patients while deliveries are on the way. Drug quality verification is extremely important, and verifying temperature results to ensure that the drug is safe before the patient receives it.  

: How has your company changed its approach to transportation management? 

: We’ve been developing a new platform, corporate-wide, for some time to replace our previous transportation management programs worldwide. This platform encompasses everything from local DTP projects to highly complex international projects. 

	We began its initial deployment in Canada. Sample shipments were handled within certain market segments, and, eventually, we plan to use this approach throughout the world as we assess timelines and functions. So, right now, we are at Release 1, and are planning to add countries and broaden the deployment scope in the weeks and months ahead.

: Do you see global clinical trials moving to a DTP model? 

Demand for direct-to-patient services is exploding. Michael Sweeney, senior director of patient-centric logistics at World Courier, discusses issues that the new model presents. 