Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

FDA’s current good manufacturing practices for finished drugs were first published in 1963 (1), a year before Bob Dylan’s song captured the spirit of change that was to define the decade. GMPs would become law in 1978. At most pharmaceutical facilities, however, little had changed since the 1950s, with the same manufacturing processes and equipment, and the same test-centered approaches to quality assurance.

	Decades later, pharma has remained in that same time warp, as Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), said at the American Association of Pharmaceutical Scientists’ annual meeting in 2011 (2). She shared predictions that pharmaceutical manufacturers would spend the next 25 years moving to cleaner, flexible, and more efficient continuous manufacturing. Years earlier, FDA had established a framework based on statistics, multivariate analysis, and more advanced process control, to help them reach this goal (3).

	Six years into that transformation, change may be more of a trickle than a flood, but it is starting in oral solid-dosage-form (OSD) facilities, as more companies explore alternatives to batch manufacturing. “In manufacturing, nobody in pharma wants to be the first to introduce anything new,” says Dave Di Prospero, director of pharmaceutical process technology at CRB USA and cofounder of the International Society of Pharmaceutical Engineers (ISPE)’s OSD Community of Practice. “But, with FDA approvals of new continuously manufactured drugs by Vertex, and the transition of a legacy therapy from batch to continuous by Johnson & Johnson’s (J&J) Janssen Pharmaceuticals, more companies are getting on board with continuous processing,” he says, “so the ‘first’ is now behind us.” The European Medicines Agency approved Janssen’s continuous line for Prezista (Darunavir) in June 2017, a year after FDA.

	Continuous processing is being used at Novartis, which first brought the technology into mainstream conversation with its 10-year, $65-million research program with the Massachusetts Institute of Technology, as well as Pfizer, Merck, and GlaxoSmithKline.

	Contract manufacturers are also investing in continuous. Patheon, for instance, completed a continuous manufacturing facility in Greenville, NC earlier this year, appointing former Rutgers post doc and Janssen process engineer Eric Jaycock (4) as director of continuous manufacturing. “I thought they would be the last ones to grab hold, but CMOs want to offer continuous processing as a service, and view it as a competitive advantage,” says Russ Somma, principal of Sommatech Consulting. “Having CMOs in the game allows more manufacturers to dip their toes into continuous processing without risky investment,” he adds. 

Generic-drug manufacturers are attracted to continuous, based on its potential to reduce the cost of goods, as well as plant footprint, staffing, raw materials, and solvent requirements, says Bayan Takizawa, an MD and chemical engineer, cofounder, and chief business officer of CONTINUUS Pharma, a spinoff of the MIT-Novartis partnership whose goal is to help more companies understand and harness the benefits of continuous processes. The company offers its Integrated Continuous Manufacturing (ICM) platform (

), which encompasses continuous production, from raw materials and APIs through finished dosage forms, and was developed through the MIT-Novartis partnership. “Generics margins are significantly lower than those of big pharma, so even if we can reduce cost of goods by 30-50%, that’s a huge impact,” he says.

	Pfizer is using continuous on both extremes of the value spectrum, reducing throughput and costs for some of its high-volume generic APIs, but also for high-end products including personalized therapies. “Inherently, you have to understand the process better in order to manufacture continuously than you do in batch, so you have to work harder upfront and invest more during the R&D period with continuous,” says Kevin Nepveux, vice-president of global technology services at Pfizer, “but it pays off in a more reliable process.”

	“Agility also becomes more important with personalized therapies,” he says. “And with semicontinuous you can reduce lead time by 50% or more, so you can respond to accelerated approvals or changes in market demand.”

	Over the past few years, adoption of continuous processes had increased at a lower than expected rate, says Pamela Docherty, life-sciences industry manager at Siemens. However, she notes that more pharmaceutical companies are now working on continuous processes for legacy products, while more equipment vendors are offering solutions designed for continuous operations. Within the next two years, she says, these changes, plus a growing number of continuously manufactured products in R&D, should result in a second spike in approvals of continuously manufactured drugs that could lead to exponential growth.

	By working with academic consortia and pharmaceutical companies, equipment manufacturers have become important partners in the move to continuous processing. “We’ve gotten to where we are now through collaboration involving pharmaceutical companies, equipment vendors, and academia,” says Di Prospero.

	GEA Pharma Systems, which entered the continuous area in 2003, established a joint venture with Siemens in 2016, leveraging the SiPAT analytic software and Siemens’ advanced process control platforms, together with its continuous OSD platform, ConsiGma, which is already being used by a number of big pharma companies. The system integrates raw material dosing and blending, wet or melt granulation, drying or cooling, tableting, and coating on one line, with online quality control built in. Other equipment vendors that are active in continuous include L B Bohle, Glatt Process Systems, and IMA, a tablet press manufacturer based in Italy, which is an investor in and strategic partner with CONTINUUS Pharmaceuticals.

	Obstacles remain to industry’s adoption of continuous, however. There are some lingering doubts about regulatory support, as well as technical challenges, particularly around real-time release testing (RTRT) (

	On the practical side, there is also a need for equipment designs that would speed cleaning and product changeovers at continuous lines. In some facilities, it can take several weeks to tear down, clean, and set up a continuous line, says Di Prospero.

	Novartis and MIT envisioned homogeneous, end-to-end continuous manufacturing in their research, and Novartis is working on an end-to-end continuous facility in Basel, Switzerland. Upstream, continuous processes are being developed for APIs (

), and for biopharmaceutical manufacturing.

	“Implementing the end-to-end approach is really challenging, from the technical but also from the corporate side, and it’s unlikely that we’ll see more than a handful of companies taking this approach in the next decade or two. It’s simply too front-loaded from a cost perspective, and there’s too much product-specific complexity to be addressed to allow the business case to work out,” says Doug Hausner, associate director of the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey. 

) has been around for 10 years now, collaborating with industry and regulatory agencies, and has transferred continuous process knowhow to industrial partners including Janssen, which collaborated with C-SOPs on the continuous direct compression process that it uses at its facility in Puerto Rico (5). Hausner expects continuous to be developed, first, for OSD and then for APIs, but sees limited instances where there will be a clear business case for integrating the two.

	Each company’s decision whether or not to adopt continuous processes, and where to use them, will be based largely on its tolerance for risk, says Takizawa. Most companies today are taking a case-by-case strategy.

	Adoption will also depend on how opportunities arise, says Jamie Clayton, operations director at Freeman Technology, a UK vendor of powder flow characterization technologies. Many different configurations are possible, involving combinations of continuous, semicontinuous, and semibatch systems, which can all be considered some form of continuous processing. “In some cases, companies may use continuous process equipment for unit operations as discrete elements within a larger overall batch process,” he says.

	On the process side, continuous processing has intensified interest in direct compression, a simpler and less energy-intensive OSD process than dry or wet granulation, which involves the addition of liquid, high-shear granulation, and drying, says Hausner.

	Continuous eliminates the need for scale up, one of the biggest bottlenecks in drug development, allowing manufacturers to move more nimbly into clinical and commercial production. “With continuous, you don’t scale up; you scale out, by extending your processing time, which can save a lot of money,” says Takizawa.

	Eli Lilly, which has also collaborated with C-SOPS, is using direct compression at two identical GMP facilities, one in Puerto Rico and another in Indianapolis, where a third development facility is based. As Hausner explains, the three facilities are identical down to the software, except for a refill system on the commercial production line. 

	The company’s strategy is designed to leverage information at earlier development stages, and streamline process development. “As soon as they get a new molecule and have enough material available for experimentation and process development, they can do development and have the commercial process figured out by the time Phase II clinical trials begin. This way, they’ve minimized variability within clinical trials, and, if and when the drug is approved, they’ll be ready to go,” says Hausner. The twin GMP plants won two category awards at the 2016 International Society for Pharmaceutical Engineers (ISPE) Facility of the Year Award program (6). 

	Advances are also being made in continuous wet granulation, aided by research collaboration with equipment manufacturers. GEA has been working with academic consortia and pharmaceutical manufacturers in this area.

Vertex uses continuous wet granulation, while Pfizer uses both continuous direct compression and continuous granulation. The company worked with GEA and other equipment vendors on a proprietary mixing platform that blends multiple ingredients and sizes particles continuously. It includes an automated weigh dispense system, continuous mixing, and continuous granulation allowing users to go from weigh dispense to mixing/granulation to a tablet press. Nepveux and his colleagues plan to add a few more unit operations to Pfizer’s continuous portfolio. “We can select all or parts of the platform to use, depending on the product,” he says, “and it will be the main way that we develop innovative OSD, and transfer legacy products from batch to continuous when it makes sense.”

	In one project (6), GEA and Freeman Technology used QbD principles to see how raw material properties influence granule properties in a wet granulation, and how granule properties then determine critical quality attributes in tablets, says Clayton. Using Freeman’s FT 4 powder rheometer and GEA’s ConsiGma 1 high-shear wet granulator, studies showed a direct relationship between bulk flow properties of granules and tablet hardness.

	“We’ve done quite a lot of work with dry and wet granulation, to learn how granulate properties can be targeted by adjusting critical process parameters, and how granule properties can then be linked to the critical quality attributes of tablets,” Clayton says. The company is currently marketing Lenterra flow measurement tools, which are process analytical technology (PAT) devices that can measure drag force and wall shear stress to monitor processes in-line or define optimal process parameters or granulation endpoints.

	Some of the most important advances in continuous OSD have come on the feed side, says Di Prospero, because it is important, but challenging, to achieve a good feed of ingredients, including API, in a controlled and accurate configuration. Lilly spent a considerable amount of time perfecting this technology, he says. Accuracy is improving as more is understood about how the physical properties of raw materials effect the process (7), and vendors are offering solutions designed for continuous processes, such as Coperion K-tron’s smart refill technology, which uses an algorithm to store and trend weight to speed measurements (8).

	GEA, meanwhile, has incorporated better feeding mechanisms in its integrated continuous equipment designs, such as ConsiGma. Miniaturization and close integration have enabled major improvements in equipment design, across the board, says Richard Steiner, business development manager for pharma applications at GEA.

	One of the biggest attractions of continuous processing is the reductions in facility size and layout that it permits, says Di Prospero. In a typical batch processing facility, dispensing, granulation, milling, blending, compression, coating, and sub operations are running, each requiring a room and additional support spaces, he says. In a continuous facility, they are linked together and can fit in a single room. “We’ve seen square footages go from 30,000 to 40,000 down to 3000 or 4000 with continuous,” he says. “And with reduced footprint comes reduced utility requirements and less heating, ventilation, and air conditioning (HVAC).

	Continuous processes also lend themselves well to containment, which has become a prerequisite since formulations have been using highly active pharmaceutical ingredients, says Somma. “With traditional batch, containment is needed at the dispenser, granulator, and every other transfer point within the process. With continuous, you’ve reduced your need for containment from 15-20 points down to two, says Di Prospero.

	Both containment and miniaturization trends come together in the Portable Continuous Miniature and Modular (PCMM), portable, GMP OSD facilities that combine G-Con’s modular production pods and GEA’s continuous processing technology. Pfizer has developed a prototype of the concept, which would allow units to be rapidly deployed where and when needed (9).

	Users say that quality by design and process analytical technologies are essential for continuous processes. “You cannot control continuous processes with traditional in-process control sampling and off-line, laboratory-based testing,” says Nepveux. 

	PAT has improved significantly in the past 5-10 years, he says, to a point where it has become an enabler for continuous, Nepveux says. “We’re getting away from big instruments that you try to plug in through a port.” In the past, he notes, it was a challenge to get a window into a process and be sure that it was truly representative of what was going on in that process. Today, Nepveux says, creative sensing technology avoids this problem.

	“There are technically effective and cost-effective PAT sensors that can look at potency, particle size, moisture, blend uniformity, and all the different types of measurements that you might want to take across a process,” he says, “so that part is there now.”

	An area where industry remains challenged is in overall continuous process control, notes Di Prospero. “As continuous OSD plants run, there may be situations where, for example, mixer speeds have to change without affecting the endpoints,” he says, so there is a need to control all the processes and have them talk to each other. “The hardware pieces are all there, but the software and the control integration with PAT is still evolving,” he says.

	Different companies may take different approaches to control, says Nepveux, with some basing it on residence time, and others on a feedback loop in which real-time results are used to modify key parameters to maintain the same output. “The question then becomes: Are you going to assume that your inputs are fixed, or do you expect them to have reasonable amount of variability, and have processes adapt to that?” he says, noting that Pfizer takes the latter approach.

	The other big challenge has been the control systems themselves, not just single loop but multivariate, high-level process control. “You can make a unit operation continuous, but if you cannot control it effectively, then, when you have to connect to other steps, it won’t go very far,” says Nepveux.

	However, pharmaceutical manufacturers are showing interest in using advanced process control, or model predictive control, for different interacting components within the line. “They want to go beyond traditional proportional-integral-derivative (PID) control and ensure that the process stays within specifications and remains stable,” says Docherty. “Pharma wasn’t using this type of control all that much in the past, but now some applications require it,” she says.

	Pharmaceutical manufacturers are also beginning to recognize the benefit and importance of soft sensors, computer programs that process different measurements and calculate new data points based on the interactions of those measurements, without requiring that data to be physically measured.

	“In the beginning, everyone was looking for the best online analytical device, but now that there is a better understanding of process control, people realize that the data required already exist. With these tools, predictive modeling makes a lot more sense,” says Steiner.

	One of the biggest concerns for pharma has been regulatory attitudes toward continuous manufacturing. With some modernization programs in the past, such as PAT and QbD, there was high-level support within FDA, but it didn’t always filter down to the troops performing inspections or reviewing products. Some companies may still be concerned about this happening with continuous says Docherty.

	“It could be an issue if a lot of people were suddenly moving to continuous,” says Hausner. “But the adoption rate has been gradual.” Besides, he notes, FDA has recruited more engineers (including some C-SOP’s graduates) and revamped its inspection program so that inspectors either specialize in food or pharma, but don’t have to do both.

	Clearly, FDA is investing more resources in better understanding continuous processing, says Hausner, and, as more successful results have been demonstrated, the agency has gone from merely accepting the technology to actively supporting, even advocating for it, he says.

	At the end of 2016, CONTINUUS began work with FDA, constructing an end-to-end continuous line that will be used to study and better understand phenomena that are critical for the regulatory review of continuous systems, such as RTRT and traceability, says Takizawa. C-SOPS has helped train FDA staff in continuous concepts and methods, says Hausner.

	Meanwhile, EMA’s approval of Janssen’s continuous line in Puerto Rico may inspire more manufacturers. Regulators have already invited companies to discuss issues with them before implementing continuous and including it in a new drug application or a post-approval change request, Hausner says.

	Because pharma is still at a relatively early stage in its exploration of batch alternatives, it faces a “chicken and egg” situation, says Hausner. Companies want more case studies to convince management to invest in continuous, while regulators want to see more applications before they issue specific guidance documents, he says, noting that lack of guidance can then detersome companies from filing applications with continuous.

	Recently, the US Pharmacopeial Convention (USP) has become more involved in continuous. The group held a meeting on the subject in June and previously released a video on the topic on YouTube (10). Its involvement could help convince more companies to evaluate continuous more closely. In the meantime, a growing number of implementations suggest that more manufacturers are questioning the status quo, nudging OSD manufacturing out of its time warp and toward more modern approaches.

,” Presentation, ISPE’s NJ Chapter Day, June 17, 2009. 
	2. S. Chatterjee, “

FDA Perspectives on Continuous Manufacturing

,” Presentation, IFPAC General Meeting, January 2012.
	3. FDA, “

Innovation and Continuous Improvement in Pharmaceutical Manufacturing

,” Report, April 2004. 
	4. Patheon, “

Patheon’s Eric Jaycock Discusses Continuous Manufacturing in Pharma

,” Video, March 28, 2017.
	5. Freeman Technology, “A QbD Approach to Continuous Tablet Manufacture, Application Note, freemantech.com.
	6. ISPE, 2017 ISPE Facility of the Year Award Winners Announced, Press Release, February 6, 2017.
	7. C. Blackshields and A. Crean, “

Continuous Powder Feeding for Pharmaceutical Sold Dosage Form Manufacturing: A Short Review

,” Report, June 23, 2017. 
	8. S. Nowak, “

Improving Feeder Performance in Continuous Pharmaceutical Operations

Paving the Way for Continuous Manufacturing

Pharmaceutical Technology Equipment and Processing Report

Pharmaceutical Continuous Manufacturing Technology and Applications

	When referring to this article, please cite it as A. Shanley, “21st-Century OSDs: Times, They Are a Changin’,” 

Articles

Pharma’s test of continuous manufacturing is starting with oral solid-dosage forms.

21st-Century OSDs: Times, They Are a Changin’

	Led by advances in oral solid dosage (OSD) form manufacturing, continuous processing is at an interesting crossroads in pharmaceutical manufacturing today, says Doug Hausner, associate director of the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey.
	
	“In less than two years’ time, we will have seen the complete wave of first adopters enter the market with their first continuous processes.”  From a regulatory standpoint, pharmaceutical manufacturers have been “learning by doing,” he says, as early adopters of continuous processing pave the way for the result of the industry.

	The technology hasn't been around long enough in pharma, and its adoption so far has been gradual, so global regulators are unlikely to issue specific guidance or directives for continuous processing in the short term, says Hausner.  instead, they are quietly encouraging use of the approach and promoting discussions with manufacturers before pharmaceutical companies implement the technology or file formal new drug applications or post-approval changes involving continuous processing.

	Lack of regulator guidance may have led to misunderstandings, since perceptions of regulators’ positions can make or break any innovative technology.  As Hausner says, work on continuous processes has been going on in pharma for more than 10 years, but early efforts were often piecemeal.  “The prevailing thinking in industry at that time was that FDA and regulators would never let us do this, so why waste our time,” he says.

	C-SOPS, like other collaborative industry-academic groups, has established an open forum and community of practice where companies could share best practices and work on technical issues.  “We were able to engage the FDA and other regulators to show the significant accomplishments that were being made in the field. As projects provided more evidence of continuous processing’s potential for reducing variability and cost and improving product quality, FDA became, not just accepting of the technology, but its advocate,” Hausner says, “which prompted companies to move forward [with continuous projects] much more so than they might have done otherwise.”

	US regulators are fully supportive of continuous processing, but there may be lingering concerns about global regulators’ positions on the technology. “European regulators are very accepting of continuous technology, but perception can have a major effect on what companies decide to do and when.”  C-SOPs has been getting the word out internationally and actively involving regulators to help clarify any misunderstandings and make it easier for companies to get acceptance for continuous from within their own organizations, Hausner says.

	On May 9, 2017, the Summit on Oral Solid Dosage Continuous Manufacturing, held in Malta, experts from industry, the government, and academia examined some of technical and regulatory issues facing companies that are moving from batch to continuous processing. The event was sponsored by the International Institute for Advanced Pharmaceutical Manufacturing (I2APM), a global coalition of academic research centers, of which C-SOPS is a founding member. Hausner offered insights into what was discussed at the summit in a recent interview with 

	In attendance were representatives from pharmaceutical manufacturers such as Janssen Pharmaceuticals and Eli Lilly, which have adopted continuous processes, as well as academics and members of the regulatory community. Since continuous and semi-continuous process technology has made the greatest gains so far in oral solid dosage form (OSD) manufacturing, that was the focus of discussion. The goal with meetings like this is to establish a global community of practice to help pharmaceutical manufacturers move from batch to continuous, says Hausner, by convening and researching, but also training the next generation of contributors to the field.

	One point that a number of speakers emphasized, Hausner says, is the richness of data that come from continuous processes.  This knowledge increases the level of process understanding for future OSD manufacturing efforts, according to Rutgers professor Fernando Muzzio, director of C-SOPS, who highlighted the various ways in which continuous manufacturing improves process understanding (1).  As he pointed out, “Continuous processes generate more information each minute than a batch process produces for the entire length of the batch.”

	Lawrence De Belder of Janssen Pharmaceutical (2) reiterated the ways in which continuous process development can increase process understanding, but cautioned the audience on the need for change management. Trust must be built throughout any organization, he said, if the vision for enabling change is to be realized. 

Need for harmonization and interoperabiity


	
	He also pointed out what equipment and technology vendors might consider doing to ease the adoption of continuous processing. Creating and adopting standards and other support for equipment interchangeability would be an important first step, he said. However, De Belder noted, regulators should harmonize global requirements and be more flexible about small formulation changes, and also enable the parallel use of batch and continuous processes as a way to build a more flexible supply chain, says Hausner. Existing regulations can prevent companies from doing this, Hausner notes, a point that was addressed by subsequent speakers on the program.

	The next few presentations focused on regulatory issues affecting continuous processing.  Christine Moore, who had championed quality by design (QbD) for 11 years, when she worked at FDA’s Center for Drug Evaluation and Research (CDER) spoke about issues that may be impeding the adoption of continuous manufacturing.  However, this time she spoke, not as a regulator but from the vantage point of industry, as executive director and global head for CMC policy at MSD in the US. 


	
	Currently, she said, the biggest challenge that pharmaceutical companies face with continuous processing is alignment (3). Specifically, she said, there is a need for alignment on control strategies, as well the ability to use multiple formulations during the transitional stage, when both batch and continuous processing may need to be used for the same product. This lack of alignment has made it more difficult for advocates in drug development and manufacturing to make a strong internal business case for continuous, and may be slowing rates of adoption, she said.

	Robert Bream of the European Medicines Agency (EMA) described an open, if not encouraging, approach to continuous processing that EMA is taking, despite lack of explicit guidance. However, Bream noted the fact that products with different compositions cannot be governed by the same marketing authorization application (MAA) and marketed simultaneously. Companies must be aware of this fact, since it can have an impact when manufacturers attempt to convert commercial products from batch to continuous operations. Janssen did this successfully with its drug, Prezista, in 2015, and more companies are now trying to gain experience in continuous by converting commercial operations from batch to continuous, Hausner says.

	An academic panel discussion followed, Hausner says, in which the different centers within I2APM spoke about their recent efforts in continuous, after which Wyatt Roth of Eli Lilly presented the company’s strategy for continuous in OSD (4).  Lilly is using continuous processing to accelerate new chemical entity (NCE) development and launch. The company has established a default continuous OSD manufacturing platform based on direct compression, implementing identical lines across R&D, clinical, and commercial manufacturing.  So far, Wyatt said, the company has processed more than 10 molecules via continuous methods.

	Returning to the regulatory sphere, Ewan Norton of the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) then shared his experience performing plant inspections at sites owned by early adopters of continuous processing (5). According to Hausner, he focused his talk on the post-approval aspect of continuous process implementation. For the most part, Norton said, inspectors treat inspections of continuous operations the same as they do batch operations, and the overall facility risk rating is unaffected. However, he noted, they may tend to focus on in-process testing, and issues related to analytical equipment malfunction/redundancy or calibration.  


	
	Sampling and control strategies for direct compression were then discussed by Robert Meyer, head of innovation and new technology development at MSD (6). So far, he said, work has demonstrated that a well developed process model, coupled with parametric feeder control, can result in less variability than an in-line analytical method.  Meyer advocated using this approach, with analytical methods used separately for sampling.

	The last few sessions on the program focused on international coordination, and public and private partnerships within I2APM and other organizations, says Hausner.  Rutgers professor Alberto Cuitino discussed public-private partnerships (7), while Ding Ming, the United States Pharmacopeial Convention’s (USP’s) vice president of innovation, spoke about the organization’s efforts to support continuous manufacturing innovation. USP is actively communicating with C-SOPs and has recently convened an expert panel dedicated to continuous pharmaceutical manufacturing, Hausner says.

	Summarizing the key points made at the Malta conference, Hausner says, the industry can expect to see an “open arms” approach to continuous manufacturing from regulators in the EU, but no specific guidance. “We will learn much over the next two years from first adopters paving the way,” he says. 

	In addition, the creation of standards and requirements will help advance adoption of continuous manufacturing, as will regulatory flexibility regarding minor formulation changes, and the use of parallel batch and continuous processing.  “In the short term, flexibility on minor formulation changes when switching from batch to continuous will be decided on a case-by-case basis,” he says. Copies of individual speakers’ presentations referenced in this article may be found on 

	Future events like this are being planned for the future, with Japan being discussed as one potential location.  Stay tuned for more information, and for special coverage of continuous processing in OSD in July’s issue of 

	1.     F. Muzzio, “Advanced Pharmaceutical Manufacturing as an Enabler of QbD and Science-Based Regulation: Solid Dose Case Study, I2APM OSD Summit, May 9, 2017.

	2.    L. De Belder, “A Spotlight on a Major Corporate Implementation Strategy for Continuous Manufacturing,” I2APM OSD Summit, May 9, 2017.

	3.    C. Moore, “Potential Regulatory Challenges for Worldwide Approval of Continuous Manufacturing,” I2APM OSD Summit, May 9, 2017.

	4.    W. Roth, “An Industry Perspective for Transferring Continuous Manufacturing from Technical Evaluation to a Default Manufacturing Platform,” I2APM OSD Summit, May 9, 2017.

	5.    E. Norton, “MHA Experience in Early Adopter Continuous Manufacturing Inspections, I2APM OSD Summit, May 9, 2017.

	6.    R. Meyer, Sampling and Control Appropriate Strategies for Continuous Direct Compression, I2APM OSD Summit, May 9, 2017.

	7.    A. Cuitiño, “International Coordination 1: Public and Private Partnership Activities Supporting International Adoption,” I2APM OSD Summit, May 9, 2017.

A recent meeting emphasized the need for more guidance and flexibility from regulators, as well as harmonization, standards and equipment interoperability.

Continuous Processing: Addressing Misunderstandings and Roadblocks

Fake pharmaceuticals continue to have an impact on people and economies throughout the world. Legal penalties for counterfeiting prescription drugs remain lax, the cost of entering the market is low, and the profits extremely high. According to one estimate, a criminal investing $1000 in fake prescription drugs can expect to earn returns of $30,000, 10-times higher than what they might gain from trafficking a comparable investment in heroin (1).

	As more criminals enter the business, counterfeit drugs are making a dent in economies, even in regions and countries with strict controls and regulations. In the European Union, for example, a study by the European Patent Office (EPO) and the EU Intellectual Property Office (EUIPO) suggested the impact that counterfeit drugs have on the economy and employment (2).

	In 2013, the study found the EU pharmaceutical industry lost more than 4% of direct total sales, some €10.2 billion in revenue, to drug counterfeiting. Countries hardest hit by counterfeiting were said to be Spain, where fakes accounted for nearly 6% of sales, and Italy, where they accounted for 4%. Germany and France each lost approximately €1 billion in direct sales, according to the study.

	For the EU as a whole, the study found that lost sales translated into 37,700 lost jobs, with nearly 7000 jobs lost in Germany, and between 3000 and 4000 pharma sector jobs lost in Italy, France, and Spain. Including indirect effects, pharmaceutical counterfeits resulted in approximately €17.3 billion in lost revenue to the EU economy, leading to additional losses of 53,200 jobs.

	In the United States, the National Association of Boards of Pharmacy has estimated that counterfeit drugs generated $75 billion in revenues in 2010, which translates into $18 billion in lost industry profits (3).

	According to the US Office of the United States Trade Representative (USTR) 2017 Special Report (4) issued in May 2017, traffic in counterfeit pharmaceutical and biopharmaceutical products, and active ingredients, continues. In 2016, the USTR reports, 90% of the counterfeit pharmaceuticals seized by the US government were found to have come from China, Hong Kong, India, and Singapore. In 2016, 16% of 31,560 US government seizures of counterfeit goods involved pharmaceuticals, down roughly 3% from 2015, when 5196 fake drug shipments were seized (5). 

	Counterfeiters no longer ship fake drugs as cargo, the USTR report says, but send them in small quantities via legitimate express mail. In 2016, more than 90% of US counterfeit pharmaceuticals seized at the borders were found in express carrier and mail, the USTR report said.

	Even counterfeit active ingredients are being shipped via express mail, for processing in “facilities,” in apartments, houses or garages, often using crude, outdated, and unsanitary equipment, according to a report that described scenarios that EU enforcement officials are more frequently seeing (6).

	In September 2016, for example, authorities in Poland shut down a large counterfeit pharmaceutical operation that included 48 pieces of equipment including pharmaceutical mixers, tablet presses, and label printers, the report said. This operation sourced partially processed products from China, Greece, Romania, and the United Kingdom, and finished processing them on this equipment to “manufacture” fake erectile dysfunction treatments, anabolic steroids, and other counterfeit pharmaceutical products. This single operation was selling millions of Euros worth of products, and it is only one of many, in a constantly changing environment.

	Lack of stiff criminal penalties is a major reason why counterfeit pharmaceuticals remain such a presence on the global market, the report says. Even in the US, attorney Sheldon Bradshaw noted, in a March 2017 legal position paper (7), penalties for counterfeiting remain in a catchall that lumps sales of unapproved drugs (that may be approved in other countries), substandard drugs, and intentionally counterfeited products. The result, he writes, is an enforcement “whack-a-mole” situation in which one illegal operation is shut down, but others take its place.

	Despite these challenges, regulations have been in force for the past few years to help pharmaceutical manufacturers stem the tide of counterfeit drugs reaching the patient.

	The US Drug Supply Chain Safety Act (DSCSA) and the EU Falsified Medicines Directive (FMD) aim to ensure the safety of the pharmaceutical supply chain. Complying with these regulations requires different, but overlapping strategies (see 
	Sidebar).

	Both DSCSA and FMD require use of serialization and improvements in IT and electronic data management to enable supply chain traceability. Large pharmaceutical companies have been working on the systems required for several years, and most are ready to meet legal requirements.

	Some companies still haven’t serialized or upgraded IT for traceability

	A number of pharma companies and contract maufacturing organizations may not be ready, however. According to a survey of both these groups by the serialization system provider SEA Vision and the life-sciences IT company Zenith Technology, 36% of respondents were not even working toward meet serialization requirements (8).

	Besides, most pharmaceutical brand protection experts agree that serialization alone will not be enough to secure their supply chains. “It should be combined with other technologies,” says Bob Migliani, chief of business development for Applied DNA Sciences, Inc. His company offers SigNature DNA, a marker that can be traced at parts-per-trillion levels, is being used in the textile industry, and has been used by global law enforcement departments and six US government agencies. 
	Instead of focusing on adding the marker directly to pharmaceutical formulations, Applied DNA is now evaluating its use in the inks that are used to print labels and bar codes on pharmaceutical packaging.

	Offering complementary technologies is Systech, which provides serialization services to the pharmaceutical industry, as well as its own patented  authentication solution, Unisecure, that compares scanned barcodes to an original “fingerprint” from when the label was first printed.

	This year, a simulation study at St. James Hospital in Ireland involving Systech, Sharp Packaging Servicesfound that both end-to-end scanning and scanning at each transfer point in the supply chain (as required by the DSCSA) still allowed some counterfeit product to reach patients. The additional authentication step prevented counterfeit medicines from reaching patients in the simulation, however. These results underscore the importance of using serialization with complementary product authentication and anticounterfeiting technologies.

	1. R. Ehrenberg, “Counterfeit Crackdown,” Science News, 2011;179:22-25.
	2. EPO/EUIPO, “

The Economic Cost of IPR Infringement in the Pharmaceutical Industry

,” September 2016.
	3. E. Blackstone et al., “

The Health and Economic Effects of Counterfeit Drugs

,” ahdonline.com, June 2014.
	4. USTR, 

, Office of the President of the United States, Office of the US Trade Representative, 2017, May 1, 2017.
	5. US Department of Homeland Security, 

On Tap Europe: Organized Crime and Illicit Trade in Tobacco, Alcohol and Pharmaceuticals

,” iog.org, February 2017.
	7. S. Bradshaw, “

Penalty Disparities Frustrate Protection of Consumers from Dangerous Counterfeit Drugs

Survey Suggests That One-Third of Pharma Companies Aren’t Ready for Serialization

,” pharmtech.com, May 16, 2007.
	9. “

Simulation Finds Weakness in System Designed to Spot Fake Drugs

,” securingindustry.com, March 28, 2017.

	When referring to this article, please cite it as A. Shanley, “Synchronizing Anticounterfeiting Efforts,” 

Serialization and complementary authentication technologies are needed in order to meet DSCSA and FMD regulations.

Synchronizing Anticounterfeiting Efforts

	Traffic in counterfeit pharmaceutical and biopharmaceutical products, and active ingredients, continues to grow. Pharmaceuticals made, sold and/or distributed in China, Guatemala, Indonesia, Lebanon, Peru, and Russia, have been receiving increased attention from global customs and other authorities, according to the United States Trade Representative’s (USTR) 2017 

	In 2016, 90% of counterfeit pharmaceuticals seized by the United States government were found to have come from China (including Hong Kong), India, and Singapore, according to the USTR.  In 2016, 16% of 31,560 

involved pharmaceuticals, down roughly 3% from 2015, when 5,196 fake drug shipments were seized. 

	US customs authorities have been working with their counterparts around the world, and most recently, with Singapore and China, to prevent counterfeit pharmaceutical sales in the US, according to the USTR Report.  In April, 2016, a month-long operation with China resulted in over 1,400 seizures of counterfeits, including some pharmaceuticals, while a cooperative program with Singapore was launched in August, 2016.

	Lack of stiff criminal penalties is a major reason why counterfeit pharmaceuticals remain such a presence on the global market, the report says.  Even in the U.S., attorney Sheldon Bradshaw noted in a March, 2017, 

, penalties for counterfeiting remain mainly in the “misdemeanor,” rather than “felony” category, in a catchall that lumps sales of unapproved drugs (that may be approved in other countries), substandard drugs, and intentionally counterfeited products, he writes.

	As a result, the potential profits for counterfeiting far outweigh punishments, while lax legal penalties reduce incentives for active enforcement. As the USTR report notes, online sales of counterfeit goods could surpass the volume of sales through traditional.

	In addition, counterfeiters around the world are relying on express mail and legitimate postal services to ship their products in small quantities, preventing potential seizure that might occur if they were sent as oceangoing cargo. Over 90% of U.S. counterfeit pharmaceutical seizures at the border were made in the express carrier and international mail environments, the USTR report said.

	Not only finished pharmaceuticals but active ingredients are being shipped via legitimate mail, for production in “facilities,” in apartments, houses or garages, often using crude, outdated, and unsanitary equipment, according to Clare Ellis, who described scenarios that enforcement officials in the European Union are seeing in a 

.  Active ingredients for these operations are often sourced from China or India, and shipped via legal postal systems or express shipping.

	In September 2016, for example, Ellis writes, authorities in Poland shut down a large counterfeit pharmaceutical operation that included 48 pieces of “legitimate” pharmaceutical processing equipment including pharmaceutical mixers, tablet presses, and label printers.  This operation sourced partially processed products from China and other regions, including Greece, Romania, and the UK, Ellis writes, and finished processing them on this equipment to “manufacture” erectile dysfunction therapies, anabolic steroids, and other counterfeit pharmaceutical products.  This single operation was selling millions of US dollars worth of products, but it is only one of many, in a constantly changing environment.

	Another problem has been transshipment of counterfeit products within certain free-trade zones, e.g., within the United Arab Emirates. Both the USTR and Ellis’ report call for increased enforcement within free-trade zones.

	Ultimately, experts agree, the key to stemming drug counterfeiting is in enforcing stiffer criminal penalties. The drug counterfeiting problem has become an enforcement “whack a mole,” writes Bradshaw.  When one illegal importer or operation shuts down, another takes its place.  Efforts must focus on stiffening penalties and improving enforcement, he writes. 

Due to weak penalties and lax enforcement, illicit pharmaceuticals continue to slip into the US, European and global supply chains.

Counterfeiting Loopholes Involve Internet, Mail, and Trade-Free Zones

Biopharmaceutical experts Stephen Perry, CEO of Kymanox, James Blackwell, principal consultant with The Windshire Group, and consultant Mike Ultee, share best practices and musts to avoid in biopharmaceutical technology transfer. 

	Some crucial takeaways?  Share all data (especially data on failed runs in the past), and include clear instructions for sampling.  In addition, aim for reproducibility.

Good project management, budgeting, planning, and clear documentation are the only ways to prevent overruns and project failure.

Getting Biopharmaceutical Tech Transfer Right the First Time

A look at how engineering-led companies from outside pharma are transforming biopharmaceutical contract services, and an interview with Samsung BioLogics’ vice president and head of business development, James Park, on the company’s history, culture, and plans.

Samsung BioLogics’ aggressive growth strategy begs the question: Are there lessons that US and European pharma might still learn from the electronics industry?