Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	In September 2013, Pfizer, GEA and G-CON Manufacturing launched the PCMM (Portable, Continuous, Miniature and Modular) collaboration with the goal of designing and building a first-of-a-kind modular and transportable oral solid dosage (OSD) drug manufacturing facility. Two years later, G-CON’s pre-fabricated cleanroom PODs and GEA’s OSD continuous manufacturing process train were delivered, installed and assembled in an existing warehouse on Pfizer’s Groton, Connecticut campus. The facility was up and running just weeks after it was delivered, and PCMM won the International Society of Pharmaceutical Engineers'  Facility of the Year award in 2016 for equipment innovation category, with judges citing:

			Its smaller footprint (i.e., 60-70% smaller than that for a conventional OSD facility)

			The fact that the same facility could be used for development, clinical trials, and commercial manufacturing

			Shorter installation and startup times (i.e., approximately one year versus two to three years for standard processes).

	Since 2015, Pfizer has used the PCMM facility internally, to develop new chemical entities and products and to manufacture clinical product, says Dennis Powers, director of sales engineering at G-CON. The company has also taken the steps to obtain FDA approval to use the facility to manufacture commercial products in the future, he says. G-CON and GEA have worked with Pfizer to optimize the existing PCMM installation and to add film coating capability to the continuous tableting operation, says Powers. 


	In October 2015, GSK joined the PCMM collaboration, opening up the possibilities of additional collaboration and alignment on patient-centered manufacturing goals. Since that time, PCMM collaborators have developed a second-generation PCMM design incorporating new process capability, improved flexibility, and an optimized POD facility layout, says Powers. Taking the lessons learned from Pfizer experience with the start-up and operation of the PCMM installation and incorporating additional continuous manufacturing expertise from GSK, as well as innovations from both GEA and G-CON, the second generation design includes:

			Tableting and encapsulation dosage form manufacturing capability

			Direct compression and wet granulation capacity

			Multiple container format handling ability

			Additional and optimized support areas.

	As Powers explains, the alignment of Pfizer's and GSK’s visions for transforming industry practices and enhancing supply chain capabilities has resulted in a design with superior process technology integrated within an improved modular and portable facility that can be rapidly deployed anywhere in the world.
	
	Members of the PCMM collaboration are promoting  this second-generation design, with the goal of having it become an industry standard for agile, flexible manufacturing of oral solid dosage drugs. "The goal is to manufacture products more quickly for the patients who need them," says Powers.
	
	Both Pfizer and GSK are considering using the second-generation modules internally, says Powers. In May 2017, Pfizer reported, the company 

started up a PCMM facility at its manufacturing site in Freiburg, Germany.

	Although it did not specify whether the facility reflected first- or second-generation PCMM design, the company is clear on its intentions. "With our PCMM system, we can accelerate the development of highly potent drugs and make new drugs available to patients sooner," explained Dr. Kirsten Lund-Jurgensen, executive vice president and president, Pfizer Global Supply. Pfizer invested 50 million Euros on its Freiburg  site, including the PCMM production unit and improvements to continuous manufacturing capacity.

Articles

The Portable, Continuous, Miniature, and Modular (PCMM) collaboration is alive and well, and the second generation of its modular continuous manufacturing equipment is now available.

PCMM, The Next Generation

	The counterfeit pharmaceuticals business is made up of networks of “affiliates,” which run illicit websites that sell the fake or substandard drugs.In many cases, the organized criminal gangs behind these networks appear to be based in Eastern Europe, but they operate globally, says David McKelvey, director of TM Eye, a detective company based in the United Kingdom that has been following these groups for years and recently launched successful sting operations in India with India’s drug regulatory authority. 

	As he explains, the operation is much like any franchise. The criminal gangs contact each prospective affiliate and carry out full due diligence on each applicant, all the while maintaining their own anonymity. Once they are convinced that the affiliate will be a good recruit, they send him or her templates to use for the web sites, instructing the affiliate to buy anonymized domains that have a link to medicines or drugs.

	Once the affiliate has set up the anonymous domain, he or she uses the templates provided to develop the website. Each affiliate site links to an “anchor” site, run by the criminal gang. The operations are extremely sophisticated and completely anonymized, says McKelvey. “If taken down, the anchor sites automatically switch to another domain with a functioning website. The links to all affiliates are automatically transferred, in less than a minute,” he explains. Prospective online customers go through the affiliate site, and when they purchase anything, they are redirected, often without knowing it, to the anchor site. Once they click on the shopping cart icon to complete the transaction, they are taken to a completely different website (e.g., the site for a clothing factory in Singapore), where they pay by credit card. Many sites are using bitcoin to hide the money trail, says McKelvey.

	Once the purchase is made, the order goes to the fulfillment house and the fake drugs are mailed to the customer in a plain brown envelope sent through the postal system.

	As McKelvey explains, affiliates are paid a percentage of every sale in the form of a monthly commission. They never touch the drugs or the money from transactions, but function simply as gateways to anchor sites.

	TM Eye worked for six months to break up one network, McKelvey  says. So far, the work has resulted in over 7000 linked affiliate and anchor sites being taken down. In addition, a raid on one fulfillment house, Dada Impex, in India, recovered significant amounts of falsified medicines.


	Vol. 41, No. 9
	September 2017
	Page: 20

	When referring to this article, please cite it as A. Shanley, “Counterfeit Pharmaceuticals: a Franchise Business,” 

David McKelvey, director of TM Eye, a detective company based in the United Kingdom, provides insight into the counterfeit pharmaceuticals business.

Counterfeit Pharmaceuticals: A Franchise Business


	As trade in counterfeit pharmaceuticals continues to increase, security and enforcement efforts are barely making a dent in a complex, multinational industry. “The trade in illicit or falsified medicines is by far the most sophisticated organized crime that any of us have ever seen, with tentacles that reach all over the world,” says David McKelvey, director of TM Eye, a detective agency based in the United Kingdom whose work recently led to the arrest, in India, of Paresh Patel, the head of a major counterfeiting ring (see 

) with operations in Mumbai and Bangalore.

	“The global scale of this type of crime is extremely difficult to investigate or tackle,” he says. One large counterfeiting ring that TM Eye is now tracking has more than 45,000 affiliate websites running all over the world, using online hosting in Canada and the United States, says McKelvey. 

	Each of its fulfillment houses, based in India but run from Romania, sends out between 300 and 500 shipments of fake medicines each day, he says, using printing facilities in India, sourcing API from China, and receiving payment through “front” clothing companies in Singapore connected to bank accounts in Panama. 

	Untangling this type of web is beyond the power of local or national law enforcement, and a major challenge to international groups as well, which is one reason why counterfeiting is increasing and the true size of the market remains a mystery, McKelvey says. 

	But if large global crime networks are at work, fake pharmaceuticals are also becoming a “local” problem. “From buying pill presses to preparing batches of illicit opioids in garages and living rooms, we’re seeing an emergence of homegrown labs,” says Bob Miglani, chief of business development with Applied DNA Sciences, which sells taggants designed to prevent counterfeiting. “Today it’s opioids, but tomorrow it could be mom’s diabetes medicine. Pharmaceutical companies, the federal government, states, and the entire supply chain must work together to increase the security of the pharmaceutical supply,” he says.

	“The ease by which counterfeiters can procure component packaging and ingredients, combined with their use of more sophisticated production and distribution methods, present a serious and ongoing challenge,” says Rich Kaeser, vice president of brand protection at Johnson & Johnson (J&J). 

	Pharmaceutical companies have been approaching this problem by layering different approaches on top of each other (see 

). “Anticounterfeiting started decades ago with holograms and UV-based covert inks, progressing gradually to solutions that included visible color-shifting inks and near infra-red covert marks, and pharmaceutical manufacturers will continue to adopt more secure technologies in the future,” says Kent Mansfield, president of TruTag Technologies, which manufactures microscopic silica taggants for on-dose brand protection. 

	Brand owners have become much more sophisticated about managing the security of their products, he notes, but so have counterfeiters. Nevertheless, progress is being made, Mansfield says, and some of these efforts hinge on collaboration. 

	“The notion of anticounterfeit strategies feels outdated,” says Miglani, “and the current model is reactive, based on tests done after a suspect product is found,” he says. “There is a need for more advanced forensics, to analyze the chemical makeup of suspicious products,” says Tom Kubic, president and CEO of the Pharmaceutical Security Institute (PSI). The idea would be to look at competing products advertised online, order samples, and test them to find out what’s in them. Sanofi set up a dedicated lab to do this in Tours, France, in 2010, and Pfizer has this capability as well, Kubic notes.

	Testing services could also be outsourced. Applied DNA Solutions plans to introduce these capabilities in the near future. “Customers would take samples from supply chains in various countries and have them tested for authenticity, with results used to develop a ‘heat map’ to display the relative strength of various supply chains and regions, much as the US Centers for Disease Control do when they map and track the flu virus each winter,” says Miglani. 

	These forensics efforts would, ideally, involve enforcement and regulatory authorities, as well as other manufacturers--perhaps, through industry groups such as Rx-360. Advanced analytics would help drive these efforts, says Steve Tallant, director of product marketing at Systech, which offers expertise in serialization, traceability, and brand protection through its Unisecure platform. 

	Manufacturers would collect data on the chemistry, or on spectroscopic or other signatures generated by counterfeit drugs, labels, and packaging. Working together, companies and law-enforcement agencies could compare recently seized materials with similar counterfeits seized in the past, and note patterns, says Tallant.  

	For now, industry is moving closer to this goal with collaborative programs. A number of pharmaceutical companies are using market-monitoring strategies, including J&J, which set up an enterprise-level Office of Brand Protection in 2010 to focus on best practices. J&J is working with Rx-360 and partnering with brand-protection technology suppliers and others focused on product security and advanced analytics capabilities, says Kaeser. 

	Kaeser and Tony Strange, director of global brand protection for J&J’s biopharma subsidiary Janssen Pharmaceuticals, both participated in the University of Tennessee Health Science Center’s first Pharmaceutical Safety Conference in June 2017. They are working closely with Michigan State University’s Center for Anticounterfeiting and Product Protection, and, in early October 2017, will be sponsoring the Brand Protection Strategy Summit.

	At this point, global law enforcement efforts are focused on anti-terrorist activities, and some agencies have not yet been convinced that drug counterfeiting is a serious crime, says Kubic. 

	Efforts in the past have shown what might be possible if enforcement agencies were actively engaged. Kubic recalls Operation Pangea in 2015, a global effort involving Interpol and 115 countries, which led to the seizure of $81 million in counterfeit pharmaceuticals and shut down 2400 websites (1). Within Canada alone, Kubic says, in eight days, 3800 packages were inspected and 90% of them seized. Then everything went back to status quo after initial efforts officially ended. 

	FDA Commissioner Scott Gottlieb has pledged to step up enforcement, by doubling the number of agents in the agency’s Office of Criminal Investigations (OCI) (2). In addition, FDA has established a program designed to make pharma professionals aware of best practices, and to help them train employees. The program will involve cooperation from the US Pharmacopeial Convention and the University of Michigan, and disseminate best practices developed by J&J and other Rx-360 members (3).

	In the US, illegal product diversion and counterfeiting increased in 2016, with 3147 products counterfeited or diverted, up by 5% from 2015, and by 51% from 2011’s figure. Theft and diversion were up 14% from the previous year, says Kubic, summarizing PSI’s most recent data. “These medications are genuine, but are getting into the country illegally, and 2016 is the first year that we saw more diversions than counterfeiting,” says Kubic.  

	Globally, arrests for pharmaceutical counterfeiting and diversion were down by 9% in 2016, says Kubic, although arrests in China increased by 24%, with 94 arrests taking place in in 2016 (compared with 19 in the US). Arrests fell by 35% in India. 

	In 2016, injectable formulations made up 18% of incidents in which a specific formulation type could be identified, compared to 13% in 2015, says Kubic. Also evident is a move from fakes that include no active ingredient at all to those using locally produced substandard generics, says McKelvey. 

Operation Pangea VII shuts down Thousands of Fake Online Pharmacies

Strengthening Enforcement and Consumer Protection

Keeping the US Prescription Supply the Safest in the World


	Vol. 41, No. 9
	September 2017
	Pages: 18-22

	When referring to this article, please cite it as A. Shanley, “From Reactive to Proactive Supply Chain Protection,” 

It’s time to stop talking about “anticounterfeiting,” and move to integrated, collaborative supply chain security, experts say.

From Reactive to Proactive Supply Chain Protection

	A wide variety of anticounterfeiting measures are available to pharmaceutical manufacturers today. Taggants, whether added directly to the drug or to packaging, are attracting interest. TruTag Technologies offers its taggants for use in on-dose production, not only for commercial products but for medications in development. “This approach allows customers to hit the ground running upon approval of the drug, with a known cost, standard operating procedures, and logistics plan,” says TruTag President, Kent Mansfield. He notes that taggants will be used in products that are expected to be commercialized in the United States, Europe, and Asia next year. The company’s facility received cGMP qualification in 2016, and TruTag has been working with partners, Colorcon and WuXi PharmTech, to test its technology in new products. 

	Applied DNA is working with two companies to determine the feasibility of embedding its taggant technology onto tablets and capsules, says Robert Miglani, chief of business development. The company is also developing plans to offer outsourced forensic testing services, he says. 

	In addition, authentication capabilities are becoming more important, both in regions where serialization mandates do not yet exist, and as manufacturers focus on preventing diversion of crucial therapies such as injectable cancer drugs, says Systech’s Jim Sinisgalli, director of brand protection solutions. Early authentication technology offered a “yes or no” answer to whether product was real or not. Today, technology can handle many use cases, including counterfeiting and diversion. “Once you can prove uniqueness, you can also provide important metadata with each item, such as where the item has been, where it is supposed to go, lot number, expiration date, active ingredient, source and manufacturing plant, as well as enabling authentication data from the field, which can be accessed via a smart phone application,” he says. The company is evaluating Internet of Things (IoT) approaches, and starting to look at the possibilities of blockchain, or advanced digital ledger technology, which could play an important role in helping to secure the pharma supply chain in the future.


	Vol. 41, No. 9
	September 2017
	Page: 22

	When referring to this article, please cite it as A. Shanley, “A Growing Number of Options,” 

Emerging anticounterfeiting technologies offer pharmaceutical manufacturers more options for supply chain security. 

A Growing Number of Options

	A growing number of companies around the world are using continuous processes to make small-molecule APIs. “There’s more potential for continuous with APIs, just from a cost standpoint, than for drug product,” says Kevin Nepveux, vice-president of global technology services at Pfizer, which is taking a hybrid, or case-by-case approach to continuous API and oral solid dosage (OSD) form manufacturing.

	“There is a lot of value to using continuous to telescope API steps and replace traditional steps that are bottlenecks or safety risks,” he says. “And you can do a lot of chemistry in flow cells that you wouldn’t want to do in a batch environment, just for safety and process control reasons.” One application would be flow hydrogenation for catalytic hydrogenations, while opportunities also exist in continuous crystallization and drying, he says. 

	The need for safer API production is driving demand for industrial-scale continuous chemical reactors, says Yi Jiang, global business director, Corning Reactor Technologies, which has developed continuous Advanced Flow Reactor (AFR) products for use in API and fine-chemical manufacturing. 

	Corning began developing the technology in 2002 and has improved it, Jiang says, to the point where, compared with traditional batch reactors, AFR reactors can enable at least 100 times enhancement in mixing and 1000 times improvement in heat transfer performance, allowing operating cost reductions of 30-40%. “Continuous flow technology has redefined reactor productivity,” says Jiang, “so that it is no longer based on volume of output, but on how effectively the chemical is processed.” Continuous also speeds up and simplifies API scale up, just as it does for OSD.

Corning’s AFR has been recognized as an inherently safer technology (IST), says Jiang, and Corning has been seeing increased demand for the technology, particularly in China. The Chinese government has mandated increased chemical reactor safety since 2016, when a major explosion at one facility in Tianjin killed more than 160 people.

	Recent years have seen growing worldwide demand for industrial-scale AFR equipment, says Jiang. In October 2016, the API manufacturer Angelini Pharma, installed an industrial-scale AFR reactor at its facility in Aprilia, Italy (1). Demand is particularly strong in India and China, which are producing more of the world’s APIs. AFR is installed at the top 10 API manufacturers’ facilities in India, says Jiang. “There is a clear need for inherently safer technology which will continue to drive growth, but in a greener way that reduces environmental impact,” Jiang says.

	Could end-to-end take off in developing markets?

	Where integrated facilities might not always make economic sense in the United States and Western Europe, there are questions about whether end-to-end continuous processing facilities might take off in developing markets. A number of countries are requiring that more drug substance be developed onshore and integrated with drug product manufacturing.

	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, recalls Kalbio Medika, an Indonesian company that won honorable mention at ISPE’s 2017 Facility of the Year awards program for its new biopharma API facility (1). Even though the facility manufactures biopharmaceuticals and is not completely continuous, the reasons for its design reflect Indonesia’s goals to have more of its pharmaceutical supply chain located on shore. Indonesia manufactures 70% of its fiinished drugs, but still imports 90% of raw materials, and the government wants its drug manufacturers to make more ingredients onshore, says Di Prospero. 

Industrial-scale continuous API manufacturing may offer cost and safety benefits.

New Reactors Spur Continuous API Manufacturing

Regulators, manufacturers, and even the media (1) often ask why more pharmaceutical companies don’t use more of the modern manufacturing and quality approaches and tools used in other industries. The answer becomes clear when one looks at the complexity and cost involved in making process improvements after a drug has been approved, and getting those improvements approved by global regulators. 

	Simplifying the process for post-approval changes is a topic that is being discussed more frequently at industry events; the Parenteral Drug Association (PDA) has launched a working group to share best practices and brainstorm solutions, and International Council for Harmonization (ICH) Q12 (2) is tackling the problem, yet little actual change is being seen. Some in the industry ask whether it will take a crisis to resolve this problem.

	“We saw what the industry can do and what regulators can support when the Ebola virus struck, and vaccines, which usually take over a decade to develop and approve, were developed and released in months,” says Maik Jornitz, CEO of G-CON.  “Why can’t we bring these approaches for the urgent to the normal, and create a more rapid approval approach?” he asks.

	Despite years of talk about regulatory harmonization, and some pilot programs and alliances, each regulatory authority still takes its own approach to looking at process improvements. When regulators disagree, they sometimes force manufacturers to choose between moving forward with an innovation or just staying with the old process to simplify manufacturing and quality and reduce costs, says Melissa Seymour, vice-president of global quality control at Biogen. “Those are the kinds of things that, if we’re not careful as an industry, will shut down innovation,” she says.

	Even proven technologies still run into regulatory snags. One example would be moving from high-performance to ultra- high-performance liquid chromatography (HPLC to UHPLC), which should be easy.  “UHPLC is a better method and it’s simple to validate, but it can still take years to get it through the process, so we’re still running HPLC because of the regulatory approval structure, not the capabilities and potential of the analytical method,” says Seymour.

	Another case in point is isolator technology. When they were first introduced to the pharmaceutical industry, isolators weren’t adopted as rapidly as expected, due to regulatory uncertainty, says consultant Jim Agalloco. Years later, that uncertainty persists. “If I want to replace a curtain-segregated with an isolator-based fill line, that change will still undergo regulatory scrutiny, even when the isolator-based containment is more robust,” says Jornitz. 

	A pharmaceutical company that sells its products globally must address post-approval change requirements for each of the regions it sells to, and that can mean dealing with more than 100 different regulatory agencies. “Many of our products are marketed in over 80 countries, so a change approval can take more than five years,” explains Seymour. The result, she says, is inventory segmentation and the need to manage several different versions of a drug over its lifecycle.

	“In some instances, we’ve had to go back to older manufacturing processes, or older and less efficient test methods to generate enough inventory for countries where those changes haven’t been approved yet,” she says. In other cases, companies may spend resources running two different analytical methods for one product for up to five years, or running under different specifications for three to five years, because of the time it takes to get changes approved globally, she adds. 

	Adding to the difficulty is the fact that, in the real world, process improvements don’t just happen one at a time, but accumulate, says Anders Vinther, chief quality officer at Sanofi. “You wind up stacking them on top of each other.” As a result, one year, he says, Sanofi produced 83 batches of one of its vaccines according to 55 different configurations/variations, depending on the region involved. 

	The costs required can be mind-blowing. Roughly 80% of the industry’s regulatory affairs professionals now spend most of their time on post-approval change-related issues, Vinther says.

	At the same time, having to maintain and run parallel manufacturing and quality processes adds complexity and can wreak havoc with workflow and production planning, he says. Consider a situation where a country needs to increase the amount of a vaccine it buys, Vinther explains. The manufacturer may have sold out of that particular version of product, so it may offer another version that the country hasn’t approved yet. Typically, the country will then expedite approval, but the manufacturer may not have enough of that version of product left over to meet other customers’ needs, forcing it into firefighting mode.

	In other cases, one set of quality tests can be effectively run on the plant floor, while, for other markets, the same tests on that product must be done in the laboratory, says Seymour. The innovation was adopted to improve efficiency, yet the result is the opposite.

	There isn’t a regulatory agency in existence that doesn’t support continuous improvement, in concept. As Vinther says, EMA regulations explicitly require it. However, regulators may send mixed messages. The same submission, containing identical data, can receive very different assessment from major regulatory agencies, resulting in the need for fragmented implementation or duplicative effort. It is time for more harmonization amongst regulators worldwide,” says Vinther. 

	In the worst case, tradition may win over good science when regulators assess new technology. Jornitz recalls a gloveless, robotic isolator-based filling system, which came under regulatory scrutiny because it did not allow settling plates to be installed for environmental monitoring.  

	As he notes, there is no need for traditional environmental monitoring in a sterile, enclosed system. “You have to be in control of your process, and not rely on dated environmental technology,” he says.

	Another example Jornitz cites is the European regulatory requirement that sterilizing grade filters undergo integrity tests before use and after sterilization. Testing is used to determine whether a flaw occurred, which might not be found in the post-use test due to blocking of the filter. As Jornitz says, the filters are scaled not to block, and are commonly used to filter clean solution. The Committee for Proprietary Medicinal Products guidelines set in April 1996 established a maximum allowable bioburden of 10 colony forming units per 100 mL in front of the sterilizing filter. “There is typically no chance that the filter will block, yet regulators insist on the pre-use and post sterilization test, which increases potential risk to the patient because the test requires manipulation of the filtrate side,” Jornitz says.

	Bearing witness to the challenges of adopting more modern technologies is single-use process equipment, which, Jornitz says, took 15-20 years to gain acceptance in pharma, but is now widely used. Rapid microbial monitoring (RMM), which has been around for about as long as single use, is being used by some pharmaceutical companies, and has received support from regulators, but still isn’t widely applied. For many companies, Jornitz says, there is a fear of the double-edged sword, and regulators requiring that the old technology be used along with the new.

	FDA and other regulators have increased staff training., FDA has moved to a team-based approach (See 

) to help make reviews and inspections more consistent. 

	In addition, FDA established an Emerging Technologies Team (ETT) in 2014 to help companies address concerns about new technologies and the impact that they might have on applications or post-approval changes (See 

). The team promotes early engagement with firms, for both new and legacy products, to discuss potential challenges to implementation of new technologies and possible paths to resolution. “With early engagement, the agency can move quickly to review and act on supplements for implementation of newer technology,” says Lawrence Yu, deputy director, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research at FDA.

	Seymour’s team has met with ETT in connection with Biogen’s candidate Alzheimer’s therapy, which has been fast tracked for approval. “It has been an enlightening experience. The team is open and collaborative. We’ll have to wait to see how everything plays out when we file for approval, but the interactions have been positive,” she says. 

	Vinther sees the team’s existence as a positive development, but, as he notes, “It doesn’t help if FDA can review a post-approval change in four months, but it takes the world five years and, in the meantime, we have to deal with all these different technologies and product versions at the same time.” 

	One of the reasons for the disconnect between manufacturers and regulators may be the huge difference in focus, he says. “Manufacturers, by definition, must think about the whole world of markets they sell to, where regulators must think nationally, and of protecting the health of people in their own countries.”

	Blaming the regulators is no solution, he says. “The industry needs to do things better, to ensure that our systems work better and that we are better at forecasting and preventing drug shortages.” 

	“If we could get all the regulators to work together that would be a great help and would allow us to innovate,” he says, but he senses that some regulatory authorities may not trust each other. “If regulators with a ‘Strict Regulatory Agency’ grade (the highest grade) from the World Health Organization see a process change as being benign or beneficial, why can’t the others?” he asks.   

	Besides, Vinther says, most post-approval changes eventually go through. “The International Federation of Pharmaceutical Manufacturers and Associations surveyed leading vaccine companies and found the success rate was over 99%. Can’t we at least reduce the number of filings required by 50-70% by doing a thorough risk assessment?” he asks.

	Rejecting innovation to save money can be the first step to neglecting facilities, milking processes but failing to maintain them, says Jornitz. That may result in shortages when there is only one manufacturing site supplying a vital drug. Once a process and facility reach a certain level of aging, they can go into a death spiral. An example could be Benvenue Labs, where $300 million in investments proved to be too little too late.

	But companies have also created the impasse in pharmaceutical modernization, says Agalloco. “Comparability and crossover studies are costly and difficult, but you cannot blame the regulators, but yourselves for not having enough conviction in the technology itself or proof of its performance,” he says, “because there can be major financial incentives for using new technologies. Failing to use any is just a big excuse. You have to take some risks, just not huge ones.”

	Besides, there may be some innovative technologies that remain unknown, even though they’ve matured to a point where they could be used. “Nobody will touch them until FDA says it’s okay, and FDA cannot approve them until someone files a new drug application specifying their use, so it’s a Catch 22,” he says. 

	Pharmaceutical companies have to incorporate innovative manufacturing practices, to lower cost and produce the highest quality products, says Girish Malhotra, president, EPCOT International. Regulators suggesting the “how and what” of innovation, he says, is putting the cart before the horse. 

	“Innovative technology implementation is a team effort between regulators, the industry and suppliers. We need to work hand in hand if pharma is to become as technologically advanced as other industries are,” says Jornitz. “Besides,” he says, “a whole new industry, cell and gene therapy, will require rethinking many areas, and the adoption of new technologies for the future.”

	“For now, the key to resolving this problem,” Vinther says, “is to take all politics and emotion out of this issue and base discussions purely on science.” 

	“We need to provide regulators with tools and assurance to prove, with solid data, that we have the capabilities within our organizations to make changes,” says Seymour. “There’s a responsibility to put the tools out there for organizations to use, to be able to manage change consistently and appropriately,” she says.  

New Prescription for Drug Makers: Update the Plants

,” wsj.com, September 3, 2003.
	2. ICH Q12 Position Paper, 


	Vol. 41, No. 8
	August 2017
	Pages: 14-19

	When referring to this article, please cite it as A. Shanley, “Breaking Through Obstacles to Improve Drug Manufacturing,” 

Systems that discourage continuous improvement threaten pharma innovation, quality, and supply. Can the industry break through this deadlock? 