Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	A number of organizations have analyzed and estimated the size of pharma’s counterfeit and diversion problem. The Pharmaceutical Security Institute (PSI), established in 2002 by security professionals who work for pharmaceutical companies, examines it from that point of view, and from the law-enforcement angle. The non-profit group is based in the Washington, D.C. area with operations in the United Kingdom and Hong Kong, and currently has 33 global members. CEO Thomas Kubic was previously deputy assistant director at the US Federal Bureau of Investigation (FBI), in charge of the white collar crime and corruption programs.

	PSI’s Counterfeit Incident System database uses both public and proprietary information to track incidents of illegal diversion and major theft (i.e., cases involving more than $100,000), as well as counterfeiting.  Some of these data are summarized in annual Enforcement Statistics and Situation reports on the organization’s website, 

	Numbers of incidents as well as confiscations are trending upward, Kubic says, noting the scarce resources that the world’s governments are devoting to anticounterfeiting efforts. Even in the US, where anticounterfeiting efforts are well advanced, only about 50 agents in FBI are working on counterfeiting of all types of products, not only medicines.

	In 2015, he says, PSI found that there were 3002 new incidents, up 37% from the previous year. Of these, 1689 involved counterfeits, 1106 were diversions, and 207 were major thefts. Seizures were up 33%, mostly due to improved customs operations and the discovery of major counterfeit sources in Cambodia and Vietnam. Kubic says he is seeing a smaller number of big-time seizures, and an increase in counterfeit injectable medicines, a very worrying trend.

	In 2015, PSI data showed an increase in diversion, theft, and counterfeiting of dermatological medicines, which were up by 57%; incidents involving central nervous system therapies were up by 29%; and cardiovascular drug incidents, 30%. Erectile dysfunction treatments remained a targeted medicines focus for counterfeiting and diversion.  In all, 1100 different types medications were seized in 2015, up from 680 in 2014, Kubic says.  
	Previous analysis of PSI data (1) noted a number of trends, with criminal groups in China implicated as the source in nearly 28% of reported pharmaceutical counterfeiting and diversion.

	Kubic sees less traditional or hieratical organized crime involvement in counterfeiting, at least in developed countries. In the early 2000s, this was clearly seen when Dora Akunyili, then director of Nigeria’s FDA, NAFDAC, took a hard line in dealing with drug counterfeiters, facing death threats, narrowly missing being shot, and having her laboratories burned down.  Her stance inspired a number of others in other developing nations. 

	Even though their government representatives may have signed on as participants in global anticounterfeiting programs, says Kubic, there is rarely any consistent follow up.

	“In some cases, criminals are suspected of making payoffs to the authorities,” he says. For example, this year, in Kenya, a whistleblower  accused the nation’s Pharmacy and Poisons Board of allowing fake and substandard drugs from unregistered suppliers into the country, issuing fake permits between 2005 and 2011 (2). In general, throughout the world, Kubic says, “We need to see more effective coordination between regulators, customs, and the police.”

	At the same time, in the US, illegal operatives have shifted from an emphasis on unauthorized online pharmacies, which were a major threat to public health a few years ago, especially during periods when key drugs were in short supply (3). 

	Since then, they have increased their efforts at direct-to-clinic sales of diverted or counterfeit drugs, Kubic says. This was first seen in the counterfeit Avastin case, when tainted materials reached the legitimate supply chain after clinics bought directly from illegal sources. “Marketers are targeting retirement homes and clinics,” he says, where diverted oncology drugs are offered at up to 40% off list costs.

	FDA’s Office of Criminal Investigations (OCI) has been stepping up investigations of physicians, clinics, and other groups suspected of buying diverted pharmaceuticals.  However, a September 2016 report (4) questions its methods.  In some cases, author Sarah Lynch found, healthcare professionals had unknowingly purchased the materials; in addition, she alleges that aggressive tactics failed to result in prosecutions or other tangible results. 

	PSI’s Kubic believes that an outreach and education effort yields better results than aggressive enforcement alone.

	“It’s more important to educate potential buyers than to try to put the genie back in the bottle,” he says. Public outreach is also important, he says, citing the International Federation of Pharmaceutical Manufacturers and Association’s (IFPMA’s) Fight the Fakes program, which features real-life stories of counterfeiting and effective response, as an example of an information program that’s being done right.

	Although counterfeiting harms the public, it is still considered intellectual property theft and prosecution is handled that way.  Generally, penalties are fairly lax. Nigeria currently imposes life imprisonment, while Israel recently increased its penalty from six months to three years. 

	Complicating the picture has been the blurring of distinctions between diverted and counterfeit pharmaceuticals, and economically motivated adulteration.  After the first Gulf War, Kubic says, security agencies learned that Saddam Hussain had looked into adulterating medicines and cosmetic products being sold to the US and Europe.  However, he notes that most counterfeiters and adulterators are in the business for the money but don’t wish to harm people.  “They don’t use poisons, although their placebos kill,” he says, and proving a link between patient deaths and counterfeit or diverted product can be extremely difficult.

, (June, 2015), June 3: 92 (Supplement 6): pp. 59-67.
	2. S. Murumba, “

Whistleblower Lifts Lid on Fake Drugs Import at Poisons Board

,” August 9, 2016, businessdailyafrica.com.
	3. B. Liang et al., 

FDA Criminal Office Draws Fire from Agents and Doctors Over Drug Import Crackdown

	When referring to this article, please cite it as A. Shanley, "Tracking a Global Problem," sidebar to "Chasing a Moving Target for Counterfeiting and Illegal Diversion,” 

Articles

A number of organizations have analyzed and estimated the size of pharma’s counterfeit and diversion problem.

Tracking a Global Problem

Although they receive less press than illegal drug trafficking, pharmaceutical diversion and counterfeiting remain huge, growing, and largely undocumented, problems (Sidebar). A report by the World Economic Forum, released in 2011, found that fake drugs have a $200-billion-per-year impact on the world’s drug manufacturers (1). The business costs of illegally diverted drugs may be several times higher than that, says Kent Mansfield, president of TruTag Technologies, which has developed an on-dose covert security solution that is now in pilot and trial programs with pharmaceutical manufacturers and film coating providers.

	“The companies we work with don’t tend to separate counterfeiting and diversion. They may have different teams working on each problem, but they don’t split out the numbers. Instead, they’ll typically say ‘This [problem] is costing me X million,’” says Jim Sinisgalli, director of marketing development at Systech International, LLC. “Generally, if a client has a good understanding of the extent of a product’s illegal diversion, they can better assess and address the entire [security] problem,” says James Lee, Systech’s vice-president of product management.

	Recently, researchers have called for better labels to distinguish between all the possible forms of counterfeiting and diversion (2). Both counterfeit and diverted drugs hurt the public, when, for example, people abuse and become addicted to drugs intended for legitimate therapeutic uses, or take products that have expired or been improperly stored or labeled, says Mansfield. Both worlds collided recently in investigations into the death of the musician, Prince, which some reports linked to diverted opioid pain killer as well as a counterfeit generic drug (3).

	Serialization and track-and-trace efforts promise to give manufacturers more control than ever in preventing illegal diversion, and they can help in anticounterfeiting efforts, but, by themselves, are not enough to prevent counterfeiting. Covert and overt brand protection technologies are also needed. All solutions must work in concert to achieve the three goals of protection, detection, and prosecution, says Shabbir Dahod, CEO of TraceLink, whose cloud-based platform is being used in many pharmaceutical serialization and traceability programs. “Security is a continuous battle, and, no matter what we do, criminal organizations are using sophisticated methods. We must continually raise the bar,” he says.

	One of the vulnerabilities of overt, visible anticounterfeiting technologies for pharmaceuticals is that they are packaging-based, and easily duplicated. Criminals have become adept at mimicking not only logos, but color-shifting inks, and holographs. As a result, the use of each of these technologies tends to be short-lived before tweaks and updates are needed.

	“Overt technologies are only good for a certain period of time until counterfeiters figure them out. They can only be expected to last so long, and they tend to be expensive,” says Lee, who sees the need for a layered approach to preventing both counterfeiting and diversion.

	“If a company is relying on a hologram to demonstrate authenticity, then both the supply chain inspector and/or the consumer need to know what the real hologram looks like, so that they can effectively spot the difference between a fake and an authentic one. These days, this [differentiation] is becoming much more difficult to do,” says Mansfield.

	He recalls situations in the past where drug companies were using scratch-off codes that could be authenticated by texting the revealed numeric code to a security database or calling the number through a special hotline. Within six months, he says, fakes were discovered where either a false hotline phone number was used, or a single authentic number was duplicated multiple times. “In the latter cases, counterfeiters copied one real code for use with multiple fake packages, knowing full well that only a small percentage of consumers were actually participating in the program,” says Mansfield.

	Although overt technologies remain important and are being improved, a number of anticounterfeiting techniques are focusing on covert, invisible approaches. One way of doing this is by incorporating taggants, tiny markers that identify the product, into its formulation.

	This approach has become more attractive to pharmaceutical companies since 2011, when FDA published its final guidance on physical chemical identification markers (4). The guidance mandates that the material already be an approved ingredient that is generally recognized as safe (GRAS) and present in extremely small amounts in the overall formulation. Providing that all requirements have been met, all that manufacturers need to do is to complete dissolution testing to ensure the release profile or stability of the drug is not affected, and to report use of the material on their annual report to FDA for the product, says Mansfield.

	A number of companies are working on taggants that would be added directly to the drug to allow for product authentication. So far, these taggants only work on pills, and some can also be used on labels or packaging, while research is evaluating their use in other dosage forms in the future.

	Applied DNA Sciences, for instance, uses a plant-based DNA marker that can be embedded in the pill’s coating or packaging. Micro-Tracers, which has sold tracers for use in coding animal drugs for more than 55 years, has taken a different approach.  Utilizing technology from the semiconductor industry, the company offers SECURtracers, edible particles 50-150 microns in size that can be embedded into pills, capsules, and labels. Each particle is comprised of GRAS chemically inactive materials, fluoresces under UV black light, and contains lettering 10-20 microns in size.

	To confirm authenticity, pills or packaging can be viewed under a simple, inexpensive microscope to read the lettering on the tracer particles. The process requires less than 30 seconds and can provide such information as manufacturing company name, lot number, production date, and expiration information.

	If tracer particles are included within pills or capsules, the dosage forms would be ground to powder, and the particles isolated magnetically before being read under a microscope. Particle design is customizable, with x and y dimensions of 50 microns or larger in size. Letters can be etched in sizes as small as 2 microns wide and 10 microns long.

	Also working on taggants is TruTag, whose On-Dose authentication solution for oral solid-dosage forms grew out of US Army medical research from 2009-2011, and work by the company’s Chief Science Officer Michael O’Neill. It features three key elements:

		Microscopic silica particles, each featuring a unique spectral code that can be used to link provenance data from a product to authenticate it, show dosage and packaging information and lot or batch numbers on the scanner’s high-resolution screen.

		Scanners designed to analyze a pill and decode and authenticate microparticles in the product, either within the excipient blend or the coating.

		Data management and storage for analyzing results.

	The solution allows for verification directly from the dosage form and would complement serialization and track-and-trace technologies. TruTag has run more than 100 pilot tests, evaluating the technology with multiple APIs via a broad number of common pharmaceutical film coatings, as well as in blends. In addition, the taggants’ impact on stability, dissolution, and efficacy have been verified, says Mansfield, who expects full-scale commercialization later this year.

	TruTag has been working on film coating application testing, using various active ingredient solid-dose products, with multiple pharmaceutical manufacturers. The company is also involved in technical collaboration with leading pharma film-coating suppliers and is about to publicly release the results of these studies to industry.  Additionally, the contract research and manufacturing company, WuXi Apptec, has invested in the company and is promoting the on-dose technology.

	Systech International, LLC, which is actively involved in serialization and track-and-trace efforts, has also developed a covert security technology, Unisecure, which clients are evaluating and using as a second layer of protection.

	The technology uses machine vision to derive unique fragments from machine-generated universal product codes (UPCs), based on imperfections caused by the paper, the printer, or other conditions. “No two labels are exactly the same,” says Lee. Mike Saborski, a vision software specialist at Systech, was able to find a way to leverage the unique imperfections inherent in any installation to come up with identifiers for each product.

	Unisecure is being added as an additional layer above serialization, Lee says, with the ultimate goal to add traceability as well. “If you have two identical serial numbers, you cannot distinguish between them, but if you look at the signature fragments for each, you’ll see differences between the two. This way, when you scan the UPC code for tracking and authentication history, you know it’s the right item in the right market,” he says.

	Using the technology does not require any special equipment, just a standard camera mounted on a production line, Lee says. Users capture the image and device fingerprint for each product, and then move on to the next.

	One pharma company that had already serialized has added Unisecure as a second brand-protection layer. After pilot testing the combined approach in April 2016, the firm now plans to deploy it on serialized lines for high-cost drugs, Lee says. Another company is evaluating it for a mix of different products, both pharmaceuticals and consumer products, he adds.

	Systech, half of whose business is in Europe and the US, has been expanding in Asia. A few years ago, the company set up an office in China, and in September 2016, it launched an office in India.

	While developers continue to improve brand-protection technologies, pharmaceutical manufacturers and their partners are making progress on serialization and traceability efforts, now mandated in much of the world. “Since January 2016, we’ve seen a ten-fold increase in the number of contract manufacturers embarking on serialization programs,” says Dahod.

	In general, he says, the technology required for brand-protection already exists. “The challenge will be integrating it into one single source to disseminate information that can be easily accessed.”

	1. K. Van der Elst and N. Davies, Editors, 

, Sixth Edition, World Economic Forum.
	2. G. Buckley and L. Gostin, Editors, 

Countering the Problem of Falsified and Substandard Drugs, Institute of Medicine of the National Academies

 (National Academies Press, Washington, D.C., 2016).
	3. Associated Press Minneapolis, “

Counterfeit Pills Found at Prince’s Home Contain Powerful Opioid Fentanyl

,” August 21, 2016, theguardian.com.
	4. FDA, Guidance for Industry, 

Incorporating Physical and Chemical Identifiers in Solid Oral Dosage Form Drug Products for Anticounterfeiting

	When referring to this article, please cite it as A. Shanley, " Chasing a Moving Target for Counterfeiting and Illegal Diversion,” 

As criminals duplicate the latest overt security technologies, pharmaceutical manufacturers are evaluating covert and layered approaches to fight counterfeiting, theft, and illegal product diversion.

Chasing a Moving Target for Counterfeiting and Illegal Diversion

Ointments and creams may be as old as humanity itself, but their formulation is extremely complex. In a category of their own, these semisolids involve many more ingredients than other dosage forms, and materials in different phases, increasing the potential for variability and interactions. As a result, achieving process understanding and control is more difficult with these materials than it might be for simpler solid dosage form.
	
	As more companies within the pharmaceutical industry, including generic-drug manufacturers, start to embrace the principles of quality by design (QbD), and regulators push for increased process and product understanding, research is under way to gain insights into how these formulations and their components work. The FDA is sponsoring research, funded by the Generic Drug User Fee Amendments of 2012 (GDUFA), into various aspects of semisolid behavior at the University of Mississippi in the United States and the University of Queensland in Australia. 

	Pharmaceutical and some excipient manufacturers are also working to optimize conditions to allow for improved and consistent quality. At the American Association of Pharmaceutical Scientists (AAPS) annual meeting in October 2015, three days of technical sessions and one full-day 

 focused on this topic (1, 2). An all-day workshop at Rutgers in May 2016, sponsored by the Center for Dermal Research and the excipients manufacturer, BASF, explored these topics in greater depth. This article will report on some highlights from the May 

	“Semisolids may contain over 20 ingredients, compared with the five or six typically found in injectables. They also contain a wider variety of excipients including oils, waxy solids, emulsifiers, polymers, solvents, and liquid humectants,” explained Bozena Michniak-Kohn, professor of pharmaceutics at Rutgers University, at the May workshop (4). Professor Michniak-Kohn founded and currently directs the Center for Dermal Research at the University. The center, affiliated not only with Rutgers, but also with the Robert Wood Johnson Medical School’s dermatology department, offers testing and research facilities and services for optimizing topical formulations, and for designing, characterizing, optimizing, and evaluating transdermal delivery, featuring microscopy, analytics, and imaging tools.  

	A large number of material interactions are possible

	Potentially, there can be interactions between all components in the formulation, Michniak-Kohn explained, while additional complexity stems from the ingredients’ source (i.e., whether from synthetic, plants or animals), as well as how they are processed. And that doesn’t even begin to address the complexity of interactions with the human skin, where the materials contend with sweat or dryness, and may undergo additional changes. “The kinetics of transport through skin layers is complex, and microstructure may also influence degree of active retention in the skin,” said Michniak-Kohn. 

	At the workshop, Sameersingh (Sam) Raney, scientific lead for topical and transdermal drug products at FDA’s Office of Generic Drugs, and former professor of pharmaceutics at the North Dakota State University, noted the need to characterize semisolid formulations, and to link potential failure modes to quality attributes and degree of complexity (5). In a typical cream, he notes, “numerous quality attributes may be critical, and numerous failure modes may exist, due to the complex composition of matter.”

	As formulation complexity increases, so does the potential number of failure modes, Raney says, but it can also be extremely difficult to distinguish the role that each ingredient plays when determining the root cause. One example that Raney points to is penetration enhancers or modifiers. “An increase in solubility in a formulation can alter the amount of drug available for partitioning into the skin’s 

(i.e., outermost layer of the epidermis), and increase bioavailability of the drug from a formulation. This [effect] may be interpreted as occurring because of the solubility enhancer, yet the same ingredient won’t give the same results in a formulation in another drug with a different API,” he said. 

	Reprising his presentation at the AAPS meeting, FDA’s Raney presented a frame for the day’s discussions by posing questions to industry. Noting that his comments represented his personal opinion rather than FDA’s official position, Ramey listed the traditional specifications for semisolids, including appearance, viscosity, particle size pH, homogeneity, content uniformity, microbial tests, and residual solvents. “Are these traditional measures a complete characterization of the dosage form and everything that matters? For example, for pH, how well are the specification ranges justified?” he asked.

	Raney went on to ask about quality risk management. “How do we attain product and process understanding where complexity is adequately characterized, potential failure modes are adequately understood, the critical range of each quality attribute is adequately well established in a relevant design space, and quality attributes that might matter are adequately controlled?”

	As he noted, the complexity of semisolid formulations has made it difficult to implement a QbD approach at all, or consistently, during topical semisolids development.

	A need to consider the impact of inactive ingredients

	Raney reiterated the potential for inactives to affect the physicochemistry, microstructure, functioning, and robustness of the drug product, and the fact that some ingredients might penetrate through the skin and alter its structure and chemistry. “Can they alter the solubility of the active ingredient in the intracellular lipids in the 

? Can they alter the ordered structure of the 

 intracellular lipids? Can they impact the diffusion of actives and inactives into the 

, and influence the partitioning diffusion and other factors related to bioavailability?” he asked.

	Raney discussed the importance of using Q3 principles encompassing qualitative and quantitative composition, as well as physicochemical attributes, rheological characteristics, polymorphic form, drug release rate, globule size, and pH. The next step, he said, is to determine which attributes are critical to product quality, and within which range a quality attribute is robust. 

	He emphasized the need to understand how differences in composition and manufacturing affect states of matter, arrangement of matter, complex dynamic distribution of the drug, and the metamorphosis of semisolid on skin. “Can we study qualitative differences and observe when a quality attribute is critical, when a potential failure mode may be at risk, and how qualities and failures are multifactorial effects?” he asked.  As an example, he mentioned pH and how it can influence ionization state, polymorphic state, stability, solubility, ratio of dissolved to undissolved, distribution of drug in microstructure, amount of drug in the phase in contact with skin, rheology of semisolid, dose application, spreading product transfer, and patient perception of quality. 

	Raney presented these challenges, but  in a practical context. “In complex products, consider how failure modes arise from and convolute among multiple quality attributes, consider how risk of failure modes can be mitigated once the associated individual and collective quality attributes are designed into the product and controlled within a well characterized design space,” he said.  
	“This requires considering which quality attributes to characterize, what measurement techniques to use and how to interpret results,” he said, “as well as such factors as patient impact, storage, dispensing and redispensing issues, dose application maintenance and removal, perceptions of quality, and the robustness of therapeutic effect in the real world.”

	Significant differences in the same product

	Following Mr. Raney, S. Narasimha Murthy, PhD, associate professor of pharmaceuticals and drug delivery at the University of Mississippi, whose group is currently performing some GDUFA-funded research, 

 how his team is evaluating Q3 critical quality attributes of semisolid topical dosage forms, and their impact on bioequivalence (6). 

	The researchers studied commercial creams containing the antiviral active ingredient, acyclovir, comparing Zovirax, sold in the US and United Kingdom, with Aciclovir and Aciclostad, sold in Austria.  There were many significant differences between these formulations of “the same” product.

	Researchers used methods that included 

 permeation and x-ray diffraction, and evaluated pH and potential failure modes for pH, as well as drug absorption versus dissolution rate, polymorphism, particle size, and particle morphology. They also evaluated undissolved active in cream and in aqueous phase. 

	Professor Murthy concluded that microstructural differences could have significant influence of the performance of the product. He also noted the need for a powerful nondestructive testing tool that would be able to characterize product without disturbing the original microstructure.

	In addition, he says, there is a need to consider potential failure modes during drug development, while attempting to design certain quality attributes into the product. As he noted, his group’s research has also shown the importance of solvent properties within the formulation. 

	The program then shifted to a focus on analytical methods and excipients within the formulation. Norman Richardson, global technical marketing manager for skin delivery, presented results of work that he, Amy Ethier, and colleagues at BASF’s global skin delivery lab in Tarrytown, NY (7), are doing to analyze excipients and their impact on the microstructure of semisolid formulations, taking a Q3-based approach. “The goal is to improve the quality of analysis and make the overall study more quantitative,” Richardson said. “Performance of semisold formulations is determined by Q3, and Q3 is determined by formulation. Microstructure provides a complementary, and sometimes predictive, component to system analysis.”

	Focusing on variability and the impact of process changes 

	Since 2014, research at Tarrytown has been focusing on the impact of excipient selection. These efforts began with polyethylene glycol ointments, results of which were presented at AAPS 2015, but the team’s focus has since moved into creams and emulsions, which are far more complex, Richardson said.

	The group has focused on different types of microscopy to study overall structure and morphology. Richardson noted that topical formulations using the same API at the same concentration can look vastly different under the microscope, with differences in structure beyond the API (e.g., in waxes and the phases that are formed). The researchers focused on elucidating the role that excipient selection and processing play in these differences.

	The BASF team demonstrated the variability of microstructure in creams by imaging five different products, including an antifungal, skin rash treatment, local analgesic and anti-itch cream. Each cream was distinctively different. The hypothesis is that these differences are driven by excipient selection.  “These are themodynamically unstable products that change over time,” Richardson said. “We also wanted to know how that affects Q3.”

	One of the team’s first observations was that different products designed for different functions appeared very different under the microscope. For instance, the local anesthetic was seen as comprised of large round bodies, where the antiseptic creme showed small droplets.

	The research also examined differences between the products in terms of performance criteria (i.e., viscosity, stability, sensory properties, appearance, API release, and absorption).

	Because of advances in microscopy, Richardson noted, it is possible to see in much greater detail. “You can extract a lot of detail with the right microscopy,” he said. The researchers are also looking at what is between the APIs crystals, and oil droplets. In some cases they have seen complex phases that form lamellar structures that extend between oil droplets, noting prior 

	In an effort to quantify the characterization of emulsion droplets and reduce variability in results, the team prepared slides to ensure that samples were the same size and thickness, by taking 3 mg of product and putting it in the middle of the microscope slide, squeezing it down to exactly 2 cm diameter.

	BASF’s team used the topical anti-fungal treatment Clotrimazole, as a model, Richardson said, changing one component at a time and observing the results. The product is not meant to dissolve entirely into the skin, but to remain on the surface of the skin.

	Using Image J, a free image-analysis software available 

 from the National Institutes of Health (9), the group identified droplets and mapped them, counting the number of pixels that each oil droplet occupied, then plotting histograms showing the distribution of the areas of these oil droplets as calculated by pixels.

	Research showed that different emulsifiers appeared to have an impact on oil phase droplet formulation and stability at 45 °C. The group compared Polyoxyl 20 cetostearyl ether, (BASF tradename: Kolliphor CS20), and sodium lauryl sulfate. Kolliphor CS20 was shown to be more stable, resulting in stability after eight weeks.  In contrast, the sodium lauryl sulfate began to separate in less than one week. 

	BASF’s team also examined the effect of accelerated aging, incubating one sample at ambient conditions and another at 45 °C for six months, then using Image J software to compare images of the two. The average oil droplet size was 50% greater for the sample held at higher temperature and humidity, where it was 5% larger for samples stored at ambient conditions. 

	Studying oil-droplet area and minimum stability

	Another set of experiments compared the average oil droplet area and minimum stability in weeks, to see if there might be a relationship between oil droplet size and stability. Researchers also evaluated flux versus average oil droplet area.  Work provided insights into the properties of components between oil droplets, and such characteristics as swellability, solubilization capacity, and permeability. 

	Richardson noted previous research on this topic (10) and emphasized the importance of phase behavior and the interaction of fats, oils, and emulsifiers, which create semisolid networks and build stiffness into creams.

	The team used x-ray diffraction to study these issues as well as micellar solubilization. Octododecanol was found to have an influence on the solubilization of clotrimazole.  “Choosing the right fatty alcohol will influence formulation and sometimes a mix of cetyl and stearyl will result in greater stability,” Richardson noted.  

	BASF researchers used differential scanning calorimetry (DSC) to examine polymorphic behavior of the waxes.  The team also examined the impact of excipient selection and fatty alcohol on rheology, and how oil and emollient affect API crystallinity, using Image J software to image and characterize results.

	Following Richardson’s presentation, Padam Bansal, senior vice-president of Amneal Pharmaceuticals, discussed how research is progressing to understand Q3 microstructure in a heterogeneous semisolid matrix, and its impact on drug product quality (11), while Michael Lowenborg, senior manager of formulation and process development at DPT Labs, focused on the impact of process development on microstructure (12). 

	The forum promoted discussion of important questions, and attempts to find answers in an area that is still relatively new. “At this point, we don’t know what we don’t know,” said Raney in a post-workshop panel discussion, but participants showed an interest in probing this topic, and applying improved analytical methods and procedures, in the future.

BASF Pharma Ingredients and Services Technical Sessions and Workshops

 December 2, 2015, PharmTech.com. 
	3. Center for Dermal Research, 

“Topical Semi-Solid Microstructure and its Significance in Product Performance and Functionality,”

 a workshop held on May 24, 2016, at Rutgers University, Center for Dermal Research. 
	4. B. Michniak-Kohn, “Introduction, The Role of Microstructure in Topical Semi-solid Product Performance and Functionality,” presented at the Center for Dermal Research, Rutgers University,  May 24, 2016. 
	5. S. Raney, “The Matter of Medicine: Does Form Follow Function, or Vice Versa?”, presented at the Center for Dermal Research, Rutgers University, May 24, 2016. 
	6. S.N. Murthy, 

“Topical Semisolid Drug Product Critical Quality Attributes (Q3 Characterization) With Relevance to Topical Bioequivalence,”

 presented at the Center for Dermal Research, Rutgers University, May 24, 2016, Accessed July 28, 2016. 
	7. N. Richardson, “The Influence of Excipient Choice on Topical Semisolid Microstructure and Performance,” presented at the Center for Dermal Research, Rutgers University, May 24, 2016.
	8. B.W. Barry, 

Topical Drug Bioavailability, Bioequivalence and Penetration

, Ed. V. Shah and H. Maibach, pp. 261-176, (Springer, NY, 1986).
	9. National Institutes of Health, 

. 
	10. T. de Vringer, et al., “A Study of the ageing of the gel structure in a nonionic O/W cream by X-Ray Diffraction, Differential Scanning Calorimetry and Spin-Lattice Relaxation Measurements,  Colloid and Polymer Science, 1987, 5, pp 448-457.  
	11. P. Bansal, “Understanding of Q3 Microstructure in the Heterogeneous Semisolid Matrix and its Impact on Drug Quality,” presented at the Center for Dermal Research, Rutgers University, on May 24, 2016.
	12. M. Lowenberg, "The Effect of Process Development on Emlsion Microstructures," presented at the Center for Dermal Research, Rutgers University, on May 24, 2016. 

Analytics and quantitative approaches are shedding more light on these complex formulations, promising to improve process control and product design.

Science-Based Topical Formulation

In 2011 and 2012, when the number of drug shortages in the United States skyrocketed, media focus intensified on the issue. Sterile injectables, particularly generics, accounted for 80% of the materials in short supply (1). As workhorse drugs became impossible for hospitals and clinics to get, there were reports of desperate attempts to buy drugs on the grey market from unlicensed distributors, drug substitutions, dosing mistakes that resulted in adverse reactions, as noted in a survey by the Institute for Safe Medication Practices (2), and patient deaths.

 reported that drug shortages were costing US hospitals more than $230 million per year, and that 90% of hospitals surveyed noted that they had experienced at least one drug shortage that year that might have caused a dosing or other error. Results suggested that the situation had not improved much since 2010 (3).

	The full impact of drug shortages has yet to be assessed, but the crisis is far from over. As seen in 2009-2011, when Teva stopped producing the anesthetic, propofol, and a number of contract manufacturers, notably Ben Venue Labs, left the market, the industry is still seeing product recalls and plant closures. In August 2016, Pfizer, which had acquired contract manufacturer Hospira in 2015, closed its facility in Chennai, India due to ongoing manufacturing and quality issues. The plant had received a warning letter from FDA in 2013 (4). A number of manufacturers issued voluntary injectable product recalls due to particulate and other contamination in 2016.

	Measuring the effect of drug shortages is proving as difficult as coming up with a solution to a multi-pronged problem that involves artificially depressed product prices, complex manufacturing and quality-control processes and outdated facilities, industry’s resistance to change, and lack of financial incentives to invest in modern filling and manufacturing technology.

	But the situation is clearly taking its toll. “When you fill out a family member’s death certificate, you only have to include the name of the disease that he or she suffered from, not what drug they were taking [or unable to get],” says Dr. Jacalyn Duffin, a hematologist and chair at Queens University in Ontario and founder of canadadrugshortage.com, which tracks drug shortages in Canada. She believes that an Essential Medicines List (5), such as the one used by the World Health Organization (WHO), and concerted global efforts, would help the situation in Canada and the US. 

 in 2011 found that at least 15 patient deaths that year could all be traced to drug shortages (6). The following are some of what has been reported:

		Sixty-four patients died and more than 800 became ill due to contaminated steroid injections (then in short supply from conventional sources) manufactured by the New England Compounding Center (7).

		Two patients died from accidental overdoses of morphine substitutes, while nine patients died and 19 became ill when they received infusions of contaminated solution that the hospital had bought from an unlicensed source (8).

		Single-use 50-mL vials of the anesthetic, propofol, were used to treat more than one patient, resulting in an outbreak of hepatitis C (9).

	The FDA Safety and Innovation Act of 2012 established processes for preventing shortages by requiring manufacturers to notify FDA, prioritizing FDA review of drug applications and supplements that might alleviate existing shortages, and requiring FDA to consider supply issues carefully when issuing warning letters (10). These efforts have had some impact, particularly in helping prevent new shortages.

	Existing drug shortages, particularly for emergency response staples, remain serious. The US Government Accountability Office (GAO) has analyzed shortages and their underlying causes. Its latest study (11), released in July 2016, shows that, despite a reduction in new shortages, existing drug shortages have remained consistently high for the past five years (

	The drugs in shortest supply are still the generic injectables most widely used in emergency and acute care. According to research (12), roughly half of the drugs in short supply are used in emergency care, and shortages of these drugs have been more frequent and prolonged than shortages of non-acute-care drugs, lasting 242 compared with 173 days.

	Another study (13) found that, between 2001 and 2014, of 1798 shortages, nearly 34% were for drugs used in emergency medicine. Of those, more than half were for treatments used in lifesaving interventions, and 10% were for drugs with no available substitutes.

	Researchers found that each shortage lasted an average of nine months. In shortest supply between 2001 and 2014 were the antibiotic acyclovir (which experienced six shortages), the pain treatment hydromorphone (with eight shortages), the antidote antivenin (which experienced five shortages), and epinephrine (which had seven shortages). Of the reasons given for the shortages, which were not reported by more than half of the manufacturers involved, more than 25% were caused by manufacturing problems, 15% by supply issues, 4% by raw material sourcing issues, another 4% by discontinued manufacturing, and roughly 2% each by regulatory actions and business decisions (13).

	Novel approaches to manufacturing will also be needed to improve flexibility and reduce the risk and cost of entering a market with small margins. Currently, the costs for building a sterile injectables manufacturing plant are extremely high, and the timelines long, with two years for approval time suggesting breakneck speed, notes Chris Procyshyn, CEO of Vanrx Pharmasystems, a Vancouver-based company. 

	Vanrx has developed automated filling technology using robotics, integrated inside an isolator. Its technology is based on the standard “workcells” used in semiconductor manufacturing--a model that, he says, helps reduce capital project lead time, investment and operating costs.

	Costs for building a traditional cleanroom facility can run up to $37 million, compared to $42 million for constructing a restricted access barrier system (RABS ) facility and $46 million for a facility using isolators, according to industry sources (14).

	Technology vendors are stepping up their efforts to develop technology that can address the need for flexibility, and automation, to minimize operator interaction with product.  Blow-fill-seal (BFS) technology, which packages products in single-dose plastic, provides a number of benefits, says Tim Kram, general manager for Rommelag Engineering in North America.  It eliminates operator intervention, because the process is automated, and obviates the need to buy high-quality glass, which is becoming increasingly expensive and in short supply.

	Unit-dose packaging also reduces the waste often found with vaccines, which are typically packaged in multidose form, especially for distribution to developing nations, Kram says. He notes that critical product can be wasted with multidose packaging, when the numbers of patients to be treated does not match the number of available doses.

	Rommelag recently introduced the Bottelpack 430 L, which is designed to bring increased flexibility to higher-speed filling and to allow manufacturers to be able to switch quickly and more easily between different products.  The company has also introduced a vision system for inspecting product for visible particles, eliminating the need for operators to do this. The system vibrates the container lightly, and if there are any, moving particles can be found by the camera system. Traditional systems, Kram explains, spin the container, stop, and then take pictures of the moving water column, and can result in inaccuracies.

	Vanrx was established in 2007 by Procyshyn, a microbiologist by training, and Ross Gold, a chemical engineer.  They had worked together at the ophthalmic drug manufacturer QLT and were frustrated by conventional fill/finish equipment. “Existing technology was not keeping up with the industry’s move to manufacture a higher number of more specific products,” says Procyshyn, who notes the need for manufacturers to adapt quickly to changing market needs.

	In response to those needs, Vanrx developed the SA25 Aseptic Filling Workcell, a gloveless isolator that eliminates operator intervention. It allows filling of vials, syringes, and cartridges within the same machine using nested containers and closures. The work cell features faster changeover times, a smaller footprint, and automation using robotics and machine vision, Procyshyn says. Employing a limited number of change parts, it relies on software for product changeover, which can take three days in a conventional facility.

	The future, Procyshyn says, will involve facilities with many small lines, not a single large filling line. This picture doesn’t yet exist in the pharma industry, but is now common in semiconductors where workcells dominate. In July 2016, Bloomington, Indiana-based Singota Solutions acquired Vanrx’s technology, and a number of other lines are already in place in Asia, Procyshyn says.

	Vanrx is also a founding member of the Matrix Alliance, a group of packaging manufacturers collaborating to optimize and standardize nested container and closure products. Alliance members believe that working together on testing and compatibility should support drug manufactures in bringing products to market more quickly. Alliance members include ARaymond Life, Daikyo Seiko, Datwyler Group, Ompi, SCHOTT, and SCHOTT Kaisha.

	The group’s efforts are currently focusing on testing pre-sterilized container and nested closure systems, and ensuring compatibility of components from different member companies. Container-closure integrity testing results are now becoming available from member companies. Greater performance certainty and component availability will contribute to solving the shortage issue by solidifying drug manufacturers’ supply chains and reducing risks in bringing products to market, Procyshyn says.

	Currently, facilities using isolators cost more to build than traditional cleanrooms or RABS, but reduce operating costs dramatically. After 10 years, operating costs for a traditional cleanroom run to $79 million, $83 million for a RABS, but $67 million for isolators (14). Automation will be crucial to preventing the quality and compliance problems that often lead to sterile injectables shortages. Says Kram, “We’re getting very close to ‘lights out’ operation.”

Drug Shortages: A Closer Look at Producers, Suppliers, and Volume Volatility,” IMS Institute for Healthcare Informatics

, IMShealth.com, November 2011, 
	2. ISMP, “

Drug Shortages National Survey Reveals Higher Frustration, Lower Level of Safety

,” ismp.org, September 23, 2010. 
	3. L. Johnson, “

Hospitals Coping Better as Drug Shortages Persist

,” Associated Press, Feb. 27, 2014, AP.com.
	4. E. Silverman, “

Pfizer Closes Plant in India After Several Regulators Find Problems

,” StatNews.com, August 8, 2016.
	5. G. Eom et al., “

,” Canadian Medical Association Journal, June 13, 2016, CMAJ.com.
	6. L. Johnson, “

,” Associated Press, September 22, 2011, posted on Cancer Survivors Network.
	7. “

Multistate Outbreak of Fungal Meningitis and Other Infections Case Count

,” October 30, 2015, Centers for Disease Control, CDC.gov.
	8. R. Stein, “

,” The Washington Post, washingtonpost.com, May 1, 2011.
	9. V. Jensen, 

, 363 (9), 2010, pp 806-807.
	10. Hyman, Phelps and McNamara, P.C.,“

Food and Drug Administration Safety and Innovation Act, Summary and Analysis

,”  July 11, 2012, hpm.com.
	11. GAO, “

Drug Shortages: Certain Factors are Strongly Associated with This Persistent Public Health Challenge

,” U.S. Government Accounting Office, gao.gov, July 7, 2016.
	12. S. Chen et al., Health Affairs, Vol. 35 No. 5, ppp. 798-804 (May 2016).
	13. K. Hawley et al., Academic Emergency Medicine, 23 (1), pp. 63-69 (January 2016). 
	14. J. Ferreira et al., “A Comparison of Capital and Operating Costs for Aseptic Manufacturing Facilities,” Chapter 12, Advanced Aseptic Processing Technology, edited by James Akers and Jim Agalloco, pp 118-143 (CRC Press, New York, NY, 2010).

	When referring to this article, please cite it as A. Shanley, “Sterile Injectables Shortages: Can Innovation End A Crisis?," 

The media blitz surrounding drug shortages has stopped, but critical medications that have no substitutes remain in short supply. Can new approaches turn this situation around?

Sterile Injectables Shortages: Can Innovation End A Crisis?

The past few years have seen, not only the introduction of major supply-chain regulations in the United States and Europe, but changes in the way that pharmaceutical excipients manufacturing sites are evaluated to assess regulatory compliance. Manufacturers can now choose to undergo third-party audits to show that their excipient manufacturing operations comply with current good manufacturing practice (cGMP) regulations. Irwin Silverstein, consultant to the International Pharmaceutical Excipients Council (IPEC), shared his views with 
	

	Are mandates needed to drive standardization?

 Has the pharmaceutical industry fully embraced the idea of standards for ensuring that excipient manufacturers follow cGMPs? 

 Excipient makers still seem to be developing plans to meet the standard. I’m not sure how many pharmaceutical users expect their suppliers to comply. 

	In addition, there is still some confusion about the differences between requirements for standards under the American National Standards Institute’s (ANSI) 363 vs EXCiPACT. In my personal opinion, there won’t be a lot of motivation for manufacturers to get certified, or to attempt to demonstrate compliance with cGMP standards, if certification is not made a regulatory mandate.

When IPEC ran the International Pharmaceutical Excipient Auditing group IPEA (now part of NSF International), I would have expected all companies certified by IPEA as complying with cGMPs to embrace the standards. 

	I’m not sure of the exact number, but I would think that, by now, the seven sites that IPEA had certified in the US would be in substantial compliance with the ANSI standard.

	More facilities are being certified to EXCiPACT. Expectations for both certifications are essentially the same. Even companies in the US are now choosing to be certified by EXCiPACT, and these are not US-based subsidiaries of European firms, but US companies, which must pay to fly auditors over from Europe for the certification. Despite FDA’s support for standards, certification with ANSI hasn’t yet gained wide industry acceptance. 

 Can you comment on the industry’s readiness for European regulations under the Falsified Medicines Directive (FMD)? How are manufacturers and customers responding?  Where do you see gaps?

 From what I’ve heard, customers are still somewhat confused about the role that excipient manufacturers should play. The regulations call for risk assessments, which require collaboration between manufacturers and customers, and, so far, I’m hearing that there hasn’t been that much contact between the two groups. 

	If you manufacture pharmaceuticals for sale in Europe, whether you make the product in Europe or elsewhere, you have to comply with terms of the FMD for excipients.  Compliance requires that users perform a risk assessment of each excipient and excipient supplier, as well as separate risk assessments of each excipient’s role in the formulations in which it is used. Based on these two risk assessments, supplier quality indicators, and evidence that the supplier meets cGMPs, customers are supposed to get an idea of the extent to which the supplier should implement cGMPs. The supplier’s role is nothing more than supplying the information that customers need for the risk assessments. This type of information would include product data and specifics about grade and quality (e.g., whether ingredients are derived from animals, or whether the material was produced in a dedicated or multi-use facility, using dedicated or multi-use equipment). 

	Their only obligation is to ensure that this information is sent to each pharmaceutical manufacturer customer, for each excipient they sell to them. They can meet this requirement by reviewing and updating their product information packages, and including all the information that will be needed for customers to be able to perform the required risk assessments.

	When pharmaceutical manufacturers have determined their suppliers’ level of cGMP compliance, they are supposed to notify suppliers of any gaps through revised quality agreements. If many of these risk assessments had been completed, there would have been more agreements stipulating the degree of cGMP compliance expected. 

	The apparent lack of information sharing involving users, manufacturers, and suppliers does not support the idea that excipient suppliers and customers have been aggressively implementing FMD requirements. Yet regulators, notably the United Kingdom’s Medicines and Health products Regulatory Agency (MHRA), have said that they will enforce this rule rigorously and would cite violating companies, as FDA would with a 483.  Even the threat of regulatory action doesn’t seem to be enough to motivate some suppliers.

	The FMD’s intent is to require site visits, where customers audit supplier sites. Given the resources available, regulators have had to allow provisions for qualified third-party audits. 

	As time goes on, there is a strong likelihood that suppliers will rush to certification, since European regulators will allow use of certification as a component of the risk assessment. Excipient manufacturers have too many customers to be able to collaborate with more than a very significant few. 

  Regulators have voiced support and acceptance of third-party audits, in lieu of on-site inspections and audits by customers.  Why aren’t more companies adopting this approach?

 Everyone seems to have reached the conclusion that third-party audit and certification is essential to meet expectations for on-site inspections. However, third-party audits will only become the norm when pharmaceutical manufacturers that rely on certification are confident that the audits will be accepted by regulators.

	Big Pharma is cautious, and some companies may be afraid to rely on certification when they can send their own people out to inspect excipient manufacturers. They can do this because they are major customers for these excipient suppliers.  Smaller companies, however, and especially generic pharmaceutical manufacturers, don’t buy enough from these excipient suppliers to be able to do an audit onsite, so many of them continue to buy from uncertified manufacturers and suppliers. 

	Lack of excipient cGMP certification does not mean that the excipient manufacturer is not complying either with the IPEC GMP guide or the standard, only that there is no independent verification. The question is how much emphasis is being placed on supplier qualification at these smaller firms.

  Data integrity has become a major compliance issue for API suppliers. Is it also a problem for excipient suppliers? What should their customers be focusing on, in vetting their quality systems and capability?  

 ANSI 363 notes, in clause 6.3.2.3 on computer systems, that provisions are to be made to ensure the maintenance of data integrity. Other clauses include portions that discuss data integrity for paper records.

	Excipient manufacturers should perform a gap assessment analyzing their procedures and practices against requirements in FDA’s draft guidance on data integrity and the World Health Organization’s (WHO) guidance to get an idea of how well they are complying.

	Data integrity is likely to be a key topic at IPEC meetings in September. IPEC has also added more training on data integrity in its general training programs, including its Level 1 course, which is geared to hourly employees. We wanted to reinforce basic best practices, such as the need to use unique passwords and not share them.

	We also see the need to drive home the idea that any data that are written on paper and then transferred into a computer database, including chromatograms, must be retained in paper form as backup and must also include metadata.  Workers need to know how to maintain audit trails and ensure that they are working. We’re now planning to take this training to the next level, with a Level 2 course for supervisors.

	It’s important to remember that data integrity does not only involve computers, but also paper documentation. Excipient manufacturers must examine the issue from various angles to ensure that they meet requirements when audited by a regulator, customer, or third-party auditor.

	If any manufacturer complains that they lack the resources to be able to do this, the only resource that excipient manufacturers need is the wherewithal to do a gap assessment.  Requirements are spelled out nicely in the WHO guidance on data integrity. If pharma firms are using computers that are validated and that comply with 21 

) Part 11 requirements, and being used correctly, they have established the right foundation for protecting data integrity.  

	Excipient manufacturers can have problems establishing this foundation, however, since chemical companies often use legacy systems. Pharma is only one of their many industry customers, so many excipient manufacturers’ legacy systems are not Part 11-compliant.  

	If you replace a programmable logic controller at a chemical plant, you need to ensure its safe operation. If you’re using a legacy system that has been running without incident for 30 years, but has no audit trails, there’s no incentive for an excipient manufacturer to invest in Part 11-compliant equipment. This is why training is so important. 

 Supplement
	September 2016
	Pages: s20-s22, s34

IPEC consultant Irwin Silverstein discusses third-party audits and regulatory compliance issues facing suppliers and their customers.