Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Possibly the most publicized and well-documented form of drug misuse and abuse has been that of opioids-prescription pain-relief medicines. The opioid crisis, which has impacted the global health community for several years, has paved the way for increased demand in abuse-deterrent formulations from pharmaceutical developers.

	Abuse-deterrent formulations essentially have the potential to provide an effective way of reducing the capabilities of an end-user to abuse or misuse a medical therapy, while maintaining the drug’s clinical benefit. To explore the topic of abuse-deterrent formulations in more detail, 

 spoke with Angela Moore, scientist, Analytical Development, Alcami.

 Could you discuss some of the reasoning behind abuse-deterrent formulations and why there may be an increase in interest in this area?

 Doctors continue to prescribe opioid medications for pain management, generating an inevitable association with abuse and addiction. Government officials and pharmaceutical professionals alike are in need of risk mitigation approaches. 

	In the United States alone, there have been estimates, released by the US Department of Health and Human Services (HHS), revealing that in 2018 over 47,000 citizens died from an opioid overdose and that two million people in the country were suffering from an opioid use disorder (1). The economic costs associated with the opioid epidemic have been estimated at $504 billion, according to analysis by Johns Hopkins University Bloomberg School of Public Health (2). And, the issue of opioid addiction is not isolated to the US, with countries worldwide experiencing significant healthcare costs associated with prescription opioid abuse, such as those experienced in the five largest European countries as reported by Shei 

	Pharmaceutical companies have responded to this need through more stringent abuse-deterrent formulations and studies. Although abuse-deterrent does not equate to ‘abuse-proof,’ medications that contain abuse-deterrent properties make it more difficult for abusers to obtain the euphoria associated with common manipulation techniques.

 Currently, what abuse-deterrent formulation approaches are available and what are the benefits and/or limitations to these approaches? 

 The current products on the market that contain abuse-deterrent labeling approved by the Food and Drug Administration fall into two categories of abuse-deterrence: physiochemical and opioid/antagonist. Physiochemical abuse-deterrent properties include products that are formulated to resist crushing, chewing, and physical manipulation. They contain excipients that will ‘gel’ upon contact with solvents to make them difficult to inject intravenously. Opioid/antagonist products contain the active opioid intended for therapeutic use and also a sequestered antagonist so that if the product is manipulated intentionally it will release a chemical that will prevent the user from feeling the euphoric effects of the opioid.

	There are benefits and challenges to both physiochemical and opioid/antagonist abuse-deterrent formulations. Benefits of physiochemical formulations include having physical barriers that make it more difficult to resist tampering and manipulation. Abusers avoid these formulations as they cannot easily crush and/or inject the drug. One of the biggest challenges of these types of formulations, however, is that there are still drug abusers who find ways to abuse these products. The excipients that are present in the formulations to prevent abuse can cause many health issues if injected. For example, OpanaER (Endo Pharmaceuticals) was an extended-release oxymorphone hydrochloride oral drug product. The drug was approved by FDA in 2006 but was being abused mainly by insufflation. The drug was reformulated in 2010 with physiochemical properties intended to be resistant to intranasal and intravenous routes. However, in June 2017, FDA requested OpanaER to be removed from the market as abusers had moved from insufflation abuse to injection abuse (4). The reformulated drug product was being shared between multiple users for injection. OpanaER was directly linked to outbreaks of Hepatitis C (New York, 2011), thrombotic thrombocytopenic Pupura-like (TTP) illness (Tennessee, 2012), and HIV (Indiana, 2015) (5,6). 

	A benefit to opioid/antagonist abuse-deterrent formulations is that the drug product contains a sequestered antagonist within the formulation. If the drug product is administered to patients as intended, it will work therapeutically. However, if a drug abuser tried to crush or manipulate the drug, the sequestered antagonist would be released and block the euphoric effects of the opioid. However, these abuse-deterrent products are not ‘abuse proof.’ Drug abusers have found ways to chemically extract the opioid from the antagonist with common household solvents to still abuse these formulations.

	Another challenge that is related to all of the eight approved, abuse-deterrent opioid products that are on the market is cost. The products are all name-brand and expensive to patients. There are currently no FDA-approved generic equivalents to abuse-deterrent formulations, and insurance companies are reluctant to pay the extra expense for an abuse-deterrent opioid when the cost is vastly different from generic non-abuse-deterrent equivalents. 

 Are there specific regulatory challenges that should be considered when approaching abuse-deterrent formulations?

 FDA is closely scrutinizing all new abuse-deterrent products and current opioid products that are on the market now. There are comprehensive, in-depth testing requirements prior to approval of these products. For example, in-vitro testing of products intended to prevent abuse can take six months to a year to complete thousands of extraction, manipulation, and syringe studies. 

	After this testing is complete, the products are then verified in a clinical setting in humans, where clinical subjects purposely take a product as intended and then in an abused form and rate their ‘drug liking,’ which is if they enjoy the product recreationally and if they would take the drug again. 

	Post-approval, FDA also requires all pharmaceutical companies that manufacture prescription opioids commercially to participate in the REMS program (Risk Evaluation and Mitigation Strategy) where they monitor the abuse of commercially marketed opioid pharmaceuticals. 

	As each formulation and mode of abuse can be different, there is only FDA published guidance, Abuse Deterrent Labeling-Evaluation and Labeling Guidance for Industry, published in April 2015 that pharmaceutical companies can use as a guide for completing the required tests. Companies must work closely with FDA to ensure the testing performed is adequate and that study designs are acceptable. It is not uncommon for FDA to request additional testing at each stage of studies, which takes considerable time and expense to execute.

 How can the effectiveness of an abuse-deterrent formulation be evaluated?

 Current FDA guidelines for determining abuse-deterrence of a drug product involve four main studies termed Category 1, 2, 3, and 4. 

	Category 1 testing involves laboratory manipulation and extraction studies. In these studies, the product is evaluated and compared to currently marketed formulation(s) for the ability to defeat or compromise the abuse-deterrent properties. This testing is performed in-vitro and provides physical characteristics of the product and its ability to resist crushing, grinding, melting, and so on, to inhibit nasal abuse. Extraction studies provide information on the product’s ability to isolate the antagonist, or resist abuse by injection, or, in larger volumes, resist abuse by ingestion. 

	Category 2 testing involves pharmokinetic studies in healthy humans. The product’s in-vivo properties are evaluated by comparing an intact formulation against the manipulated formulation through one or more routes of administration. Comparator products are also evaluated for comparison. 

	Category 3 testing evaluates the clinical abuse potential of the product. These are large, complicated in-vivo studies that are generally conducted with recreational drug users as test subjects. These test subjects are screened prior to the study to ensure that they are able to distinguish between active drug and placebo in a drug abuse setting. In these studies, the test subjects are provided with the drug product being developed and suitable comparators. The drugs are administered through the route of abuse that is being studied (i.e., oral or intranasal) and the patients provide not only pharmokinetic data, but also subjective data on the drug liking (how high they are) and if they would take the drug again. 

	Category 4 assessment is a post-approval study that determines if the product has resulted in meaningful reductions in abuse, misuse, or adverse clinical outcomes (addiction, overdose, and death). These evaluations are conducted by the product manufacturer. Currently, there are no products on the market that contain the Category 4 label for abuse-deterrence. 

 What trends, potential new approaches, and considerations do you foresee as being important in the field of abuse-deterrent formulations in the near future and why?

 One of the biggest trends in abuse-deterrent formulations is the development of abuse-deterrent generic products. FDA has published guidance for industry, General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, for companies that are developing generic products comparable to the approved abuse-deterrent products on the market (7). The intention of the guidance is to reduce the amount of testing required for the generic product by showing equivalence or superiority to the name-brand product in laboratory-based, abuse-deterrent tests so that human trials (Categories 2 and 3) are not required. Additionally, any new opioid drug that is being developed must demonstrate resistance to abuse in order to grant FDA approval. 

	There are many considerations for manufacturers developing abuse-deterrent opioid formulations. Most importantly, the product must be considered safe and effective, and it must adhere to all regulatory manufacturing and testing guidelines. From a chemistry and biologic perspective, the product must resist dose dumping and abuse, but still release the active ingredient when ingested as intended. From the commercialization perspective, key considerations are developing a product that has a competitive advantage over what is on the market today. The company must differentiate their product so that they can answer the question: ‘What product characteristics will make a doctor want to prescribe the new product over what is on the market?’ Furthermore, insurance companies, governments, and patients must be convinced that the new product is worth more compared to cheaper, non-abuse-deterrent products on the market.

	1. HHS, “What is the US Opioid Epidemic?” 

, Epidemic Informatic last updated Sept. 4, 2019 [accessed May 12, 2020].
	2. D.H. Lin, et al., 

, 1 (2) e180235 (2018). 
	3. A. Shei, et al., 

FDA Requests Removal of Opana ER for Risks Related to Abuse

, Press Release, June 8, 2017.
	5. H. Mehmood, et al., 

, Published Online Jan. 31, 2018.
	6. Endo Pharmaceuticals, “Opana ER-Oxymorphone Hydrochloride Tablet, Extended Release,” 

, Prescribing Information [accessed May 12, 2020].
	7. FDA, 

General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products Guidance for Industry

https://academized.com/blog/us-opioid-epidemic


	Vol. 44, No. 6
	June 2020
	Pages: 24–27

	When referring to this article, please cite it as F. Thomas, “Reducing Risk with Abuse-Deterrent Formulations,” 

Articles

Increasing prevalence of drug misuse and abuse is driving a heightened and more stringent approach to abuse-deterrent formulations.

Reducing Risk with Abuse‑Deterrent Formulations

As the world becomes more heavily reliant on connected devices, it is little wonder that the connected drug delivery devices market is set to witness significant growth in the coming years. According to market research, the sector is expected to grow at a compound annual rate of 35.4% in the forecast period of 2019–2026 (1). Suggested drivers of this projected market growth include a rise in the number of patients suffering with chronic diseases globally, increasing emphasis on preventive care, a general shift towards connected devices rather than manual ones, and improved procedural outcomes offered through connectivity (1). 

	Delivering drugs through connected devices, such as auto-injectors, smart inhalers, and closed-loop solutions, has been documented as a potential way of improving patient adherence and reducing dosing errors, particularly in the home setting (2–5). “It is widely recognized that the effectiveness of drug delivery devices can be compromised by adherence and patient use error, the likelihood of which are impacted by numerous factors,” confirms Andreas Meliniotis, director, device development, Vectura. “Tracking and reporting use via connected devices can highlight use errors and compliance with therapies, and, therefore, can be used as a tool as part of the process towards improvement in the delivery of almost any therapy.” 

	“The most critical aspect to connected drug delivery is improving patient adherence to get desired outcomes from prescribed medications,” says Bill Welch, chief technology officer, Phillips-Medisize. “First and foremost, connected drug delivery is about creating an engaging experience so that patients have the best tools and technology available to help manage their disease.”

	Traditionally, the connectivity interface was built into the delivery device, such as medication reminders, timers, and alerts, notes Welch; however, with smartphone apps, it is now possible to further enhance the patient experience and the ability to share information. “With patient permission, information can be shared to the patient’s healthcare providers and even family members,” Welch continues. “This dynamic enables the entire care team and loved ones to be equally invested in the patient’s health to improve adherence and outcomes within the greater scope of a connected care ecosystem.”

	Lawton E. Laurence, director, Radical & Disruptive Innovation, West Pharmaceutical Services, iterates the importance of defining the limits of connectivity. “Connectivity is communication. Communication among devices, among stakeholders, and then between those two groups. Connectivity is not a panacea for the pain of poor patient adherence,” he says. “Without an intimate understanding of your target patient population, device connectivity may only shine a spotlight on the overall weaknesses of the product. Consider it as a tool that can help you more effectively collect information and execute on the appropriate mitigation strategies for your patients.”

	However, once the appropriateness of a drug–device combination product for a specific patient population has been discerned, using connectivity to then target specific issues underlying non-adherence can be exceptionally effective, Laurence adds. “In the distilled words of Lord Kelvin, ‘What gets measured, gets managed’ and there is no doubt that transforming the drug delivery space from one of ephemeral delayed reaction to a data driven ecosystem of aligned stakeholders is the core promise of connectivity,” he states.

	“In order to consider the impact of connectivity on adherence, we should first explore what factors affect adherence,” remarks Meliniotis. By way of an example, Meliniotis referenced a research paper on inhaler adherence, which noted that although adherence can simply be defined as to how a patient follows a prescription, there are many variables, such as dose frequency, taste, and route of administration, that can actually influence the use of a medication (6). 

	“With regards to therapies where connected drug delivery can provide otherwise non-existent feedback, connected devices can provide both feedback and metrics to encourage patients to comply, changing their mind-set,” Meliniotis continues. “Gamification can be used, which uses an app or other feedback interfaces to encourage compliance, and there are suggestions that to ensure long-term compliance, constantly changing aspects, (i.e., new targets or ongoing metrics) can keep patients interested, and have a longer-term effect than more basic systems.”

	“To be sure, the ability of connectivity to improve patient adherence in the short term has discrete merit; however, the real payback is how we can leverage the information to feed the next generation of drug-device combination products,” adds Laurence. “The first movers will be privy to a treasure trove of usability information and their ability to operationalize that intelligence will position them to be the leaders in the next generation.”

	“Connected drug delivery should be focused on areas where the impact can be the largest,” explains Meliniotis. “One example is by providing immediate feedback to a therapy that would otherwise be unavailable, for instance, an asthma maintenance therapy, where adherence may be poor due to no immediate decline in health, rather than insulin injections for diabetes, where adherence is generally high due to immediate severe outcomes.”

	Adoption of connected solutions is already being seen in the fields of certain rare and orphan diseases, where there is a high cost per patient per year, Welch confirms. “Outcomes are important as payers move pharma toward performance-based contracts. Having confidence in patient adherence and the ability to get the best outcomes has, therefore, never been more important,” he adds. “Connected drug delivery can help facilitate outcome optimization by providing real data to healthcare providers to enable better informed treatment decisions.”

	Other areas that can particularly benefit from connected drug delivery solutions include chronic diseases that need to be managed hourly or daily and for patients that require more acute care or rescue devices for emergency use, Welch notes. “Better ways to manage chronic, orphan, and emergency conditions with connected drug delivery are being looked at currently,” he says. “It is not a ‘one-size-fits-all’ solution, rather the connected health ecosystem must be built for the disease and patient population.”

	According to Laurence, the bio/pharma industry is just beginning to tap into the opportunity afforded by connected drug delivery solutions to create value for its diverse stakeholders, with some therapeutic areas that were ‘early adopters’ demonstrating transformative changes. Some examples of changes from ‘early adopters’ include the Type I diabetes market where the stakeholders demanded transformation to have connectivity between devices, or with therapies for respiratory problems where connected inhalers are used to offer the histogram of doses and inform whether the drug was delivered appropriately, he notes.

	“Some therapies can be impacted significantly by user technique and identifying this can have a dramatic effect in the efficacy of treatment, particularly if it prevents a patient being prescribed a medication at a higher level in order to compensate,” agrees Meliniotis.

	Taking into account how bio/pharma companies investing in connectivity could drive superior solutions in the future, Laurence stresses that one of the most underreported opportunities in connected devices relates to clinical trials. “If you want to study the adherence of your patient population and even access unassailable retrospective dose data, a mere notification in their patient-facing app presents a revolution in cost and time to collect that data,” he states. “It may be feasible to look at how changes in formulation, device characteristics, or nurse interventions impacted a patient’s adherence. Gone will be the days of supposition reaction; connectivity will usher in data-driven therapy evolution.” 

	There are a couple of prominent limitations of connected drug delivery solutions, namely cost and environmental waste, explains Welch. “When electronics and sensors are added to make a traditional mechanical drug delivery device digitally connected, this drives up the cost. So, it is important to find a balance between the value of data and patient adherence versus the added cost of the electronics and sensors,” he notes. “Likewise, while the traditional single-use or disposable devices may have cost production advantages, companies and consumers should also consider the impact of a disposable device on the environment.”

	It is the industry’s dependence on disposable devices that Laurence states as being the most insidious of limitations. “It is imperative that a sustainable solution is found that can improve a patient’s experience while reducing the burden on the ecology,” he says. “Another pressing barrier to connected solutions is patient trust in what will be done with the data collected by the device. Success will be unattainable if industry acts in a clandestine fashion on this matter. Every moment the security of drug delivery devices is called into question will be the nucleus of setbacks in our mutual goal to improve the standards of the patient.”

	With many connected drug delivery solutions currently taking the form of an ‘add-on’ feature to an existing product, functionality is limited somewhat as the base device has not been originally designed with connectivity in mind, asserts Meliniotis. “As time progresses, delivery devices are likely to be increasingly designed with connectivity in mind, which could open up possibilities for integrated connectivity of high functionality add-on devices,” he states.

	Some key considerations when developing a connected drug delivery device include optimization of the patient experience, significant market research to achieve a detailed target product profile, and taking a holistic approach with platforms and technology providers. Data privacy and security must also be considered thoroughly, particularly in light of the current focus in this area, continues Welch. “Pharmaceutical drug delivery devices are highly regulated and you have to be cognizant of the diligence and development rigor required on the device, the app, and the data access portals to meet the underlying regulatory criteria,” he says.

	Looking at potential trends for the future, Laurence noted the movement toward advanced therapies, which is driving elevated prices. “It is increasingly important to be able to prove quantitatively the value being wrought in these therapies,” he says. “Pay for results and accountable care organization models are becoming more commonplace and connected drug delivery devices will be another wave of the same swell.”

	For Meliniotis, the full potential of connected devices will only start to be unlocked once ‘true adherence’ is measurable. “Once devices are capable of measuring signals from the patient, monitoring ‘true adherence’, and automatically administering or prompting administration of medication, it will be possible to attain a closed feedback loop, which could ultimately optimize efficacy for patients individually,” he states. “Once the benefit of connected devices has been clearly demonstrated, pharmaceutical companies will invest more heavily in this field.”

	“Another avenue for future trends is to consider the impact of prescription digital therapeutics as a combination with traditional injectables,” adds Laurence. “Like many things, it’s possible the combination of the two is significantly more powerful than either could be alone.”

	Sustainability is high on the agenda for the future in Welch’s opinion. “There’s a real push from the industry, especially in the European regulatory environment, to manufacture products that are more sustainable and environmentally friendly from both a raw material utilization standpoint, but also in regard to the supply chain, logistics, and transportation considerations,” he adds. “Developing connected devices that achieve a balance between disposable and reusable will, therefore, be highly desirable. Sustainability, connectivity and cost must all come together to address the trends shaping the future of patient care with more efficient drug delivery that leads to better outcomes.”

	“It would be difficult to describe a future state where every therapy wouldn’t benefit from connectivity,” Laurence continues. “The back-end infrastructure to convey the value to the stakeholders isn’t necessarily available today, but I’m quite certain it will be.”

	Even though it is now possible, as it never has been before, to easily track aspects of drug delivery, it must be remembered that the effectiveness of any treatment is a combination of numerous factors, emphasizes Meliniotis. “As the availability of connected devices increases, so the effect of this data-driven therapy adjustment is likely to become increasingly apparent, which in turn will increase the desire to connect more therapies,” he says.

	“At the end of the day, it’s all about accountability,” confirms Welch. “There are several dimensions of connected health that contribute to the overall picture. Creating a better user experience with a connected drug delivery device that drives higher patient engagement and ultimately improves health outcomes is the end game. To get there, everyone involved must assume a level of accountability.”

	For pharmaceutical companies, accountability lies in providing drugs and connected delivery systems that can demonstrate improved outcomes supported by data, while the device manufacturers are accountable to their pharmaceutical partners to design and develop innovative products that optimize patient engagement, lower the cost of connectivity, and reduce waste, Welch emphasizes. “As the world becomes more connected, we all must do our part to keep the population-and the environment-healthy,” he concludes.

	1. Fortune Business Insights, “Connected Drug Delivery Devices Market Size, Share, and Industry Analysis, By Type (Injectable Devices and Inhalation Devices, and Others), By Technology (Bluetooth, NFC, and Others), By End User (Homecare Settings and Hospitals), and Regional Forecast, 2019–2026,” 

, Market Report (November 2019).
	2. I. Kleiter, et al., 

, 17 174 (2017). 
	3. B. Bittner, et al., 

, 12 101–127 (2019). 
	4. A.H. Chan, et al., 

, 3 (3) 210–219 (2015).
	5. A. Blanco-López, et al., 

, Open Access Article, Published Online April 1, 2020.
	6. J.R. Jardim and O.A. Nascimento, 


	Vol. 44, No. 6
	June 2020
	Pages: 16–19

	When referring to this article, please cite it as F. Thomas, “Better Connected: The Value of Connected Drug Delivery,” 

Connected delivery solutions can provide value to industry and patients, through improved medication adherence and outcome optimization.

Better Connected: The Value of Connected Drug Delivery

The global population is ageing, the prevalence of chronic conditions is rising, and medicines are becoming more widely accessible globally, which are all leading to greater demand and growth in pharmaceuticals and pharmaceutical ingredients. According to market research, the API market is expected to experience a compound annual growth rate of 6.7% in the forecast period of 2020–2027 (1).

	Production of pharmaceutical ingredients has gradually shifted over the course of several decades to Asia, rather than Western-based countries, which has been driven largely by cost savings. This global access to supply has been largely beneficial to the industry and patients alike, expanding access to medicines for many more people around the world. 

	“Beginning in the 1980s, the pharmaceutical industry experienced a gradual shift in the manufacturing of some APIs and finished drug products from Western-based countries to China and India. This transition not only better served growing regional demand across Asia for high-quality healthcare products, but helped to reduce drug manufacturing costs,” confirms Dr. Andreas Meudt, vice-president of exclusive synthesis for the Health Care business line of Evonik. “The low-cost benefits of manufacturing APIs and drug products within Asia has helped to turbocharge the generic drug industry and expand global access to a range of lower-cost medication options,” says Meudt.

	One of the most obvious changes to the pharmaceutical manufacturing supply chain has been the increased reliance on external partners for the development and commercialization of products, notes Lonnie Barish, vice-president, business development and marketing, Bora Pharmaceuticals. “The shift has been positive for patients, allowing consumers to benefit from lower cost drugs from US Food and Drug Administration (FDA) and European Union (EU) inspected current good manufacturing practice (cGMP) facilities while still maintaining quality, innovation, and allowing efficient drug development and commercialization routes,” he says.

	“Companies have been engaging offshore, international manufacturing partners for several reasons. The initial drivers have been accessing lower cost supplies and proximity to emerging markets,” Barish continues. “While managing costs has been a central theme, access to capacity, technical capabilities, and cutting-edge science at high quality CGMP facilities have also prompted many offshore partnerships, especially for more commoditized and high-volume products.”

	Through the purchase of former ‘Big Pharma’ facilities, many offshore contract development and manufacturing organizations (CDMOs) are now capable of offering high levels of product quality, Barish stresses. “However, the nature of pharma is increasingly global, and whether offshore or not, CDMOs must compete internationally on a number of challenging fronts,” he adds. “If a supplier can offer flexible scale and capacity, efficient processes, and specific technologies and capabilities all designed to optimize manufacture of a drug product, then that CDMO is already providing distinct advantages.”

	In addition to the move to offshore manufacturers, companies have also been outsourcing more complex APIs and drug products to specialized contract manufacturing organizations (CMOs) and CDMOs. “One reason for this change is that an increasing number of APIs are highly complex, with many requiring more than a dozen steps for synthesis. Most require a range of advanced technologies that go far beyond the realms of classical chemistry,” explains Meudt. “In many cases, there are only a few CMOs in the world that have the necessary core competencies to manufacture such complex APIs. These CMOs tend to have a Western-centred global manufacturing network. In addition to these CMO sites providing proximity to core regional healthcare markets, pharmaceutical companies also benefit from the reliability of these CMO partners when it comes to quality consistency, supply security, and intellectual property protection.”

	However, in the advent of a global pandemic, such as that of COVIDâ19, potential vulnerabilities in the current pharmaceutical supply chain have been highlighted (2). In a position paper from the European Fine Chemicals Group (EFCG), concerns on the potential threat of medicines shortages as a result of the dependency on Asian countries for APIs, which is stated as being close to 80% for EU medicinal products, were laid out (3). A possible three-part solution to preventing drugs shortages in the future was specified in the paper, including a plan to “bring critical off-shore technology back to Europe” (3).

	Even in cases of less complex APIs, and with some products being considered essential to the provision of patient care, a shift in strategy is being seen across the industry, asserts Meudt. “Rather than seeking short-term, price-sensitive supply contracts with a range of CMOs, many companies are instead prioritizing long-term supply relationships with a short-list of preferred CMOs,” he says. “While manufacturing cost will always be important, pharmaceutical companies are increasingly selecting their long-term CMOs based upon other factors including security of quality and supply, regulatory track record, data control, and environmental sustainability. Regardless of geography or price, customers want CMOs that can deliver long-term value and peace-of-mind.”

	COVID-19 has elevated the issue of API and drug product supply further to industry and governmental bodies, Meudt continues. “Healthcare systems are coming to recognize that domestic or regional access to API manufacturing, together with national safety stocks for essential medicines, must be a strategic imperative to maintain continuity of supply during future pandemics or other globally disruptive events,” he says.

	India and China are currently in a strong position as many of the necessary raw materials that are required to manufacture certain APIs are only available in those regions. “However, it is becoming increasingly apparent to many European and North American leaders that they must re-evaluate their regional API, intermediate, and drug manufacturing capabilities to further reduce the risk of critical supply chain breakdowns occurring in the future,” Meudt asserts. “Close interaction between pharmaceutical companies, CMOs (such as Evonik), industry groups, and governments will be required to ensure that the regional supply of APIs to local healthcare systems can be better maintained even during periods of global crisis.”

	“The current COVID-19 pandemic has re-focused the spotlight on the preparedness and resiliency of pharma’s contract manufacturing and API supply chains. Offshore or domestic suppliers are going to have to redouble their efforts to assure reliability, redundancy, and quality,” emphasizes Barish. “Going forward, I think there will be significant pressure on pharmaceutical companies to strengthen their own supply lines, obtaining secondary sites, and additional partners.”

	Furthermore, increasing regulatory scrutiny is another factor affecting outsourcing decisions by pharmaceutical companies. “The ability of a CMO to prevent product contamination, avoid occupational exposure to highly potent APIs, minimize emissions, and maintain the integrity of pharmaceutical manufacturing data are all growing areas of scrutiny,” Meudt confirms.

	Typically, a pharmaceutical company will employ one of two potential strategies to transfer manufacturing activities from one region to another, explains Meudt. “For APIs used with already commercial products, companies will undertake a multi-year process to shift at least some portion of the manufacturing to an alternative local CMO,” he says. “Although, it is more common that companies simply revise their manufacturing strategy for pipeline drug products before they reach late-stage clinical trials and commercial approval. Either way, the company will typically have a shortlist of prospective CMO candidates within a local region that have the necessary competencies, capacity, and regulatory track record.”

	Transference of API manufacturing from a CMO in one site to another in a different region can aid in the improvement of supply continuity, but Meudt stresses that this sort of change should only be done with a CMO that can demonstrate a track record in areas, such as capacity expansion, process and equipment harmonization, and quality management, so that any potential risks are minimized. “It can further help to reduce supply chain risk if the CMO is either backward integrated in the production of some of the associated raw materials required to manufacture the API or has experience in the qualification of other prospective suppliers,” he adds.

	It can take several years for a company to transfer manufacturing from one region to another, typically between three to five years, notes Meudt. During the transition period, companies must perform the review and selection process for a new CMO partner, complete audits and technical transfer, as well as implement the processes to support scale-up to the required clinical or commercial volumes. “Around two years are also required to complete the regulatory approval process,” Meudt says. “While the COVID-19 situation may incentivize companies and governments to try and accelerate such transfers, it is of critical importance that key process steps are maintained to the highest quality and regulatory standards. Qualified teams with technical experience in the technical transfer process for such APIs and drug products are important.”

	As the current global pandemic has made clear the critical issue of API and drug product manufacturing, there have been concerns raised by industry officials globally about the potential risks of losing access to essential medicines. “Comments from officials within several governments worldwide indicate that countries could in future choose to prioritize the supply of locally manufactured APIs and drug products for use within their own healthcare systems,” states Meudt. “Fortunately, the global pharmaceutical supply chain appears to have held up well to-date due to normal stockpiling strategies and the continued operation of core manufacturing and logistical activities.”

	Given the fact that the pharmaceutical supply chain is a global and highly complex system, Meudt iterates that the current status quo of ingredients manufacturing will largely stay the same. “Pharmaceutical manufacturing capacities will continue to expand across North America, Europe, China, India, and other markets to meet the growing healthcare demands of local populations,” he notes. “In parallel, CMOs within each country or region will continue to specialize in their respective areas of core competence.”

	Agreeing, Barish adds that there will inevitably be a place for both onshore and offshore manufacturing simply due to the global nature of the pharma industry. “There will always be some products, controlled substances for example, that cannot be produced in certain facilities in a specific market,” he says. “Other reasons, such as drug strategy and cost will have an impact as to where manufacturing takes place. A novel drug with a smaller batch size, for example, may not be suited to offshore manufacture as the economies of scale will not be beneficial.”

	Asia is expected to continue to be a primary source for the world’s generic APIs and drug products; however, Meudt specifies that there are also expectations that some companies, with a strong manufacturing presence in Asia, may seek to further reduce short-to-medium term supply chain risk by having a larger percentage of their total global production requirements either made, or stockpiled, in Europe or the United States. “For new complex APIs or highly specialized drug products, it is expected that most production will continue to occur at established sites that have the right capabilities, quality culture, and record for project execution,” he adds. “This shift not only reflects the need to reduce regulatory risk and improve proximity to key healthcare markets, but the advanced technologies and precise processes that CMOs need to possess to successfully commercialize such APIs and finished drug products at desired levels of quality.”

	Simultaneously, Meudt predicts that regional and national governments will further encourage companies to increase the manufacture of essential APIs and drug products at local sites to ensure preparedness in any future pandemics. “It is likely that many governments will review what financial incentives can be put forward to accelerate investment by pharmaceutical companies and CMOs to further strengthen regional capacities,” he says.

	“As we move into a post-COVID-19 world, managing supply chain risk must become integral to business planning, risk management, and long-term drug strategy,” summarizes Barish. “It is therefore important to engage with partners that offer logistical advantages, whether they be domestic or offshore, and can contribute to the security and reliability of the drug supply.”

	1. Grand View Research, “Active Pharmaceutical Ingredient Market Size, Share, and Trends Analysis Report by Type of Synthesis (Biotech, Synthetic), by Type of Manufacturer (Captive, Merchant), by Type, by Application, by Region, and Segment Forecasts, 2020–2027,” 

, Market Analysis Report (February 2020).
	2. EFCG, “API Manufacturers Address Critical Medicines Shortages Leaving Europeans and Americans Vulnerable and Dependent on Asian Supplies,” 

, Press Release, 12 March 2020.
	3. EFCG, “Addressing the Acute and Complex Challenge of Medicine Shortages,” 


	Vol. 32, No. 6
	June 2020
	Pages: 38–40

	When referring to this article, please cite it as F. Thomas, “Securing the Supply Chain,” 

The global COVID-19 pandemic has highlighted the need for the pharmaceutical industry to strengthen its supply chain.

Securing the Supply Chain

	The pharma industry’s reputation with the global public has been patchy at best, with various scandals being highlighted in the press over the years giving rise to scepticism over the integrity of companies, particularly ‘Big Pharma’, working to develop therapies. However, in light of the recent efforts to combat COVID-19, some polls are showing an upswing in the public’s perception of the industry.

	The issue of reputation in the bio/pharma industry has been considered for many years now. Gallup, a global analytics and advice firm, for example, has evaluated the opinion of the pharma industry since 2001, finding that the view of the industry by Americans has been overwhelmingly negative in nearly two decades (1).According to research from GlobeScan, stakeholders have a tendency to believe that the pharma industry’s reputation is poor, with a particularly negative environment seen in Canada and the United Kingdom caused by campaigns from non-governmental organizations or films (2).

	In one of the latest polls from Gallup, published in 2019, the pharma industry had dropped to the bottom of the list in terms of public opinion in the United States (1). And, the problem of pharma’s reputation is not isolated to North America. In Europe, and particularly focusing on the UK, PatientView highlighted that factors, such as Brexit, were causing lower public opinion of the industry’s reputation in 2018 (3).

	According to Talking Medicine’s Pharma Reputation Thermometer, there has been a ‘softening of negative public opinion’ in the UK towards the industry during the COVID-19 pandemic (4). Results of the health-tech data company’s research, which will be repeated on a monthly basis to track changes in attitude to the industry, has shown small improvements across each reputation measure-trust, transparency, product usefulness, patient-centricity, and overall industry recommendation-from before COVID-19 to May 2020 (4).

	“For many reasons, the pharmaceutical industry has always suffered from negative perceptions among the general public. However, these latest findings show that there have been improvements on a number of key reputation measures,” said Jo Halliday, CEO and founder, Talking Medicines, in the press release (4). “Maybe we should not be too surprised, given the situation we find ourselves in, pinning our hopes on the industry finding a vaccine and antigen tests and drugs to be able to create a ‘new normal’ for society. However, based on these results, it seems as if pharma has an opportunity to develop a closer and more open relationship with people and communities.”

	As pharma companies continue to forge ahead, collaborating with others that may be considered as competitors in a ‘normal’ situation, there is a chance that the overall reputation of the industry can be further improved. However, the task of developing and delivering an effective vaccine for COVID-19 is by no means a small feat and will require great effort from the industry as a whole. 

	“Not only does the science have to be on our side if we are to quickly find a coronavirus vaccine, but we also have to find ways of being able to produce hundreds of millions, possible billions of doses of the new vaccine,” said Thomas Cueni, director general of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), in a press release (5). “The only way to deliver on our promise of safe, equitable, affordable coronavirus vaccines is for science and collaboration on a global scale to prevail. Be in no doubt, our member companies are fully engaged in the race to find a vaccine. We are fully committed to playing our full role within existing partnerships on the basis that we wholeheartedly embrace the goal of providing new coronavirus vaccines for all.”

	1. Gallup, “Big Pharma Sinks to the Bottom of US Industry Rankings,” Press Release, 3 Sep. 2019.
	2. GlobeScan, “The Pharmaceutical Industry; Issues & Reputation,” Intelligence eBrief, 4 July 2013.
	3. PatientView, “Pharma Reputation in 2018-Among UK Patient Groups-Falls Due to Brexit and Other Factors,” Press Release, 16 July 2019.
	4. Talking Medicine, “Pharma’s Reputation Shows Uplift During Pandemic,” Press Release, 27 May 2020.
	5. IFPMA, “Pharma Partners in Efforts to Give Coronavirus Vaccine for Everyone,” 

	When referring to this article, please cite it as F. Thomas, “A Little More Respect,” 

Pharma’s reputation is being boosted in light of the current COVID-19 pandemic efforts.

A Little More Respect

With an aging population, the resultant increase in prevalence of chronic diseases, and more demand from patients for dosing convenience, the biopharma industry has seen an exponential increase in adoption of biological therapies delivered in prefilled syringes. The overall prefilled syringes market is forecasted to be worth nearly $10 billion by the year 2025, according to market research (1), driven in part by the rise in use of biological drugs. This article discusses the challenges, safety considerations, and emerging trends in the field of pre-filled syringes for biologics.

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing


	eBook: Biologics and Sterile Drug Manufacturing, May 2020
	May 2020
	Pages: 20–23

	When referring to this article, please cite it as F. Thomas, "On Point: Biologics Drive Growth in Pre-Filled Syringes," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

As a result of the rising use and development of biological drugs, the biopharma industry is witnessing an increase in the adoption of prefilled syringes.


On Point: Biologics Drive Growth in Pre-Filled Syringes

In 2018, regulatory authorities were alerted of nitrosamine impurities in valsartan that had originated from an API manufacturer based in China (1). “Within Europe, the issue is generally considered to be centred around a report of a non-good manufacturing practice (GMP) compliance (2), which was submitted by the competent authority of Italy in September 2018,” explains Diego Martinez, senior manager CMC at PharmaLex. 

	This report pertained to an inspection of Zhejiang Huahai Pharmaceutical (a Chinese manufacturer of a valsartan API), which led to dozens of recalls of various sartans medicines, Martinez continues. Furthermore, the US Food and Drug Administration (FDA), after completing its own inspection, issued an import alert on Zhejiang Huahai Pharmaceutical (3) and then, a few months later, a warning letter (4), iterating the deviations from current GMP for APIs. Other ingredients manufacturers have also been issued warning letters by FDA, including Aurobindo Pharma, Hetero Labs, Lantech Pharmaceuticals, Torrent Pharmaceuticals, and Mylan (5).

	“The change that resulted in the formation of the potential carcinogen, N-nitrosodimethylamine (NDMA), was introduced into the manufacturing process of the valsartan API in approximately 2012 or earlier, but was not uncovered by regulators until more than five years later,” says Martinez. “Since its discovery, recalls have been conducted by a variety of firms that purchased the contaminated API from either the same or a limited number of API manufacturers.”

	In September 2019, the same potential carcinogen (NDMA) was identified by FDA in Zantac and other generic versions of the drug (ranitidine) (6). “The contaminants have also been found in low levels in batches of pioglitazone produced by Hetero Labs (7), indicating the potential for the carcinogens to affect products other than sartans and ranitidine medicines,” adds Martinez.

	The European Medicines Agency (EMA) has been actively investigating the origin and prevalence of nitrosamine contaminants in human medicine, reveals Martinez. “Both EMA and FDA have established limits for nitrosamines in the affected medicines,” he says.

	In a recent publication from EMA on the topic, requirements on manufacturing authorization holders (MAHs) have been imposed (1). These requirements include an evaluation of all finished pharmaceutical products (FPPs) that contain chemically-synthesized APIs by MAHs to assess any potential presence of nitrosamines. “EMA has requested that MAHs complete the review before 1 October 2020,” asserts Martinez.

	“Revisions are being made to the European Pharmacopoeia to the drug substances monographs for the sartan series to include testing for nitrosamines,” Martinez continues. “In addition, the general monograph for APIs (General monograph 2034) is under revision and will also include appropriate tests.” 

	Similarly, FDA is actively working to identify and recall medicines that have nitrosamine levels above interim acceptable limits and regularly updates its published list of angiotensin II receptor blocker (ARB) products with respect to nitrosamine content (5). “However, both EMA and FDA have emphasized that the risks associated with an abrupt discontinuation of ARB products, such as stroke, far outweigh the low risk associated with continuing to take medications with nitrosamine impurities,” Martinez adds.

	“As a result of investigations into the presence of nitrosamines, it is apparent that a complete consideration of potential nitrosamine contamination in an FPP must be broader than whether sources of amines and nitrites are concurrently used in the preparation of the API,” says Martinez. “Manufacturers of all FPPs should be assessing their products for any circumstances that might inadvertently lead to nitrosamine content and taking steps to mitigate these risks.”

	Manufacturers must also make all relevant information, required for an appropriate risk assessment, available to MAHs, Martinez explains. “For those products that have active substance master files (ASMFs) and certification of suitability to the monographs of the European Pharmacopoeia (CEPs), MAHs remain responsible for ensuring that robust risk evaluations have been appropriately performed prior to taking responsibility for the quality of the API and medicinal product,” he adds.

	These robust evaluations, either performed by the MAH or API manufacturer (including ASMF or CEP holders), must be performed in accordance with Article 46 of Directive 2001/83/EC, Martinez stresses. “MAHs should apply for a variation in a timely manner to introduce any required changes,” he notes. “The variation should contain information on amendments to the marketing authorization-i.e., module 3 (3.2.S and 3.2.P), the active substance master files (ASMF), or certificates of suitability (CEP)-that are necessary to amend the method of manufacture or control of the active substance and/or finished product.”

	Health authorities have issued general recommendations that MAHs of all FPPs evaluate whether or not nitrosamines are present in products that contain chemically synthesized APIs. “Although nitrosamines are not expected to form during the manufacture of the vast majority of medicines, the possibility of cross contamination or unintentional introduction of amines and nitrites has prompted the request for companies to undertake this precautionary review,” Martinez confirms. “MAHs together with API and finished product manufacturers are required to perform risk evaluations using quality risk management principles, as outlined in [the] ICH [International Council for Harmonization] Q9 guideline. The principles described in [the] ICH M7 guideline in relation to toxicology assessment, control strategy, and changes to the manufacturing processes for active substances should be applied.”

	In any products that are likely to include nitrosamines, it is recommended that MAHs perform confirmatory testing on the API, the FPP, or both, Martinez iterates. However, as the low levels at which nitrosamine impurities occur can prove problematic in testing, several test methods have been published for assistance in this area.

	“FDA has recommended the use of a liquid chromatography–high-resolution mass spectrometry (LC–HRMS) method when testing ARB drug products as a result of the lower temperature conditions of the method (8)-higher temperature conditions of some test methods may cause the sample to generate NDMA,” says Martinez. “Similarly, the Official Medicines Control Laboratories (OMCLs) Network of the Council of Europe has also published several methods (9), which may be used when testing for nitrosamines in various drug substances.”

	“In my opinion, the nitrosamine impurities issue could be useful as a ‘lesson learned’ that following procedures is important,” Martinez says. “It is beneficial to view the issue as a way of enhancing the value of risk assessment tools, particularly from a regulatory standpoint. These tools have been frequently used in quality processes as they employ scientific data to direct the best course of action and now they should be implemented in regulatory procedures more regularly too.”

	European authorities are conducting an exercise to establish what lessons can be learned from the identification of nitrosamines in sartans. At the time of writing, this ‘lesson learnt’ group is in the process of finalizing its recommendations on how the presence of impurities can be prevented and better managed in the future (10).

	“Several conclusions can be drawn from the experiences with sartans,” summarizes Martinez. “We need continuous and continuing safety surveillance of drugs-even very old drugs and those presumed to be quite safe. The safety profile of a drug is never fully known. We cannot become complacent. A high level of suspicion must be maintained particularly with odd and unexpected safety signals and serious adverse events. Late appearing safety issues can be totally unexpected.” 

Information on Nitrosamines for Marketing Authorization Holders

EU Inspection Finds Zhejiang Huahai Site Non-Compliant for Manufacture of Valsartan: EMA and National Authorities Considering Impact on Other Active Substances Produced at the Site

, Press Release, 28 Sep. 2018.
	3. FDA, “

Warning Letter: Zhejiang Huahai Pharmaceutical

FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)

 [Accessed 21 April 2020]. 
	6. FDA, “

Statement Alerting Patients and Health Care Professionals of NDMA Found in Samples of Ranitidine

, Press Release, 13 Sep. 2019.
	7. EMA, “

Update on Nitrosamine Impurities: EMA Continues to Work to Prevent Impurities in Medicines

, Press Release, 26 April 2019.
	8. FDA, “

Liquid Chromatography–High-Resolution Mass Spectrometry (LC–HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs

,” fda.gov, 21 May 2019.
	9. Council of Europe, “Ad-Hoc Projects of the OMCL Network,” 

 [Accessed 21 April 2020].
	10. EMA, “


	Vol. 32, No. 5
	May 2020
	Pages: 30–31

	When referring to this article, please cite it as F. Thomas, “Complying Confidently? Learning Lessons from Nitrosamine Impurities,” 

Industry must never become complacent about the safety of drug products and should seek to continually perform surveillance even if the drug is well-established.
