Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	The past year has seen an aggressive push to close the gap between demand for and capacity to produce cell and gene therapies. Kite and Novartis have both built new facilities in the United States and Europe. Contract development and manufacturing organizations (CDMOs), such as Fujifilm Diosynth Biotechnologies, Lonza, and WuXi Biologics, have been expanding manufacturing capacity to meet explosive growth in demand for clinical supplies of new therapies. At this point, however, a gap still exists between demand and current good manufacturing practices (CGMP)-scale production capacity. Scientists may wait up to 18 months, experts say, for the products they need for clinical research (i.e., customized cells and viral vectors that meet cGMP requirements). 

	Partners in a new collaborative center plan to address this gap head on. On Nov. 25, 2019, Harvard University, the Massachusetts Institute of Technology, CDMOs and technology vendors such as Fujifilm Diosynth, GE Healthcare Life Sciences, and MilliporeSigma, and local teaching hospitals disclosed 

plans to establish a new center in the Boston area for developing and manufacturing cell and gene therapies.

 The $50-million Center for Advanced Biological Innovation and Manufacturing aims to accelerate innovation in immunotherapy, cell therapies, gene editing, and other technologies, with the goal of broadening access to new therapies. The Center will foster collaborative innovation in both manufacturing processes and drug development and is expected to be incorporated in 2020 as an independent non-profit corporation.

	“This new center aims to accelerate developments in immunotherapy, cell and gene therapies, and other technologies that will have an impact on  human health. Its overall mission is to catalyze the development of transformative and advanced therapeutics by shortening the time between clinical research and application. With more than 1000 clinical trials underway for cell and gene therapies, we need to develop better solutions and no one organization can do it alone,” Emmanuel Ligner, president and CEO of GE Healthcare Life Sciences commented to 

on November 26. “The full potential of the regenerative medicine industry can only be realized if we collaborate to improve access, quality, and accelerate innovation,” he said. 

	Modular, adaptable design aims to increase agility

	The new facility will offer partners access to a new CGMP manufacturing facility at favorable pricing, reducing the wait and cost for researchers at universities, hospitals, and start-ups. Plans call for the facility building to feature a modular design, to make it easier for partners to adapt quickly to changes in technology, as improved methods continue to be developed for gene manipulation, gene editing, oligonucleotides, peptides, and other new methods and discoveries.  

	Currently, the Center’s design is envisioned to include a shared collaborative space as well as eight cleanrooms for production of cell and viral vector products and raw materials for Phase I or Phase II clinical trials. It will also provide a platform for training and workforce development in a field that faces a critical need for people with diverse, specialized skills. GE Healthcare Life Sciences will be sharing technologies and expertise in biomanufacturing with members, said Ligner, who emphasized the importance of collaborating, and sharing and managing collective knowledge and best practices. “Given how rapidly the industry is growing, consortiums such as this one are vital to advancing the industry because they provide [stakeholders] opportunities to learn from one another and build off one another’s advances,” he said.               

	Ligner also pointed out the need for continuous improvement in workforce training, an area that GE has been emphasizing recently in initiatives including 

a collaboration with Ireland’s National Institute of Bioprocessing Research and Training

. “It’s an exciting time in the cell and gene therapy industry, with more than 1000 regenerative medicine clinical trials taking place globally,” he said. “In addition to bringing together leading life-sciences organizations to advance clinical research, one of the most exciting and valuable aspects of this partnership will be the workforce training and development. While we work to get novel therapeutics to patients faster, we must also train and develop the right talent to continue building and advancing the industry,” he said.

	CDMOs have been expanding CGMP capacity for cell and gene therapies. Fujifilm recently invested nearly $119 million (13 billion yen) in gene therapy alone,

 including an expansion of its Center of Excellence in College Station, Texas

. The company will be adding new laboratories for upstream, downstream, and analytical development, which are expected to start up in the fall of 2021. The company is also expanding CGMP manufacturing capacity with the addition of new cleanrooms and eight new 500/2000L single use bioreactors. Fujifilm began to offer clinical and commercial gene therapy fill/finish services early in 2019, and expects to complete the first stage of its CGMP expansion in College Station by the Spring of 2021. 

 with a Center of Excellence in Houston including a fill/finish suite and capacity for developing viral vectors for cell and gene therapies, while WuXi AppTec 

expanded Phase I GMP manufacturing capacity for cell and gene therapy at its San Diego facility.

	Building a new logistics and IT infrastructure

	As efforts to speed manufacturing and clinical development expand, the industry is also working to develop a new infrastructure to support these efforts. Given the diverse stakeholders involved in cell and gene therapies and personalized medicine, the approaches to information technology, data management, and logistics that have worked for so long in the small-molecule and traditional biopharmaceuticals areas will no longer work for autologous and allogeneic cell and gene therapies.  

	In 2019, alliances have started up to streamline data management and access, to improve the transmission of data from patient collection points to manufacturing, and to patients at the point of use.  IT companies, including the manufacturing execution systems (MES) provider Werum, are working on new data platforms, while TrakCel and Vineti are collaborating with CDMOs, logistics companies, and clinical partners in “vein-to-vein” programs designed to develop standardized approaches to data management and to improve risk management and supply chain transparency.

launched a vein-to-vein program with Vineti and Lonza on November 5

introduced a dedicated fleet of specialty shippers for cell and gene therapies on Dec. 2, 2019, including a validated cleaning program designed to eliminate cross-contamination by reducing contaminants by 99.9999%. According to the company’s Chief Commercial Officer, Mark Sawicki, one of the most challenging aspects of working within this new space has been dealing with the complexity and variability of its supply chain. This is particularly true for autologous therapies, where the origin of the supply is not some distributor but patients themselves. “As a result, [developers are often] extending instrumentation and processes that have been used for single patient production to large-scale manufacturing in a commercial manufacturing environment. The interconnectivity and optimization of workflow isn’t there yet,” Sawicki said, in a recent interview with 

	Working to address the need for interconnectivity on the data management level is Vineti, an IT company dedicated to the cell and gene therapy market, which grew out of GE’s Venture Capital business. The idea for the company came after noticing the challenges that a regenerative medicine pioneer faced back in 2012, as it pushed manual methods to their limits to handle a much more complex workflow and deliver a new innovative therapy during the clinical trial phase. “There was a real need to extend GMP into clinical work and to scale out supply chain solutions,” cofounder and CEO Amy Du Ross told 

	Vineti started up formally in 2015 to focus on the need to integrate the development, manufacturing, and logistics systems that innovative therapies required, and to ensure the chain of custody of the product. “It’s not about workarounds, but building for purpose,” Du Ross said.  The company is currently working with leading CDMOs and innovator companies in the cell and gene therapy space and with Cryoport and other logistics providers. 

https://www.harvard.edu/media-relations/new-center-for-innovating-and-manufacturing-next-generation-medicines-planned-for

	http://www.pharmtech.com/ge-healthcare-partner-nibrt-biopharma-education-program

https://www.fujifilm.com/news/n191114.html

https://www.lonza.com/about-lonza/media-center/news/Tensid/2019-11-05-14-47-English.aspx

	https://www.lonza.com/about-lonza/media-center/news/Tensid/2018-02-14-06-00-English.aspx

				https://www.cphi-online.com/wuxi-apptec-expands-site-in-california-for-news075747.html

Articles

Aiming to break the bottlenecks that are slowing commercialization of innovative therapies, a new $50-million center in Boston will develop both cell and viral vector products within a single facility.


New Center Marks Aggressive Push into CGMP Manufacturing of Cell and Gene Therapies

As the pharmaceutical supply chain becomes more complex, potential vulnerabilities are increasing. Adding to the challenge are random and unpredictable supply disruptions caused by acts of violence, fires, floods, or natural disasters. Survival depends on understanding and collaborating with suppliers, customers, and insurance companies to manage risk, and ensuring that effective emergency response plans are in place. 

	Without the right approach, the economic losses from inability to operate, product contamination, or loss of income can be devastating, says Frank Russo, founder and principal of Procor Solutions LLC, a risk management and claims consultancy. Manufacturers that have been slow to develop strategies may soon get a push from regulators. FDA has proposed requiring drug companies to conduct periodic risk assessments to identify and mitigate supply chain vulnerabilities (1).

	This legislative proposal is in President Trump’s fiscal year 2020 budget, which notes that many companies do not have such plans in place and are thus at risk for lengthy drug supply disruptions, especially after hurricanes or other natural disasters. Based on results of the assessment, some companies would be required to have risk-mitigation plans, such as having redundant manufacturing capacity in place. FDA would use a risk-based approach to determine which companies would have to do this. The agency plans to apply these requirements to drugs that are considered “life-supporting, life-sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery” (2). They would apply to drugs that have been on the FDA drug shortage list within the past five years, or that meet one or more criteria that FDA has determined will increase the risk of shortage. 

	Some smaller companies may not have business continuity or crisis response plans in place. Overall, however, pharmaceutical companies are quite sophisticated about risk management when compared to companies in other industries, says Russo. 

	Russo sees natural disasters, which have stepped up in frequency and severity over the past 15 years, as the industry’s top business continuity threat today. Other problems are more frequent upstream outages that occur when key suppliers cannot ship APIs or other materials that are required to make the drug. Often, these glitches occur because of quality and compliance problems (e.g., when regulators place a supplier’s facility on import ban) or result from accidents or other problems at supplier plants. “Given pharma’s complex and increasingly efficient just-in-time supply chains, these scenarios can be a recipe for disaster,” says Russo. “A minor calamity at a supplier’s location can have a significant impact, interrupting production and revenues for extended periods upstream, ultimately reaching the retail pharmacy level,” he says. Although the severity of each loss depends on the companies and products involved, each blip can cost in the tens of millions of dollars if it goes on for too long without mitigation options, he says.

	Cyberattacks and computer hacks are also a factor. Ransomware can make discussions with insurance companies difficult, says Russo, because these programs are often installed well before they are detected, so it can be hard to pinpoint when the company’s financial loss actually began, he says.

	New pharmaceutical products also challenge manufacturers to quantify losses once a supply disruption occurs. “Without a history of revenues from that drug, companies may struggle to demonstrate lost income to insurers,” he says. Therefore, they must document everything, have clear projections of product revenue from the start, and share that information with insurers, Russo suggests. “Companies need to accurately and adequately convey what the loss was, one component at a time,” he says. 

	In order to ensure cash flow, Russo recommends that companies maintain steady communication with their insurers. Instead of waiting to have the claim paid in full, it is better to request payment in installments, he says. 

	A growing number of websites, applications, and other platforms are available to help companies better respond to crises and to sharpen their resiliency and business continuity efforts. One example that Russo cites is In Case of Crisis, a mobile application that helps team members communicate, share standard operating procedures (SOPs) and checklists, and file incident reports. 

	Investing in risk mitigating technology will help speed recovery. Not only can it prevent damage to company assets, it can also reduce insurance costs, says Russo, as a growing number of insurers take a more holistic approach that considers the total cost of risk. Some insurers now offer discounts and other benefits to companies that invest in preventive technologies, for example Internet of Things water sensors that collect real-time data on plant equipment. “This kind of approach is becoming more common,” says Russo. 

	In 2017, Hurricane Maria provided the ultimate test of pharmaceutical company emergency response and business continuity programs, as companies with production facilities in Puerto Rico, including Amgen, Johnson & Johnson (J&J), AbbVie, and Eli Lilly faced flooding and loss of power and communication systems. Most of the island was without power for months, with some areas enduring blackout conditions for almost one year; in some cases, companies were not able to locate employees for several weeks. Pharmaceutical manufacturers in Puerto Rico were equipped with diesel power generators but many struggled with communication and network connectivity. 

	Speeding data and IT system recovery after a major disaster demands careful planning and documentation well in advance, says IT consultant Orlando Lopez. Not only should all possible failures and risk scenarios be determined and written down, but their impacts should be carefully assessed and staff mobilized, he says. In addition, he says, alternative systems should be made available, and teams should be dedicated to handling corrective actions, troubleshooting, error diagnostics, and preventive actions.

	“Procedures to be followed in case of failures and outages should be carefully described and documented, as should the system rebooting process after bugs have been fixed,” says Lopez. The same goes for maintaining data that were first entered using alternative means (e.g., cell phones or paper) and later entered into computerized systems. Lopez notes that the National Institute of Standards and Technology’s (NIST’s) Contingency Planning Guide for Federal Information Systems can be very helpful in these efforts. One lesson that emerged from the hurricane was the importance of testing the procedural controls used to restore computer systems after the storm struck, says Lopez, who notes the need to avoid a single point of failure by having diverse sites for recovering basic IT and communication functionalities.

	In the end, companies continued to operate after a devastating storm. What may have enabled productivity was the fact that companies supported their staffers, some of whose homes had been damaged or destroyed or who had lost loved ones. This driving force, which risk-management and business continuity consultant Steve Goldman calls “the duty of care,” may ultimately be the key to business continuity. “At Amgen, one of our priorities is to prepare all our staff so they can manage a crisis event, not only from a business-continuity perspective but from a personal one,” says Arleen Paulino, the company’s senior vice president of manufacturing. “Following Hurricane Maria, we mobilized resources to support our staff with pay continuity, access to food, water, showers,  laundry service, as well as gas and generators. Their safety and well-being were our priority,” she says. 

	After Hurricane Maria, Amgen was able to maintain supply of products to patients without any misses or shortages. Paulino attributes this fact to a robust business resilience strategy that leverages investments that the company has made, not only in staff training and support, but in infrastructure, technology, inventory, diversification, and business continuity. Well before the storm hit, Amgen had already upgraded its sites on Puerto Rico so that they could withstand the force of a Category 5 hurricane. In addition, she says, staff had been trained and [crisis response] tools had been continuously tested to ensure that plans would work as expected. 

	Inventory strategy was also crucial, Paulino says, and safety stocks helped ensure sufficient product supply, while back-up manufacturing locations relieved pressure, aiding recovery. A mindset of continuous improvement is essential for any business continuity strategy to work, says Paulino. “At Amgen, business continuity plans are tested constantly, across the company,” she says, noting that internal critique sessions are crucial. “They help us better understand potential disaster scenarios in the future, to learn how we can be more effective,” Paulino notes.

	When operations are running normally, it can be easy for companies to become complacent about keeping records updated, even documents as basic as organizational charts. At one customer facility, Goldman found that organizational contact lists included the names of people who had left the company or died. 

	Another missing link for some manufacturers is any deep knowledge of their suppliers, and little regular communication with them. The automotive industry is a model for doing this right, says Russo, and proactive companies such as J&J and Amgen have adopted supply chain mapping, a tool first used in other industries, for pharmaceutical manufacturing operations. 

	Amgen began to explore the approach in 2011 after the tsunami in Japan, and began mapping its supply chain in 2013, running a small pilot with close suppliers. Efforts have paid off so far, and by 2018, the company reported having visibility into all tier 1 suppliers and a large percentage of tier 2 suppliers. It can even get down to tier 3 suppliers in some cases (3). 

	At the highest level, management and customer expectations will drive emergency response plan development, and each must be thoroughly documented, said Aaron Duff, global director of EHS process excellence and standardization at J&J, in a webcast hosted by Pharmaceutical Supply Chain Initiative (PSCI) in June 2019 (4). There must be alignment and agreement between the two if efforts are to succeed, he said. 

	On the ground, however, all utilities must be evaluated, including wastewater and fire wastewater operations, as well as electric power outage preparedness. One important detail with floods is determining in which direction the storm water will run, he said.

	Both engineering controls (e.g., fire or water-level emergency alarms) and administrative controls (e.g., staffing, and who has specific training) must be examined, Duff said in the webcast. Another crucial step is to communicate and develop a relationship with local emergency response organizations. “They should be involved in drills and training exercises. You don’t want to be meeting them for the first time when an emergency occurs,” he said. 

	Identifying high risk operations is then key, and examining any gaps between existing control measures and what will be needed to keep the facility safe. The next step is developing a risk matrix to define the severity and likelihood of the emergency occurring and designating a cross-functional crisis-management team of at least three people. The team will need an incident commander, and training and drills should be scheduled at least once or twice a year, involving site management and staff as well as emergency responders and even government responders. Drills should be challenging, and engage employees to imagine emergency conditions if they are to be effective, says Goldman.

	A formal written policy must also be established for communicating with the public, says Goldman, in particular, a social media strategy geared to mobile phone users. He suggests that companies dedicate a website, and have several Facebook pages, a Twitter, and a LinkedIn account ready to go and that a dedicated team monitor and respond to comments on social media as the event unfolds, to avoid the propogation of “fake news” and rumors.

	Business continuity is becoming more prominent as a field, with a number of companies staffing at the vice-president level, says Goldman. It may build upon emergency response, but can be weakened by a disconnect between enterprise-level risk management and site-level efforts. At some companies, silos may separate business continuity from enterprise risk management (ERM) teams, even though both involve the same stakeholders and both focus on risk.  

	Experts note the need for a common language and for synchronizing efforts (5). Ideally, they say, data from business continuity exercises should be used to improve ERM activities, while key risks that have been identified by ERM teams should be used to frame business continuity exercises. Operations and business continuity teams should also work more closely together, says Goldman, but senior management support is essential. “Risk is not a crisis response, it’s a probability of something happening, and once a disaster hits, it’s 100%. In the end, it’s not what got you into the crisis but how you deal with it that counts,” he says.

	1. FDA, Fiscal Year 2020, Justification of Estimates for Appropriations Committees, 

, www.fda.gov., www.fda.gov/media/121408/download
	2. FDA, “Drug Shortages: Root Causes and Potential Solutions,” 

, p. 76, www.fda.gov/media/132059/download
	3. “How Amgen Manages Supply Chain Risk,” Video, 

, March 15, 2019.
	4.   A. Duff, Emergency Preparedness and Response, Webcast, Pharmaceutical Supply Chain Initiative, June 27, 2019.
	5. “ Are Your Business Continuity and ERM Teams Collaborating?” Podcast, 


	Vol. 43, No. 12
	December 2019
	Pages: 16-19

	When referring to this article, please cite it as A. Shanley, "Mitigating Risk to Secure the Drug Supply Chain," 

Communications and planning are crucial to recovering from supply, operations, and facility disruptions. 

Mitigating Risk to Secure the Drug Supply Chain

	loped in the 1920s, design of experiments (DoE) has become an indispensable tool for drug developers who seek to gain deeper insights into their products and processes. Instead of taking a univariate approach, changing one factor at a time and studying the impact on results, DoE uses statistical methods to perform multivariate analysis. This approach allows users to assess the impact of various factors on each other and on an outcome or product, allowing them all to be studied all at once.  

	Applied by Toyota engineers to understand the impact of variability on product quality, the method was first used for chemical development in the 1950s. Over the past few decades, its use in pharmaceutical development has grown dramatically, spurred by guidelines such as International Council for Harmonization (ICH) Q8 (R2), and FDA-driven initiatives such as process analytical technology (PAT) and pharmaceutical quality by design (QbD).

	Although the mathematical underpinnings of DoE have been around for a hundred years, advances in computing and graphics, and software improvements made by vendors such as Umetrics, JMP, Stat-Ease, SaaS, and Camo have increased the power and user-friendliness of DoE software, according to spectroscopist and PAT expert Emil Ciurczak, head of DoraMaxx Consulting. Combined with the miniaturization of analytical instrumentation and the increasing sophistication of PAT, users can now run complex studies within labs or on the plant floor, and get results that would once have taken weeks, within days.

	Design of experiments (DoE) can be used in applications ranging from pre-formulation and formulation to finished drug manufacturing, says Ciurczak. To give an example of how DoE can enrich understanding in preformulation, consider tests that might be designed to study the interaction between an API and a single excipient, and how they affect stability. 

	Using a univariate method, without DoE, one could take a mixture of active ingredient and excipient and put it through different stability studies (i.e., exposing it to heat, cold, light, and other variables)and hold it for 4–20 weeks and look for the breakdown point.This would provide information on interactions between the API and excipient, Ciurczak explains, but only one combination could be tested at a time. The time required for testing would be significant, after which high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC) testing would still be required, and, overall tests would take several months to complete. 

	Using DoE, one could choose to consider the API, plus seven of the excipients that are most often used with that active, and test for eight different parameters, says Ciurczak. This would mean 8 times 7 mixtures, which would be put in vials in test tube racks. Near Infrared (NIR) or Raman spectroscopy could then be used to test these samples every day and to plot any changes. After that point, the vials would be tested with chromatography. Not only would this approach be much faster, it would be much more exact, and show clearly when each different combination of API and excipient reacted.  

	In drug synthesis, where chemists look for the highest yield, the best chemical for increasing yield may also be the least stable, DoE could be used to select the most stable alternative with the highest yield. In formulation, DoE would help determine the best formulation based on stability and release pattern, Ciurczak explains.

	In pharmaceutical quality by design (QbD), DoE methods are used to define the design space for a product, correlating critical quality attributes and process parameters, allowing product quality to be optimized by staying within specific boundaries. For these tests, one would need to know the process parameters and to test a wide range of combinations of API with various excipients, disintegrants, lubricants, and other additives, and to use a full-sized batch for testing.  

	As Ciurczak explains, the Plackett Burman approach (1) would often be used for the first phase of testing, to develop a matrix. Optimum levels would be set for each parameter, with a deviation of plus or minus 10%. The Partial Least Squares regression method would then be used to show whether deviation is positive or negative.

	A second stage of testing would then determine upper and lower limits to the design space, allowing formulators to tweak formulations and to ensure that variations in ingredients or raw materials (e.g., between different lots of the same excipient or excipients from different suppliers) did not have an impact on product quality. Not only could this approach allow testing to be accomplished in a few days, says Ciurczak, but results could be applied to optimization in other areas. For example, using DoE and stability data, product shelf life could be maximized to extend expiry dates and reduce costs, Ciurczak says. 

	In the small-molecule world, a major advance was made in the 1990s when near-Infrared (NIR) spectrometers were made small and versatile enough to be used in the lab or on the production floor. Pfizer and Carl Zeiss pioneered the first such PAT devices in the 1990s using a benchtop NIR device, a V-blender, and a rotator, and employing DoE to study solid dosage blends. Similar setups were later used by other companies for small-molecule solid dosage form testing.  

	Not only did this approach allow the first new drug applications incorporating PAT methods to be submitted to FDA, it represented a breakthrough by allowing development and quality testing to be done continuously for batch products using a multivariate approach to analyze data. Now that more companies are evaluating or using continuous processes to make solid dosage forms, applying DoE with PAT and QbD in continuous testing can eliminate the need for large and expensive pilot plants, offering considerable savings, says Ciurczak. 

	An analogous trend has been happening in upstream biopharmaceutical process development, as equipment has been developed to facilitate the use of PAT and DoE much earlier in the process. Within the past five years, high-throughput miniature bioreactors, which were previously used in pre-clinical screening, have been replacing bench-scale bioreactors in scale-down exercises. Scale-down is an important step in scaling up processes for current good manufacturing practices (cGMP) manufacturing in late-stage clinical development.  

	The devices eliminate the problems found with microtiter plates, spin tubes, and shake flasks, which can be difficult to automate (2), and allow more than 24 bioreactors to be run in parallel. They are also fitted with analytics that can take continuous readings on such crucial variables as pH, dissolved oxygen, and pressure for each of many samples. 

	Although developers have not yet filed new drug applications (NDAs) with FDA mentioning this technology, more companies including Genentech, Merck, Biogen, Lonza, and FujiFilm are working on this approach to scale-down (3). Developers are using devices such as Sartorius Stedim’s ambr 15 and 250 bioreactors (4).  Starting in 2015, Sartorius Stedim Stedim Biotech has integrated Umetrics’ DOE software with its ambr 15 and 250 high throughput minibioreactors, later incorporated Nova Biomedical’s BioProfile FLEX2 automated cell culture analyzer, to simplify PAT and QbD work, and make scaleup and process optimization more efficient (5). The approach is also being evaluated for use in gene and cell therapy development. 

	If anything, these developments show the durability and importance of DoE as a way to make drug development (whether for small molecules or biopharmaceuticals) more systematic.  Equipment and software evolution promises to make these techniques, as well as QbD approaches, easier to apply in the future.

When and How to Use Plackett Burman Design,

, pp 58-68.
	3. F. Slingsby and S. Dewar, “

Use of the ambr 250 in Conjunction with High Throughput Design and Analysis Tools for Rapid, Scaleable USP development,

” Fujifilm White Paper, January 15, 2015
	4.V. Sandner et al, “

Scale-Down Model Development in Ambr Systems: An Industrial Perspective

,” 2018,
	5. Sartorius-Stedim Biotechnology, Product Brochure, 2019 

â¨
	Vol. 31, No. 12â¨
	December 2019
	Pages 26-27

	When referring to this article, please cite it as A. Shanley, "Design of Experiments Gains Ground in Biopharma Development," 

As equipment evolves and use of PAT increases, DOE is becoming an integral part of upstream bioprocess development.


DOE Gains Ground in Biopharmaceutical Development

Although therapeutic creams and ointments have been in use for centuries, development of topical pharmaceuticals is complex and costly. Many topical formulations involve multiple excipients and active ingredients. Their manufacturing is also expensive, requiring large-scale mixing and heating and precise volume filling and packaging, as Markham Luke, director of therapeutic performance of generic drugs at FDA, pointed out in 2017 (1).

	But individual patient differences increase the challenges involved. On the most basic level, each topical formulation will penetrate the skin differently in individuals of different ages, sexes, and races, and occur at different rates in different parts of the same person’s body, says Vijendra Nalamothu, CEO and chairman of Tergus Pharma, a contract research and development company that specializes in topicals. “Skin absorption for a psoriasis treatment used on the hands will be very different from that for an alopecia therapy targeting the hair follicles on the scalp,” he says. 

	Given the variability, cost, and complexity of developing topicals, generic pharmaceuticals have not made significant inroads into the specialized and highly segmented market. At a time when generics account for more than 90% of the drugs prescribed in the United States, 80% of name-brand topical drugs on the market have fewer than three generic equivalents, according to Sam Raney, lead for topical and transdermal drug products at FDA’s Office of Generic Drugs. Most name-brand topicals do not even have one generic equivalent, Raney noted during an FDA workshop held on July 30, 2019 at the University of Maryland’s School of Pharmacy (2). 

	Also inhibiting topical generics development is bioequivalence testing, which demonstrates that both name brand and generic release active ingredient where it is needed within the body at the same concentration at the same time and under the same conditions. Bioequivalence for topicals has traditionally been determined in the clinic, using comparative endpoint studies, which can involve “enormous risk and investment,” and require thousands of patients, Raney said. Manufacturers and regulators are establishing a framework for more efficient science-based approaches, not only to testing for bioequivalence but for ensuring product quality. For regulators, the goal is to enable more generic manufacturers to enter the market. 

	To consider questions of bioequivalence in a more scientific way, regulators developed the Topical Classification System (TCS), a framework analogous to the Biological Classification System (BCS) for solid dosage forms, which classifies them based on solubility, permeability, and dissolution. Just as the BCS allows developers a biowaiver in some cases so they can bypass clinical bioequivalence testing, so does the TCS, Raney explained in a webcast for the Product Quality Research Institute (3). 

	The Q1 category represents an “outer bound,” for demonstrating qualitative similarity, in which reference and test product both contain the same components. The Q2 category goes a step farther: in order to be similar, the generic and reference drug would not only have the same components but they’d follow the same exact recipe and composition. Q3 similarity would mean that, in addition to having the same recipe and containing the same ingredients, the two would show a similar microstructure or arrangement of matter (i.e., physical and structural properties), he explained. This structure would make it “thermodynamically impossible” for them to behave differently, Raney said. 

	Q1 and Q2 similarity might mitigate product failure due to irritation or sensitization, where similar Q3 would reduce the risk of product failure due to differences in pH, polymorphism, rheology, entrapped air, drying rate, and other factors, Raney said, noting that excipients can have a major impact on structural properties ( i.e., Q3). 

	Under TCS, Class I topicals (for which Q1, Q2, and Q3 are the same for both the generic and the reference drug) and Class III topicals (for which Q1 and Q2 are different but Q3 is the same) would be eligible for biowaivers. 

 release testing [IVRT], as standardized by the US Pharmacopeia’s (USP) <1724> using static Franz diffusion cells or in-line devices); physical tests for rheology and viscosity; and 

 permeation tests (IVPT), which examine pharmacokinetics of the product, are playing a much more important role in topical product development. As Raney emphasized, no single test can definitively show Q3 microstructural similarity. The tests provide insights into product performance and critical quality attributes such as release rate.

	Through the Generic Drug User Fee Amendments Act (GDUFA), FDA has sponsored research to study in-vitro testing methods, which resulted in product-specific guidance documents for performing bioequivalence testing for topical generics. The most far-reaching was its draft guidance for determining the bioequivalence for acyclovir cream, published in 2016 (4), which spelled out clearly how 

 permeation study data might be used to enable the issuance of a biowaiver. In this case, a developer could skip clinical bioequivalence testing if both test and reference drugs showed Q1, Q2, and Q3 similarity; they both showed an equivalent rate of API release based on IVRT testing; and they were shown to be bioequivalent based on acceptable IVPT results.

	FDA is clearly stepping up its efforts to facilitate development of topical generics. To date, the agency has published seven product-specific guidance documents specifying how to establish bioequivalence. By September 2019, topicals accounted for 12 of the 45 product-specific guidance documents for complex generics that were issued by FDA’s Office of Generics, and minor revisions were planned for another 53 topical product-specific guidance documents, representing more than 60% of the total (5). 

	In addition, the principles of pharmaceutical quality by design (QbD) are becoming better established within the industry. Vijendra Nalamothu shared his views on how topical development is evolving with 

: When did you first start using quality-by-design (QbD) principles for topical development?

: As part of the SUPAC (short for Scale-Up and Post Approval Changes: CMC, IVRT and In-Vivo Bioequivalence) initiative (6), we were already using 

 release testing methods, so we began to use them to develop a design space for QbD. Back in 2012, we used 

 permeation testing (IVPT) plus tests for rheology and viscosity as a way to measure critical quality attributes (CQAs). We then took a deeper dive into determining CQAs using microstructure (or, according to the Topical Classification System, the Q3 characterization), applying specific rheological profiles, such as stress and shear curves and other methods. The industry started to use more of these tools to take a QbD approach to topicals. Now, FDA is requiring that generic pharmaceutical companies use IVPT, rheology, and polymorphic data. 

: Do you expect FDA to issue more generalized guidance on 

: FDA has issued seven product-specific guidances so far for topical bioequivalence. There are still some technique and data-related questions to address before a generalized guidance can be published. The most detailed of the product-specific guidances so far was for acyclovir cream.  

:  Why isn’t development of a more generalized guidance industry guidance for semi-solid topicals possible now?

:  One major challenge is the fact that the phenomenon of skin absorption is yet to be thoroughly understood. Systemic absorption is well understood, and we have mathematical models that can be used to predict absorption, but actual skin absorption varies greatly. There is no universal absorption. Other issues concern the IVPT procedure itself. Performing it correctly requires skilled technicians, and results can vary, due to differences in operator training, in instrumentation, and other factors. In addition, unpredictable things can happen during testing. A single air bubble can form under a skin sample, for example, affecting the data. Finally, there are questions about how to process data, in particular, how to deal
	with outliers.

	1. M. Luke, “Overcoming Barriers to Development and Patient Access,” a presentation at FDA’s Topical Dermatological Generic Drug Products meeting, Oct. 20, 2017.
	2. S. Raney, “A Generic Perspective on the Use of 

Assessment Methods,” a presentation at the FDA meeting: Topical Drugs: Development and Evolution of Science and Regulatory Policy, University of Maryland School of Pharmacy, July 30 2019.
	3. S. Raney, “Questions About the Proposed Topical Classification System and What to Do With It,” a webinar for the Product Quality Research Institute’s BioPharmaceutics Technical Committee, June 19, 2018.
	4. S. Raney, “The Journey from Developing the Research Study to Drafting a New Regulatory Standard, the case of Acyclovir Cream,” a presentation at FDA’s Topical Dermatological Generic Drug Products meeting, October 20, 2017.
	5. FDA, 

Upcoming Product-Specific Guidances for Complex Generics

	6. FDA, Nonsterile Semisolid Dosage forms: Scaleup and Post Approval Changes: MCM, IVRT and 


	Vol. 43, No. 11
	November 2019
	Page: 55-56

	When referring to this article, please cite it as A. Shanley, "QbD Takes Shape for Topical Pharmaceuticals," 

As they seek to increase the number of generics available, regulators are requiring that in-vitro and other test data be used for ANDAs, and promoting the concept of biowaivers that would allow such data to replace costly clinical studies.


QbD Takes Shape for Topical Pharmaceuticals

	Developing cures for infectious diseases has always promoted the image of pharma as a healing industry. Today, however, few companies remain in a business that is becoming increasingly unprofitable. According to data presented by the Pew Charitable Trust, the profitability (as defined by net present value [NPV]) of a typical antibiotic stands at $100 million, compared with $1.1 billion for a muscoskeletal therapy, $720 million for a neurology treatment, and $300 million for a cancer drug (1,2).  Not surprisingly, 42 antibiotics were in the clinical pipeline in June 2019 (3), compared with over 1,000 oncology therapies.  

	Even small innovators are leaving the market. In April of 2019, Achaogen, a biopharmaceutical company whose plazomicin therapy had been approved by FDA, declared bankruptcy (4). “There has been a large exodus of Big Pharma companies from the whole antimicrobial area and small biotechs are coming forth with research programs, but many are struggling financially, even after successful product launches,” said Greg Frank, executive director of BIO’s new initiative, 

Working to Fight Antimicrobial Resistance (AMR)

, which was launched in August 2019 (5). “We can expect to see more bankruptcies until the business landscape changes.” 

	Lack of innovation is creating a public health crisis. As surgical procedures continue to advance, more patients are exposed to the risk of infection, while micro-organisms are becoming increasingly resistant to existing treatments. 

	“Diseases such as sepsis are on the rise, and there is increased resistance to existing drugs,” said Susan C. Bleasdale, medical director of infection prevention and control at University of Illinois Health and chair of the Infectious Diseases Society of America’s (IDSA’s) clinical affairs committee. “There is a need for better tracking of AMR and recording the data.” 

	The World Health Organization (WHO), which has estimated that 350 million people could die prematurely over the next 35 years due to AMR, considers it of the world’s top healthcare problems (6). In the United States, a recent study found that AMR leads to 164,000 deaths per year, making it the third leading cause of death (7). This figure is seven times larger than the previous figure given by the Centers for Disease Control (CDC). 

	The past few years have seen more attention and public outreach devoted to ARB. Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARBX) was established with a $500-million budget to fund research aligned with the most serious ARB threats, as defined by WHO and CDC, and to bring new therapies to Phase I.  Partnering in this effort are Boston University, the Biomedical Advanced Research and Development Authority (BARDA), the United Kingdom’s Wellcome Trust and Global Antimicrobial Resistance Innovation Fund, Germany’s Federal Ministry of Education and Research, the Bill and Melinda Gates Foundation, and the NIH’s National Institute of Allergy and Infectious Diseases 

	On a grass roots level, physicians are being more conservative about prescribing antibiotics, while hospitals are launching stewardship programs designed to study and improve the way antibiotics are used, to ensure better patient outcomes.  Although these programs are showing results, they won’t be enough says Frank. “Of course, we need to use medicines more appropriately,” he said. “But we can’t steward our way out of this problem.” The key will be stimulating innovation, he says. 

	In December 2018, senators Orrin Hatch and Bob Casey proposed the DISARM (short for Developing an Innovative Strategy for Antimicrobial Resistance) Act (8) to stimulate antibiotics research. Among other things, the Act would require Medicare to pay an additional fee to hospitals that use an antibiotic developed via DISARM, and also require that hospitals participate in a CDC stewardship program in order to be eligible to use the new products. “The goal is to improve the pipeline and to require participation in stewardship programs,” said Bleasdale. 

	 “The DISARM Act signals that Congress wants to address these issues,” said Frank.  “But we also need to advocate for financial incentives.” Approaches such as pull incentives, which were supported by former FDA commissioner Scott Gottlieb, would separate product sales volumes from profitability, and create new reimbursement models with milestone payments for new antibiotics that could address priority microbes or treat multiple infections at once.  In Europe, the DRIVE-AB consortium has proposed a number of alternative commercialization options, including awarding developers $1 billion once a new antibiotic product is approved (9).

	Where traditionally, antibiotics have been small molecules, research is now focusing on biotech-based solutions. Both Bleasdale and Frank see a greater role for biomaterials with new mechanisms of action in the future.

	Testing is another area where innovation is needed, since traditional culture-based tests can take 42 to 72 hours to yield results, and, in the treatment of conditions like sepsis, every hour that treatment is delayed counts. So far, some tests have already been commercialized such as procalcitonin (PCT) assays for sepsis, which measure levels of PCT (which is released by cells together with cytokines, after exposure to toxins from bacteria). IDSA is sponsoring research in this area. 

	“Improvements have been made in rapid diagnostics,” Bleasdale said, and research is ongoing into genetic markers for resistance.  In the end, when it comes to beating AMR, she said, “a combination of new drugs, new tests, and stewardship will be the answer.”

	1.Pew Health Group Conference Proceedings, “Reviving the Pipeline of Life-Saving Antibiotics,” 

https://www.pewtrusts.org/-/media/legacy/uploadedfiles/phg/content_level_pages/issue_briefs/aippipelineproceedings9webpdf.pdf

	2.S J Projan, “Why is Big Pharma Getting out of Antibacterial Drug Discovery?,” 

	3. Pew Charitable Trusts, Infographic, “Antibiotics Currently in Global Clinical Development,”

,  June 2019, www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development

	4. Center for Infectious Disease Research and Policy at the University of Minnesota, CIDRAP News, “Achaogen Bankruptcy Raises Worry Over the Antibiotic Pipeline,” 

www.cidrap.umn.edu/news-perspective/2019/04/achaogen-bankruptcy-raises-worry-over-antibiotic-pipeline

	5. A. Segerman, “New Coalition to Raise Awareness of Antimicrobial Resistance Threat,” 

www.biotech-now.org/health/2019/08/new-coalition-to-raise-awareness-of-antimicrobial-resistance-threat-call-for-urgent-solutions

	6 World Health Organization, “Ten Threats to Global Health in 2019,” 

www.who.int/emergencies/ten-threats-to-global-health-in-2019

	7. J. Burnham et al., Re-estimating Annual Deaths Due to Multidrug Resistant Organism Infections,” 

Infection Control and Hospital Epidemiology

, 40 (1), January 2019, 112-113, www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/reestimating-annual-deaths-due-to-multidrugresistant-organism-infections/C9B09A787FCCA1EA992AF45066F3FF7C

	8. US Senate, “Hatch and Casey Put Forward Bill to Encourage Antibiotic Innovation, 

www.finance.senate.gov/chairmans-news/hatch-casey-put-forward-bill-to-encourage-antibiotic-innovation

, March 18, 2019, http://drive-ab.eu/wp-content/uploads/2018/01/CHHJ5467-Drive-AB-Main-Report-180319-WEB.pdf

Antimicrobial resistance is now the third leading cause of death in the US. As developers continue to leave an unprofitable market, legislation and new reimbursement models propose to stimulate development of new antibiotics.

Restoring the World's Antibiotic Pipeline

, FDA noted that the company had failed to meet requirements for current good manufacturing practices (cGMP) at its facility in Mandideep, Madhya Pradesh, India. As stated in the letter, regulators found that many of these problems, which were documented in late 2018 inspections, had previously been pointed out in 2017, when FDA inspectors visited the company’s facilities in Goa and Indone. Specific compliance issues included inadequate investigation into the causes of out-of-specification (OOS) conditions, undocumented procedures, problems with corrective and preventive action (CAPA), and insufficient cleanliness. The letter underscored the need for greater oversight of cGMPs by top-level managers.  

	According to FDA, the company did not sufficiently investigate the root causes (whether in the testing laboratory or in manufacturing) of OOS or batch failures, or any quality problems with batch ingredients, whether or not product batches had already been distributed. As the letter stated, although a number of OOS tests had been performed on numerous products since 2016, investigations were often closed before a root cause for the problems had been found. Once batches passed retests, the product was often released. 

	FDA asked for an independent review of all invalidated OOS results for all United States drug products since July 1 2016, and an assessment of whether justification for each invalidated OOS result was conclusive. When manufacturing was found to be the cause of the problems, the regulators asked that the company review all aspects of production thoroughly, including batch manufacturing records, process capability, raw material variability, deviation, complaint, and batch failure histories.

	In addition, the regulators asked for analysis of trends in operations and identification of “systemic factors” that might be leading to variation in testing and manufacturing results. The agency also asked that the company assess the way it investigates deviations, atypical events, complaints, OOS results and failures, and that it revisit its CAPA plan and assess its effectiveness. 

	Another fundamental problem found was inadequate written procedures for control of production steps and product quality, including inadequate identification of potential reasons for variation in product quality. Regulators asked that the company examine process validation for manufacturing and for in-process containers, and that it have an independent third party assess its manufacturing processes to determine the state of control, touching on equipment suitability, raw material quality, and other issues.

	Inspection of a tablet press at the facility found unknown residues on several contact surfaces, raising the possibility of cross-contamination. The company responded that it had addressed the problem and retrained the operators, but FDA’s letter demanded a more comprehensive assessment and documented improvement of cleaning and cleaning validation procedures, and an approach that utilizes “worst case” assumptions.

	Because many of these violations had been seen at other company sites previously, FDA reaffirmed the need for greater management oversight of cGMP, and asked that the company assess its global manufacturing operations “immediately and comprehensively.”

Over a two-year period, FDA inspections at company facilities found repeat problems with quality systems including lack of written procedures, inadequate investigation of out-of-specification conditions and corrective and preventive action, and insufficient cleaning and cleaning validation. 