OR WAIT null SECS
Eric Sanchez is a senior consultant of Integra Continuous Manufacturing Systems with a special focus on the implementation of continuous manufacturing methods. He joined the firm after a successful 31-year career with Janssen Pharmaceuticals.
Fernando J. Muzzio, PhD, is distinguished professor of the School of Engineering at Rutgers, The State University of New Jersey, Piscataway, NJ 08855. Dr. Muzzio is a member of Pharmaceutical Technology's editorial advisory board and President of Integra Continuous Manufacturing Systems.
Advanced manufacturing technologies are available, but challenges need to be addressed.
The application of innovation strategies often achieves a business’ competitive advantage. One definition of innovation is either doing different things or doing things differently (1). In the past few decades, creating new ways of doing business has encouraged global corporations to look at competitive scenarios that provide lower-cost advantages. The innovation strategies designed to achieve cost improvements included business orchestrations or alliances, outsourcing, supplier leverage, and the offshoring of companies’ manufacturing activities to either lower tax or lower labor cost jurisdictions (2,3).
As demonstrated by recent experience during the COVID-19 pandemic, despite the expectation of providing a company with competitive advantages, the risks of extensive offshoring likely surpass its benefits (4–6). The pandemic showed that the potential impact of commerce disruptions on the worldwide supply chain of goods sold is a significant risk element of offshoring strategies. Moreover, other supply chain disruption events such as geopolitical situations, as well as other business risks such as competencies and knowledge loss, brand damage, or deficient intellectual property protection policies of manufacturing recipient countries are significant sources of risk to weight against offshoring benefits (2,5,7). Specifically, regarding pharmaceutical products, the risks of disrupting the supply chain are much deeper than simply financial; literally, tens of millions of patients in the United States and abroad depend critically on reliable access to medicines to maintain quality of life, and in many cases, life itself.
In the light of the significant threat that a future geopolitical or pandemic event poses to the pharmaceutics supply chain, reshoring manufacturing activities is the right business decision both for business continuity and for national security reasons. The translation of both needs to a coherent and viable business model for pharmaceutical manufacturing depends upon our ability to establish a strong foundation of technology innovations. It is important to identify innovations that would support making a reshoring strategy successful, not only in the short term when supporting government policies are in place, but in the long term, when sustainability depends on profitability. Taking generic-drug pharmaceutical manufacturing as an example, the authors seek to propose a viable pharmaceutical manufacturing reshoring strategy. A significant number of generic-drug products are essential and needed medicines that most people depend on. Still, manufacturers neglect to make them on US soil due to profit margins and capacity constraints (8). If a case can be made for successfully reshoring manufacturing of generic pharmaceutical products, where profit margins per product unit are small, it is then likely that a reshoring innovation strategy can be successful for any pharmaceutical product.
Generic-drug manufacturing has been under close attention by the US Congress and FDA due to the importance of these drugs’ availability as a public health imperative need. The causes of generic drug shortages belong to three primary sources: price of products, quality issues, and manufacturing capacity constraints (6,9–11). Additionally, the COVID-19 pandemic caused lockdowns in China, India, and Europe, unveiling the heavy dependence of the US supply of critical medicines on products manufactured in these countries (6,12). The shortage of drug supply due to the pandemic is actively tracked by FDA and kept current on the agency’s web page (13). The shortages affect almost every type of product and medical need, from over-the-counter analgesics (e.g., ibuprofen or acetaminophen) to antibiotics, sedatives, respiratory support products (e.g., albuterol), and many others. In the case of APIs, the magnitude of the US dependence on offshore manufacturing is enormous; at least 72% of drugs used in the US are manufactured abroad (6). The impact of this trade imbalance on the US trade deficit is tens of billions of dollars per year. The need for drug manufacturing in-source balancing is immense. The regulators are aware of the need to increase the domestic manufacturing capacity and our ability to reshore them (6,12,14).
The fundamental question is: Are we ready to execute a massive initiative focusing on API and dosage forms reshoring? Considering the cost elements that affect current generic manufacturer decisions, including the labor intensity, the environmental controls, and capacity constraints, the answer is that we have gaps in the technology available to support this endeavor successfully. The follow-up question is: Are we capable of such transformation? The answer is likely affirmative, in particular if we take full advantage of advanced manufacturing methods that can enable many advantages, including a substantial reduction in the cost of manufacturing in general and the cost of labor in particular. Let’s consider the required steps.
Continuous manufacturing (CM) and process analytical technologies (PAT) available for final dosage manufacturing can be used to expand domestic manufacturing capacity rapidly, at moderate cost, and at significantly lower operating cost than the batch methods that are prevalent in overseas manufacturing activities. Companies can build CM lines capable of real-time quality control, with the capacity to make more than one billion tablets (or capsules) per year in a single room using dry blending/direct compression continuous manufacturing (DCCM) methods. Existing integrated PAT tools can enable assurance of quality of 100% of the product stream, to allow real time release of products. Moreover, in such a situation where quality can be assured for essentially every unit of product, processes can be developed and should be approved by regulators much more quickly.
Mechanical and computer systems integration for such advanced manufacturing systems is possible within a few months, in a small footprint (i.e., 1000-ft2 is enough), and at an affordable cost (in the order of five million USD investment per line). Building such lines on movable skids to make them portable and capable of manufacture at distant geographical locations is also feasible, as demonstrated by projects such as the collaboration between Pfizer, GSK, GEA, and G-CON (15).
Emerging methods for pre-conditioning APIs to make them more manufacturable are radically expanding the range of applications of continuous direct compression. In fact, as demonstrated by recent work at Rutgers University in collaboration with Janssen Pharmaceuticals, products can be developed using DCCM methods in a matter of a few weeks of effort per product due to the knowledge-based available leverage, including material property databases, libraries of models for process equipment, rapidly growing capabilities in PAT, demonstrated soft-sensing methods for predicting product quality attributes (including dissolution profiles), and growing expertise in application of automated process control.
The primary constraint for reshoring generic drug manufacturing pertains to the API. Table I shows the nature of the limitations that need to be considered and the strategies to mitigate them. Amongst the most important is the availability of locally available intermediate materials used in the API synthesis. Moving the final stages of API manufacturing to domestic facilities might well be an exercise in futility if it does not include a strategy to obtain the intermediate materials from local sources. Otherwise, we would simply be moving our dependence on external sources upstream on the supply chain, while leaving our supply chain vulnerabilities intact.
Design and integration of unit operations for continuous flow synthesis and purification started several years ago. Still, aspects related to scale-up, flexible design of the synthesis platform, and optimization through flow-sheet modeling needs additional development. Interestingly, since the basic process science for liquid-based systems is significantly better developed than for powder-based processes, very rapid gains are possible in integrating advanced manufacturing systems for APIs, oral liquids, and sterile injectable liquids. However, FDA had approved only one API for continuous manufacturing (16), and there is no continuously manufactured parenteral product yet developed and approved by FDA. Clearly, additional experience in regulatory evaluation of such applications of advanced manufacturing is needed to enable industry to move forward with confidence.
One of the most promising new continuous flow synthesis systems is the SRI AutoSyn multistep flow synthesis system. SRI developed this continuous flow synthesis system as a multistep universal synthesizer to develop new drugs using SRI’s artificial intelligence proprietary tools. The speed at which this system can generate a small molecule synthesis route allows for the development of new synthetic pathways for generic drugs based on intermediate synthesis materials available in the US. The main technology drawback preventing its current use as a pure continuous flow synthesis is the units’ current scale, designed to produce grams per hour. Nevertheless, translation of continuous flow synthesis pathway into the traditional batch process or hybrid continuous and batch process design is an option that can accelerate the development of the needed commercial scales of high demand generic products.
An important constraint faced by companies that seek to implement advanced manufacturing methods, in particular generic-drug companies with limited experience in this area, is that advanced manufacturing is knowledge intensive. Many decision makers at generic-drug companies currently have limited visibility into the entire set of issues required to implement these technologies successfully and to develop processes that can be approved by regulatory agencies. In the past 15 years, the authors of this article have supported many such efforts to successful conclusion. In our opinion, access to knowledge and expertise, and management commitment, are by far the most significant elements required for success. Fortunately, due to the efforts of C-SOPS based at Rutgers University, the Massachusetts Institute of Technology, the National Science Foundation, FDA, and leading US-based pharmaceutical companies, such as Janssen, Vertex, Pfizer, and Eli Lilly, the US is in a position of leadership in access to the knowledge base required to implement advanced pharmaceutical manufacturing applications.
Securing medicinal product availability in the event of a supply-chain disruption is a problem that needs a robust solution. An effective approach will take years to implement, which simply means that we need to start as soon as possible, and we need to mobilize resources based on a lucid, long-term implementation plan. Patients worldwide, particularly our fellow US citizens, need to have affordable, available, and high-quality medicines produced within our geographical boundaries, to ensure that they are accessible under any supply-chain circumstances. The advances in pharmaceutical technologies achieved in the US are crucial elements of an innovation strategy that promises to solve the issue sustainably. It is a matter of starting and getting the work done as soon as possible.
Eric Sanchez is a senior consultant of Integra Continuous Manufacturing Systems. Fernando J Muzzio, PhD is the President of Integra Continuous Manufacturing Systems; distinguished professor of the School of Engineering at Rutgers, The State University of New Jersey; and member of the Pharmaceutical Technology Editorial Advisory Board.
Vol. 45, No. 2
When citing this article, please refer to it as E. Sanchez and F. Muzzio, " Reshoring Pharmaceutical Manufacturing to the US: Can We Do It?," Pharmaceutical Technology 45 (2) 2021.