How to Design and Implement Powder-to-Tablet Continuous Manufacturing Systems

How to Design and Implement Powder-to-Tablet Continuous Manufacturing Systems provides a comprehensive overview on the considerations necessary for the design of continuous pharmaceutical manufacturing processes. The book covers both the theory and design of continuous processing of associated unit operations, along with their characterization and control. In addition, it discusses practical insights and strategies that the editor and chapter authors have learned. Chapters cover Process Analytical Technology (PAT) tools and the application of PAT data to enable distributed process control.

With numerous case studies throughout, this valuable guide is ideal for those engaged in, or learning about, continuous processing in pharmaceutical manufacturing.

• Discusses the development of strategy blueprints in the design of continuous processes
• Shows how to create process flowsheet models from individual unit operation models
• Includes a chapter on characterization methods for materials, the use of statistical methods to analyze material property data, and the use of material databases
• Covers the evolving regulatory expectations for continuous manufacturing
• Provides readers with ways to more effectively navigate these expectations

• Language: English
• Publisher: Academic Press
• Release date: Mar 29, 2022
• ISBN: 9780128134801

Book preview

Chapter 1: Introduction

Sarang Oka ¹ , ² , and Fernando J. Muzzio ¹       ¹ Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, United States      ² Hovione, Drug Product Continuous Manufacturing, East Windsor, New Jersey

Keywords

Continuous manufacturing; Innovation; Pharmaceutical manufacturing; Solid oral drug products

1. Foreword—our journey in CM

After decades of near stagnation, pharmaceutical manufacturing is experiencing unprecedented innovation. In the last decade, the pharmaceutical industry and its technology and ingredient suppliers have embraced a worldwide transformation from traditional, inefficient batch methods to continuous manufacturing, which is an emerging technology that has been shown to greatly reduce both the time and the cost of developing and manufacturing new medicines, while enabling significant improvements in the quality of the final product and the reliability of the manufacturing process.

How did this happen? Like many good ideas, continuous solid dose pharmaceutical manufacturing has been thought by many people in the past. In fact, many of the unit operations used in batch manufacturing (mills, tablet presses, roller compactors, packaging equipment) are intrinsically continuous. The so-called batch process is not truly batch, rather it is actually a mishmash of intrinsically continuous and intrinsically batch processing steps, utilized in asynchronous sequence. So, it was only natural, and only a matter of time, until someone decided to remove the intrinsically batch steps and replace them with intrinsically continuous steps, to enable the whole process to be continuous and to enjoy the many advantages discussed in the next section and also throughout this book.

For the team involved in writing this book, efforts to achieve complete implementation of a continuous line going from powder raw materials to finished products started around 1998, during a visit by F.J. Muzzio to the GSK (then Glaxo) facility in Verona, Italy, to teach a week-long course on pharmaceutical manufacturing methods focused on a topic that commanded enormous attention at the time: powder mixing and blend homogeneity sampling. As part of many discussions with the excellent team of Italian GSK scientists regarding this topic, an idea emerged—if most blending problems were caused by the basic approach of using batch blenders, which are intrinsically difficult to sample and which promote blend segregation during discharge, why not avoid the problem altogether by creating a continuous feeding/mixing system that would be easy to characterize (as the stream discharged by the blender could be conveniently sampled), would not promote segregation, and would even be amenable to closed-loop process control?

Following these discussions, the Muzzio team at Rutgers University wrote many proposals to industry seeking funds to create this technology. Invariably, industry representatives rejected those proposals, indicating that they believed that regulators would never approve continuous processes. The argument, more or less, boiled down to the regulatory framework requires a batch process. It took 5years to change this mindset, but in 2003, during discussions of the CAMP consortium in New Brunswick, NJ, focusing on the PAT initiative, Dr. Janet Woodcock of the US Food and Drug Administration (FDA) indicated that efforts to implement continuous manufacturing methods would be welcome by the US regulatory authority. FDA documented this conceptual support in 2004 in the revised PAT guidance. Since then, progress has been rapid, fueled by unwavering support from the FDA, soon followed by European and Japanese regulators.

The rest is history. In 2004, the Rutgers team formed a continuous manufacturing consortium, integrated at the time by Merck, Pfizer, Apotex, and GEA. This small band of confederates focused primarily on feeding and blending, demonstrating, using rudimentary versions of the technology, that continuous feeding and mixing was indeed feasible, generating some of the first conference presentations and papers in this area [1–5]. Soon thereafter, in 2006, the Rutgers team, in partnership with Purdue University, NJIT, and the University of Puerto Rico, succeeded in attracting significant funding from the National Science Foundation (NSF) to establish the Engineering Research Center on Structured Organic Particulate Systems (C-SOPS). C-SOPS was entirely dedicated to the systematic application of engineering methods to pharmaceutical product and process design. In the 14 years since C-SOPS was established, more than 60 companies, as well as the FDA and the USP, would join C-SOPS, which focused on continuous manufacturing as its main research effort. This academic–industrial–regulatory partnership attracted research funding in excess of $100 million, published over 500 peer-reviewed papers, and enabled implementation of advanced manufacturing methods at numerous companies.

Rapid progress followed NSF funding. C-SOPS formed a mentor team that included more than 20 industrial representatives, who worked closely with the students, postdocs, and the occasional professor, to integrate a working system. By 2008, this team had integrated gravimetric twin screw feeders, a continuous tubular blender, and a tablet press; implemented hyperspectral NIR sensing; and closed the mechanical controls loop using both Siemens and Emerson control systems.

Shortly thereafter, representatives of JnJ approached the Rutgers and UPR teams and challenged them to reach a new milestone—to create a commercial system. This effort was the development of Prezista continuous manufacturing, described in Chapter 15. Many more collaborations followed, both with JnJ and with other companies, expanding from continuous direct compression (CDC) to continuous wet granulation (CWG), continuous roller compaction (CRC), and more recently, continuous API manufacturing.

Since then, continuous manufacturing has become a reality and is quickly becoming a major modality of manufacturing with active projects all over the world. Importantly, many other organizations have made very substantial contributions to the current state of the art. While JnJ was working closely with C-SOPS, many other companies, among them Vertex, Pfizer, Eli Lilly, GSK, Merck, and Novartis, were working on their own in-house efforts. Many of those efforts have begun to bear fruit, as we currently see, about a decade later, with rapid growth in both the number of approved continuous processes and the number of companies that are able to implement continuous methods to completion.

To be fair, C-SOPS was not the only academic/industrial coalition that contributed to this major change in manufacturing methods. Several others took place in parallel, or soon thereafter. A major effort funded mainly by Novartis at MIT undertook the development of end-to-end continuous manufacturing, integrating the process from the final steps of organic synthesis all the way to the finished product. Another major effort, the Research Center for Pharmaceutical Engineering (RCPE), emerged around 2009 in Austria, led by the Technical University of Graz. Among many accomplishments, the RCPE team took discrete element method (DEM) simulation of pharmaceutical processes to the next level and also demonstrated full integration of a holt-melt extrusion (HME) system. Shortly thereafter, another major effort, CMAC, emerged in the United Kingdom, focusing primarily on continuous API synthesis and crystallization. In the last few years, these efforts have been joined by more consortia, centered in Dublin, Ghent, Sheffield, and Kuopio and more recently in Japan and China.

At about the same time when C-SOPS was getting started, equipment suppliers begun to offer process components and eventually fully integrated systems. The first company to do so was GEA, which launched the ConsiGma system for commercial implementation, soon to be joined by the Excellence United consortium led by Glatt. GEA and Glatt were soon joined by LB Bohle and Powrex, more recently by Bosch and Fette, and soon, we anticipate, by many others.

Finally, funding agencies and regulatory agencies of the US government have played a really important role in enabling and fueling this progress, both by reassuring industry and by providing funding to academia to continue the effort. Our team is forever grateful to both NSF for the early funding and the FDA for its enduring support.

2. The many benefits of continuous solid dose manufacturing

As discussed throughout this book, continuous manufacturing methods enable modeling, sensing, and closed-loop real-time process control. This can lead to better understood processes, better product quality, increased process reliability, facilitate real-time release, enhanced product quality, lower manufacturing cost, increased yield, smaller process footprint, and many other self-evident advantages.

2.1. Improving product quality

Continuous manufacturing processes can enable superior product quality. Our collaborations with the FDA and industry, and our partnership with organizations like the United States Pharmacopoeia, help to ensure this outcome. There are three main reasons for this. First, the near-steady nature of the process enables all portions of material to be processed under equivalent conditions at a constant state of control. Second, because only a small amount of material is processed at any given time, quality attributes of every portion of the process stream can be rigorously monitored to assure quality. Any defective product units can be tracked and scrapped, while retaining only quality-compliant product units. Third, and again because the system is nearly steady and continuous, real-time monitoring, active control, and advanced optimization can be used to ensure that the process remains within operational specifications at all times. In addition, continuous manufacturing enables detailed and accurate computer modeling, assuring a much deeper scientific understanding. This improvement in quality can translate directly into health benefits because defective product may fail to provide its therapeutic benefit or, in extreme cases, cause harm to patients.

2.2. Faster product and process development

For solid dose products such as tablets and capsules, which comprise the great majority of drugs taken by patients, continuous manufacturing has been shown to greatly reduce both the time and cost of developing new medicines. A typical continuous manufacturing line for solid dose product reaches an operational state of control in a matter of minutes. Therefore, extensive studies examining alternative product formulations and multiple process conditions can be performed in just a few days, using only a small amount of raw materials. Moreover, because such development studies are performed using the same equipment that will be subsequently used for manufacturing, no scale-up studies of the process are needed, and process development is further accelerated. As mentioned, this ability to develop products and processes faster and with less waste can have a major impact on the profitability of both brand-based products (which are protected by patents with finite life) and generic products (where the first company to file an approvable application often accrues a larger share of profits). In our opinion, an even more important benefit is the ability of accelerating access to life-saving new medicines to patients that literally cannot wait, providing the strongest incentive for implementing technologies that enable rapid product and process development.

2.3. Faster responses to shortages and emergencies

By enabling faster product and process development, continuous manufacturing can allow manufacturers to develop products quickly to respond to emergencies, to address shortages, and to bring breakthrough therapies to market. The current state of knowledge often enables a skilled practitioner to create a formulation and a process for a given product in just a few weeks. Under emergency conditions, such processes need not be optimum, just adequate, which further enables rapid development. As mentioned, such processes can be developed at the full manufacturing scale and using only a small amount of material, which is often critical early in the life cycle of a product, or when quality issues are detected, because under such conditions, suitable raw materials can be scarce. Moreover, the intrinsically higher reliability of continuous processes should make them safer and easier to approve by regulatory authorities, further enabling rapid response during emergencies.

We believe that this ability to enable faster product development will become a major driver for the implementation of continuous systems in the post–COVID-19 world, not only for solid dose products but also for APIs, injectable products, vaccines, and other product forms. How such an initiative will come together remains to be seen, but the potential benefit is so large that in our opinion it is only a matter of time.

2.4. Potential for reducing drug prices

Continuous manufacturing can help reduce the cost of both prescription and over-the-counter (OTC) drugs in multiple ways. Some of the impact is direct: continuous manufacturing processes have smaller footprint, achieve higher yields, and require less direct labor than their batch counterparts, so they are able to directly impact the cost of making pharmaceutical products. Some of the impact is indirect: because continuous manufacturing processes also enable the manufacture of products with superior quality, and because they enable real-time quality control and, if desired, release, they reduce the cost of assuring product quality. While continuous manufacturing processes require upfront investments in both physical and human infrastructure, they can return this investment rapidly. Moreover, as mentioned, continuous manufacturing products and their required manufacturing processes can be developed faster than their batch-based counterparts. As a result, products developed and manufactured using continuous manufacturing technology can reach the marketplace faster, extending profitability periods for the companies making them. These factors could contribute to lower drug prices to the US consumer, if continuous manufacturing technologies could be adopted in the highly price-competitive generic and the OTC sectors of the pharmaceutical industry.

3. The engineering toolbox, applied to pharmaceutical manufacturing process design

While not entirely new from an engineering perspective, implementation of continuous manufacturing systems in the pharmaceutical industry brought renewed interest in various methodologies, including materials characterization and process modeling, and redefined their use in pharmaceutical process design. The higher level of complexity of continuous systems, emerging from the need to operate multiple processes simultaneously all at the same rate and interacting with each other, enhanced the need for in-depth process understanding and required the creation of new pathway for regulatory evaluation. Traditionally, except perhaps for API synthesis and purification, process engineering methods had encountered little use in pharmaceutical process design. Continuous manufacturing changed this almost overnight, as the need for process modeling and process control became immediately apparent. Responding to this need was an inherently multidisciplinary effort that required the creation of public–private partnerships to bring the technology forward. As mentioned, these partnerships emerged in multiple places in the United States and Europe and more recently in Japan and China.

By the mid-2010s, the question was whether all of this research activity would result in a major new manufacturing mode. Today, with six solid dose continuous manufacturing approvals in the United States as of early 2020 and a similar number in other countries, and dozens of ongoing filings with the US FDA both for dose and drug substance, this manufacturing approach has reached the full commercialization stage. We expect that the adoption process will continue to accelerate, until reaching full maturity.

As the rate of adoption increases, a concise resource on the basic principles of the technology, focusing on providing practical advice regarding implementation, appears to be needed. This book, How to Design and Implement Continuous Manufacturing Systems for Solid Oral Dosage Pharmaceutical Products, seeks to meet this need. Our aim is to present the engineering toolbox, as it is applied to continuous pharmaceutical manufacturing process design for solid dose products. Much of the material in the book comes from firsthand experience of the authors and their collaborators as first adopters of the technology. The book follows a systematic stepwise approach to the Design of an Integrated Continuous Manufacturing System. To be successful at implementing or at evaluating continuous manufacturing systems, the reader needs to gain an appreciation of the highly integrated nature of continuous manufacturing processes before getting started. One of the key aspects of advanced manufacturing and continuous processing is the ability to work with increased amounts of information and to relate process data to the variability of inputs. These concepts were examined in detail in a previous publication of the authors [6]. Although not collated in a single chapter in this book, the concepts have been revisited in the individual chapters as