Continuous Manufacturing of Pharmaceuticals

Peter Kleinebudde, Johannes Khinast, Jukka Rantanen, Peter Kleinebudde, Johannes Khinast, Jukka Rantanen

• Publisher: Wiley
• Year: 2017
• Print ISBN: 9781119001324
• eBook ISBN: 9781119001355
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals

As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.

This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles. 

• Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
• Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
• Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
• Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products

Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.

Chapter 1
Continuous Manufacturing: Definitions and Engineering Principles

Johannes Khinast^1,2 and Massimo Bresciani²

¹Institute of Process and Particle Engineering, Graz University of Technology, Austria

²Research Center for Pharmaceutical Engineering, Graz, Austria

1.1 Introduction

1.1.1 Definition of Continuous Manufacturing

In chemical engineering, manufacturing processes can be categorized in different ways, one being the mode of operation with respect to the strategy of feeding and removing materials from a process unit. Specifically, one distinguishes between:

• Batch manufacturing: All materials are charged before processing and are discharged at the end of processing (example: batch crystallization).
• Semi-batch manufacturing: Some materials may be continuously added during processing and discharged at the end (example: air feed during batch fermentation).
• Continuous manufacturing: Material is simultaneously charged and discharged from the process (example: flow-through reactor cell).
• Quasi-continuous manufacturing: Material is treated in batches, yet removed in defined intervals (example: fluid-batch drying of intermediate batches).
• Semi-continuous manufacturing: Like continuous manufacturing, but for a defined time period (example: continuous manufacturing on a campaign basis).

Thus, continuous manufacturing (CM) is a method of manufacturing products and processing materials without interruption and with constant material feed and removal. Also tableting, which actually is a batch operation on the scale of a single die, can be viewed as a continuous process. In contrast to batch manufacturing, in a continuous process materials remain constantly in motion, undergo chemical transformations, or are subject to mechanical or heat treatment. Continuous processing on a large scale generally means operating 24 h/day, 7 days/week (often called 24/7) with infrequent (weekly, monthly, semi-annual, or annual) planned maintenance shutdowns. However, continuous manufacturing can also be carried out on a campaign basis, that is, semi-continuous manufacturing of an intermediate chemical compound for a few weeks in a continuous plant.

The concept of continuous processing is not new. It has widely been used across the industry, including oil refining and the production of chemicals, fertilizers, paper, and foods. One of the earliest continuous processes relates to the paper industry (Fourdrinier paper machine, patented in 1799). Automotive manufacturing (at least the assembly part) can also be viewed as a continuous process. Here, the first assembly lines were installed at the beginning of the twentieth century by Olds (Oldsmobile) and, with more publicity, several years later by Ford (Ford model T).

1.1.2 Continuous Manufacturing in the Pharmaceutical Industry

Although not used on a broad basis, continuous manufacturing is not new to the pharmaceurical sector. Some pharmaceutical manufacturing processes (e.g., separations) have operated continuously for decades [1]. Furthermore, many pharmaceutical unit operations, such as plug-flow reactors, roller compaction, tablet compression, extrusion, and capsule filling, are inherently continuous process steps. Yet, since continuous quality assurance was not integrated in these processes in the past, they remain continuous processes operated in a batch way and will only become truly continuous when real-time quality assurance is fully implemented in the process control.The first publication by ICI, clearly outlining the advantages of continuous manufacturing (as they are cited today), dates back to 1984 [2].

On the academic side, continuous manufacturing of pharmaceuticals has been studied for more than two decades. In the early 1990s, Muzzio at Rutgers University launched the first research program for the continuous manufacturing of pharmaceuticals. In addition, Leuenberger (University of Basel) early on pointed out the advantages of continuous manufacturing in the pharmaceutical industry [3]. Since then, significant efforts have been made in this field, and several focused research programs are currently underway. For example, the Novartis-MIT center for continuous manufacturing (USA) focuses on primary active pharmaceutical ingredient (API) manufacturing and integrating drug synthesis into a continuous production line [4]. Continuous manufacturing and crystallisation (CMAC) at Strathclyde University (UK) investigates related topics that range from synthesis to crystallization. A series of white papers from the International Symposium on Continuous Manufacturing of Pharmaceuticals [5], organized jointly by MIT and CMAC, highlights the current view on CM. In the field of secondary manufacturing (drug product), together with its partners at Purdue University, NJIT, and University of Puerto Rico, Rutgers University developed a continuous manufacturing plant based on blending and direct compaction within their NSF-funded research center C-SOPS [6]. The Research Center for Pharmaceutical Engineering (RCPE) currently leads the European Consortium for Continuous Manufacturing, fearuring three continuous lines. Its partners are the groups of Ketolainen at University of Eastern Fin...

Table of contents

• Cover
• Title Page
• Copyright
• Table of Contents
• About the Editors
• List of Contributors
• Series Preface
• Preface
• Chapter 1: Continuous Manufacturing: Definitions and Engineering Principles
• Chapter 2: Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products
• Chapter 3: Regulatory and Quality Considerations for Continuous Manufacturing
• Chapter 4: Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology
• Chapter 5: Continuous Crystallisation
• Chapter 6: Continuous Fermentation for Biopharmaceuticals?
• Chapter 7: Integrated Continuous Manufacturing of Biopharmaceuticals
• Chapter 8: Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs
• Chapter 9: Continuous Line Roller Compaction
• Chapter 10: Continuous Melt Extrusion and Direct Pelletization
• Chapter 11: Continuous Processing in the Pharmaceutical Industry: Status and Perspective
• Chapter 12: Design of an Integrated Continuous Manufacturing System
• Chapter 13: End to End Continuous Manufacturing: Integration of Unit Operations
• Chapter 14: Methodology for Economic and Technical Comparison of Continuous and Batch Processes to Enhance Early Stage Decision-making
• Chapter 15: Drivers for a Change – Manufacturing of Future Medicines for Personalized Drug Therapies
• Chapter 16: Perspectives of Printing Technologies in Continuous Drug Manufacturing
• Chapter 17: Development of Liquid Dispensing Technology for the Manufacture of Low Dose Drug Products
• Index
• End User License Agreement