Pharmaceutical process research and development is an exacting, multidisciplinary effort but a somewhat neglected discipline in the chemical curriculum. This book presents an overview of the many facets of process development and how recent advances in synthetic organic chemistry, process technology and chemical engineering have impacted on the manufacture of pharmaceuticals. In 15 concise chapters the book covers such diverse subjects as route selection and economics, the interface with medicinal chemistry, the impact of green chemistry, safety, the crucial role of physical organic measurements in gaining a deeper understanding of chemical behaviour, the role of the analyst, new tools and innovations in reactor design, purification and separation, solid state chemistry and its role in formulation. The book ends with an assessment of future trends and challenges. The book provides a valuable overview of: both early and late stage chemical development, how safe and scaleable synthetic routes are designed, selected and developed, the importance of the chemical engineering, analytical and manufacturing interfaces, the key enabling technologies, including catalysis and biocatalysis, the importance of the green chemical perspective and solid form issues. The book, written and edited by experts in the field, is a contemporary, holistic treatise, with a logical sequence for process development and mini-case histories within the chapters to bring alive different aspects of the process. It is completely pharmaceutical themed, encompassing all essential aspects, from route and reagent selection to manufacture of the active compound. The book is aimed at both graduates and postgraduates interested in a career in the pharmaceutical industry. It informs them about the breadth of the work carried out in chemical research and development departments, and gives them a feel for the challenges involved in the job. The book is also of value to academics who often understand the drug discovery arena, but have far less appreciation of the drug development area, and are thus unable to advise their students about the relative merits of careers in chemical development versus discovery.
About the Author
Michael T Williams, formerly at Pfizer, now carries out independent consulting work and is an Associate Consultant with Scientific Update, in addition to his work in editing and scientific writing. After completing a BSc Sp Hons in Chemistry at King's College, London, he won a Science and Industry Award giving him a year of industrial experience as a medicinal chemist at ICI Pharmaceuticals, and an earmarked SRC grant. Following his PhD with Prof. Charles Rees at the University of Liverpool, he joined the Chemical Research and Development department of Pfizer. His mid-career responsibilities at Pfizer included the Medicinal Chemistry/Development interface, outsourcing initiatives and technology adoption. In addition to his experience with about 50 early drug candidates, he played a significant role in the late development, filing and commercialization of many agents including ZoloftTM, ViagraTM and RelpaxTM. He rose to become Executive Director and Departmental Head of UK Chemical Research and Development in 2003 and he also spent a 10 month secondment leading 75 formulators, and helping to build a 40 strong Material Sciences group. John Blacker holds the Chair of Process Chemistry and is Director of the Institute of Process Research and Development, positions held jointly between the School of Chemistry and School of Process Environmental and Materials Engineering at the University of Leeds. Until recently he worked as Research and Development Technical Director at Piramal Healthcare and has been in the fine chemicals industry for over 17 years with predecessor companies Avecia, Zeneca and ICI. Prior to this, he was a post-doctoral fellow with Prof. Sir Alan Fersht at the University of Cambridge; did a PhD and DEA in Chimie Organiques with Prof. Jean-Marie Lehn at the University Louis Pasteur Strasbourg, and a BSc Sp.Hons in Chemistry and Biochemistry at the University of Sheffield. As an industrial chemist, he has made contributions to asymmetric catalysis, pharmaceutical process research and development, with over 80 original research articles, patents and many presentations at international conferences, and was awarded the RSC Process Technology Award in 2006. He is also involved in establishing an Institute of Process Research and Development aimed at bridging the innovation gap and supplying the chemical industry with valuable and competitive new technology.
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Pharmaceutical Process Development
Current Chemical and Engineering Challenges
By A. John Blacker, Michael T. Williams
The Royal Society of ChemistryCopyright © 2011 Royal Society of Chemistry
All rights reserved.
A. JOHN BLACKER AND MIKE T. WILLIAMS
1.1 Process Research and Development in Context
Pharmaceutical process research and development (R&D) is a complex, challenging and exciting endeavour that crosses the boundaries between synthetic organic chemistry, process technology and chemical engineering. This book will explore the various aspects of process research and development for small-molecule manufacture that must be brought together to provide sufficient quantities of reliable and cost effective medicines, made with low environmental impact, to make the drug both a success for the company and a safe, affordable and sustainably produced medicine for society.
The pharmaceutical industry has grown inconceivably since early drugs such as aspirin and penicillin were discovered and developed. The growth was first fuelled by post-war increased healthcare requirements in North America, Western Europe and Japan. The undoubted impact of wide access to medicines has been the increase in life expectancy, which has doubled and continues to increase. The growing populations within the economies of Asia and South America are not only starting to benefit from cheaper and more available medicines, but especially in the case of Asia are increasingly responsible for their production. Traditionally poor economies such as Africa are also starting to access cheaper, more widely distributed, medicines which may help alleviate suffering and improve mortality rates. More recently in Western economies there has been an increased demand for medicines to manage lifestyle in areas such as type II diabetes, anti-cholesterolaemics and infertility, and this is similarly expected to continue rising.
The discovery of a drug candidate by medicinal chemistry is the first step in a long journey to the marketplace, and the vast majority of candidates fall by the wayside. The timescale of the overall drug discovery and development process, and the high attrition rate, are illustrated in Figures 1.1 and 1.2. As the drug progresses through clinical trials, the demands for material increase. Not only is drug substance required for clinical trials, but also for analytical, stability, formulation and in vitro studies. Whilst the total amount of drug active required depends upon its activity, effect and physical properties, typical requirements are 1 kg at phase I, 50–100 kg at phase II and at phase III up to 1 tonne. As the drug progresses through the development pipeline, the project team estimates the likely commercial demand profile and ensures that it orders a sizeable contingency to avoid demand outstripping supply. Once launched, the successful drug sees growth in volume that for high-dose drugs (g d-1) may exceed 1000s of tonnes per annum, or for low-dose drugs 100 kg per annum. The period approaching expiry of the main patent sees a significant change in the management of drug supply. Competition from generic producers affects the amount of drug manufactured, partly controlled by their interest in attacking the market and partly by the originating company's strategy. Over the past decade, only about 25 new chemical entities (NCEs) have been approved to enter the global market each year, and the cost of discovering and developing each NCE has been estimated to be in the range of $500–2000 million, depending on the therapeutic area and developing company.
As the drug development programme proceeds, the process R&D group will scale-up new synthetic processes from the laboratory, through to the pilot plant and ultimately into full-scale commercial manufacture, if the programme is successful. In the course of this endeavour, the process R&D group will serve three disparate customers:
The development process requires escalating quantities of the active pharmaceutical ingredient (API) of the requisite purity for toxicological, clinical and other studies.
Production requires a synthetic route and a robust manufacturing process to operate if the API is commercialised.
Regulatory agencies require that the developed process is demonstrated to reproducibly produce the API of the approved high quality, when operated within defined and validated parameters.
1.2 Aims and Scope of the Book
The book is aimed at chemistry, engineering and pharmacy under- and postgraduate students and early to mid career professionals, but may also be of interest to those in allied disciplines such as biologists, medical and business people. To adequately cover the field, the book considers each aspect of process R&D more or less chronologically as it occurs during a project. For example, deciding what equipment will be required for manufacture requires good definition of the chemical process, which in turn necessitates a clearly defined route. The interdependency of each area must be recognised and the book will try to point these out within each chapter. Process R&D expertise resides largely within industry, which is why most of the chapters are authored by currently practicing experts. A number of academic institutions and funding organisations now recognise the need for strategic research and specific training requirements to support the pharmaceutical industry.
This book thus differs from most others that have been published in the area as it is organised to try to walk the reader logically through key aspects of the pharmaceutical chemical R&D process, covering the essential aspects encountered in both early and late stage process development toward manufacture. In this way it is hoped that the reader will gain an appreciation of what is involved in working in this environment. Rather than relying on separate case history chapters, this text incorporates mini-case histories within the chapters to bring to life different aspects of the development process. The book aims to provide an overview of:
How safe and scalable synthetic routes are designed, selected and developed.
The importance of the chemical engineering, analytical and manufacturing interfaces.
The importance of the green chemical perspective and solid form issues.
Every pharmaceutical company planning to launch, or be responsible for manufacturing, medicines must employ or have access to process development capability. The consequences of failing to develop manufacturing processes that give consistent, high-quality product can have serious adverse consequences for both the consumer and the producer. Many steps are put in place, by both the company developing the drug and independent regulatory bodies, to ensure this does not occur. These control measures provide the most important framework which the process R&D scientist must be aware of and operate within. However, this is only one aspect of the many varied responsibilities that these teams of skilled development professionals have.
Although this book aims to cover the breadth of process development activities as an advanced single volume text, it will not be able to provide the depth of coverage of a comprehensive handbook. Areas within product development that the book is unable to cover include formulation, packaging and distribution, or wider issues around generic drugs. Furthermore, whilst it is recognised that biological medicines such as vaccines, antibodies, peptides and nucleotide-based therapeutics are an important class of medicines that are being increasingly adopted to treat patients, small-molecule drugs remain the largest part of the market. Since the skills and infrastructure required to develop biomedicine processes are so different, it is beyond the scope of this book to discuss their development and manufacture. The reader interested in this area might refer to the book by Dutton and Scharer.
1.3 Outline of Contents
The starting point for process development usually follows the identification of a bioactive molecule. To increase understanding of its effects, more material is required and commercial pressures often demand rapid scale-up to make kilogram quantities. To produce these quantities the company must be able to access, either internally or externally through contract or collaboration, a laboratory and people having the equipment and expertise. The chemical route is often inherited from the medicinal chemists and, whilst sub-optimal, is often used with the minimum number of changes to ensure safe but rapid delivery. Since the failure rate of early phase drugs is so high, process R&D effort is minimised to avoid wasted resources. Nevertheless, a host of factors need to be considered, including availability of materials, chemical safety and whether to accept chromatographic separations. Looking towards the need for larger quantities of the API, one of the first considerations is whether the route initially used is suitable. Often quite substantial changes are made which markedly improve the efficiency, cost, reliability and environmental impact of the route. Successful scale-up should then entail detailed pre-work to understand, for example, the rates of reactions, pre-equilibria, physical aspects such as multi-phasic mixing and reactor design (an activity involving both chemists and engineers). Even at this stage a broad idea of the type of equipment and methods of separation and purification should be part of the project team thinking. When scaling-up batch reactions beyond a laboratory scale of about 1 L, process safety aspects must be considered, as the ratio of surface area to volume and the ability to remove heat both decrease, and the ability to remove heat is limited. The consequent auto-heating of the reaction can lead to decomposition of any thermally unstable materials present in the reactor, runaway reactions and potentially to an explosion.
As shown in Figure 1.3, late phase clinical trials require substantial quantities of the API, which may require tonne volumes of starting materials in a carefully planned production campaign involving multiple batches.
Since the API is used in human clinical trials, the manufacture requires careful regulation and quality assurance to ensure that the product is fit-for-purpose with a traceable origin. A key advisor in this, and an essential part of the process R&D team at all stages of development and production, is the analyst, responsible not only for measuring the API purity, but also for understanding impurities that emanate from the process. If appropriate process analytical technology (PAT) systems are put in place, with the capability to analyse and interrogate the data, much can be learnt about the process from initial bulk campaigns that can assist in further scale-up. A high-purity API is usually obtained by controlled crystallisation processes in which the crystal lattice rejects impurities. Much science is involved in optimising such processes to ensure that a consistent product is made in high yield. Finally, as the drug moves towards approval, its manufacture must be planned. A dedicated plant is nor- mally employed, and all the process R&D studies to date are used to define its layout and construction. The plant must not only produce the required quality of product to cover predicted future demands, but must also, for example, be designed to be safe, easily cleaned, low maintenance and cost efficient.
The book is organised in the following manner:
Chapter 2 provides some historical background to how pharmaceutical companies themselves emerged. This then leads to an examination of how the discipline of pharmaceutical process R&D has evolved, and the significant changes that have occurred in the past 20 years.
Chapter 3 sets out what a synthetic or semi-synthetic API is, together with some of its typical physicochemical characteristics. An examination of some common features of small-molecule APIs leads into a discussion of how this impacts the design of drug syntheses, and the types of reactions that can be used on scale and frequently occur in API syntheses.
Chapter 4 covers the interface with medicinal chemistry, the high attrition rate in early development and the "fit-for-purpose" strategies that are often used to progress drug candidates through key early decision points with limited resources. The safety, reliability and efficiency criteria that guide decisions about expedient syntheses used to prepare multi-kilogram early development batches are discussed and exemplified.
Chapter 5 picks up the story once the drug candidate has successfully cleared early development hurdles, perhaps achieving clinical proof-of-concept (POC). The factors are discussed which affect the timing and intensity of the search for longer term synthetic routes. For APIs of only moderate complexity, a large number of potential routes will be possible. The criteria used to compare these candidate routes, and decide upon the one which will be developed for registration and production, are laid out with a range of examples.
Chapter 6 focuses on the importance of green chemistry within the pharmaceutical industry; the metrics used to assess the green chemical performance of routes and processes, and the importance of solvent selection, are also highlighted. Three case histories are then used to illustrate the progress that is being made in the "greening" of API syntheses, and the importance of biocatalysis.
Chapter 7 introduces the need for deeper understanding of chemical processes to ensure robust and reproducible operation. The use of different calorimetric techniques to determine reaction kinetics and test mechanistic models, particularly for catalysts, has over recent years been an important addition to the tools available for helping improve process performance.
Chapter 8 considers the crucial aspect of process safety. When up-scaling from the laboratory to plant the impact of process failure increases, and both chemical and operational hazards must be carefully evaluated. The identification and measurement of hazards will lead to adoption of a safe operating regime.
Chapter 9 discusses the key chemical engineering interface by considering the kinetic, thermodynamic and physical aspects of reactions that affect selection of reactor type, feed regime, types of mixing required and under- standing of molecular interdependencies. The result is often improved yield, higher selectivities and more robust operation.
Chapter 10 introduces the importance of solvent selection, particularly in liquid–liquid extraction. The design and understanding of these systems is recognised to be crucial in sustainable processing due to its impact upon reaction efficiency, product separation, purification and operability.
Chapter 11 discusses some of the recent innovations and tools being adopted by the process chemist which assist in the gathering and interpretation of data.
Chapter 12 looks at the key interface between analytical and process development scientists, and the essential role analysts play in helping process chemists develop more efficient processes. The evolution of analytical equipment and techniques used to provide more rapid and detailed assessments of product purity, reaction kinetics and the levels of impurities is discussed.
Chapter 13 presents information required about the product in solid form. Detailed understanding of the crystallisation process is essential as this is the primary method for purification of the API, which must be produced to a high specification.
Excerpted from Pharmaceutical Process Development by A. John Blacker, Michael T. Williams. Copyright © 2011 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Table of Contents
Foreword; Preface; Introduction; Process Research and Development in the Pharmaceutical Industry: Origins, Evolution and Progress; Active Pharmaceutical Ingredients: Structure and Impact on Synthesis; Rapid Early Development of Potential Drug Candidates; Route Design and Selection The Importance of Green Chemistry in Process Research and Development; Kinetic Approaches for Faster and Efficient Process Development; The Design of Safe Chemical Reactions - It's No Accident; Physicochemical Data Requirements for the Design of Fine Chemical Processes - Acquisition and Application; Liquid-Liquid Extraction for Process Development in the Pharmaceutical Industry; Development Enabling Technologies; The Analytical Interface and the Impact on Pharmaceutical Process Development; Materials Science - Solid Form Design and Crystallisation Process Development; Technology Transfer of API; Future Trends and Challenges;
What People are Saying About This
Drug discovery and development requires the active collaborations of researches from many scientific disciplines and sub-disciplines and the RSC has created a great opportunity to provide the necessary range of publications to facilitate this.
Professor Robin Ganellin, University College, London,UK