Practical Process Research and Development / Edition 1 available in Hardcover
Practical Process Research and Development / Edition 1
- ISBN-10:
- 0120594757
- ISBN-13:
- 9780120594757
- Pub. Date:
- 03/20/2000
- Publisher:
- Elsevier Science
- ISBN-10:
- 0120594757
- ISBN-13:
- 9780120594757
- Pub. Date:
- 03/20/2000
- Publisher:
- Elsevier Science
Practical Process Research and Development / Edition 1
Hardcover
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Overview
Product Details
| ISBN-13: | 9780120594757 |
|---|---|
| Publisher: | Elsevier Science |
| Publication date: | 03/20/2000 |
| Edition description: | New Edition |
| Pages: | 384 |
| Product dimensions: | 6.00(w) x 9.00(h) x (d) |
About the Author
Read an Excerpt
Chapter 1: Approaches to Process Development
I. Introduction
The cost and pace of developing active compounds for the pharmaceutical and agricultural industries is dramatically increasing. The estimated average cost of developing a drug has risen from $350 million in 1997 [2] to $500 million in 1999 [3]. Combinatorial chemistry and high-throughput screening increase the rates of identifying new lead compounds [3-6]. New screens are being considered to aid in selecting compounds with desired biopharmaceutical properties [7]. Pressures to produce are increasing as companies set ambitious goals to transform active leads into approved, revenue-producing agents. Efficient development of processes to prepare kilogram quantities of drug candidates and active ingredients is necessary to sustain the pace of drug development and recoup the expenses of development. As part of development efforts, those involved in process research and development (process R & D) must keep pace by developing processes for large amounts of drug candidates and drug substances.
Devising and implementing a reliable manufacturing process in a timely fashion are keys to maximizing profits from a drug or chemical within the exclusive marketing period allowed by a patent. Gone are the days when most drugs could be prepared in as few as tour relatively simple steps. Today's typical "small molecule" (generally a compound with molecular weight no more than 750 daltons) requires 10-15 reactions, some of which are likely to be fairly complex. One error during the process of preparing the drug substance (active pharmaceutical ingredient, or API; sometimes known as bulk drug substance, or BDS) orintermediates can have tremendous financial impact by delaying key toxicology studies, clinical trials, or delivery of the drug to pharmacists' shelves [8]. The urgency commonly felt in the pharmaceutical industry weighs heavily on process research and development: for instance, for a drug selling at $400 million annually, a one day delay in the approval or delivery of the drug substances can cost $1 million! The timely implementation of reliable processes is key to the continued financial health of pharmaceutical companies. As may be seen in Table 1.1, the cost of drug development provides tremendous pressure to reduce development time [2], and the pressures to decrease development time are ever-increasing.
The role of process R & D is to ensure that high-quality material is provided in a timely fashion to fill the needs of developing a compound. The process chemist must satisfy two groups of clients: those who use the drug substance (primarily toxicologists and pharmaceutical chemists) and those who use the processes (scale-up operations, manufacturing, and suppliers for outsourcing). The criteria of the first group are that a high-quality drug substance be prepared in the desired physical form and that the expected amount be delivered in a timely manner. This group is rarely concerned with how the drug substance is prepared. The second group, those who use the processes, want reliable procedures to prepare the drug substance and intermediates. How smoothly the operations proceed determines whether the organization can meet goals of supplying material to users. Those involved in process R & D must evaluate and evolve processes to meet current and future needs. By incorporating the approaches of those who develop processes for large-scale production early in the development of a drug candidate, one can compress the development cycle.
The emphases of process R & D change as a compound is developed (Table 1.2) [2]. In the early stages of a drug development, discovery chemists use expedient routes to prepare compounds. Quantities as small as 10 mg, prepared in the laboratory, allow for in vitro screening. Once a promising compound has been identified, the kilo laboratory may prepare more material to fuel additional studies, including toxicological studies, formulation studies, and perhaps early testing in humans (Phase I). The key is to prepare enough material to enable the scheduled studies. The discovery route is often employed, so any changes that are made are aimed at making larger-scale preparation more practical. For full-scale development, efficient routes are developed in the laboratory and tested in the pilot plant. Material prepared through pilot plant runs will be used for further studies in humans (Phase Il and III) and to develop optimal formulations of the active ingredient into dosage forms. For full-scale manufacturing the optimal route is ideally used. This route considers all factors involved in preparing the drug substance by the most cost-effective means possible.
The appreciation for process R & D is changing. Decades ago the prevailing thought was that large amounts of material could be generated by a process used in the laboratory to produce gram amounts of product, and it was necessary only to use larger equipment. This notion is lampooned in Figure 1.1. Process chemistry was viewed as dull compared to drug discovery. More recently pharmaceutical companies are placing some of their best minds into process R & D efforts, as the significant financial benefits of developing efficient processes are recognized. There is also growing recognition that successful process R & D requires different equipment and different approaches from those used in conventional laboratory work for discovery of active compounds.
TIP: As an analogy to the layman, one may consider the process of baking bread. When more loaves are made from a single batch, efficient mixing of the dough takes longer and may require specialized, powerful equipment. Baking more loaves may require more time and perhaps higher temperatures than that prescribed in a cookbook. For overall baking efficiency, it is not enough to simply buy more loaf pans!
Thorough science is the basis of high-quality process research and development. Practical processes must be developed to reap the rewards of basic research, and without down-to-earth applied research there will be no sustained basic research [9]. For the successful practitioner of applied research, rewards come from the satisfaction of thoroughly understanding a process, successfully carrying out a large-scale operation, and preparing a compound that has been identified as having potential benefits for humankind.
The pharmaceutical industry serves two purposes: to prepare medicinal agents that reliably serve consumers, and to return a financial reward for the investor. Thus pharmaceutical companies operate from a mixture of altruism and pragmatism.
Financial reward is the underlying pressure for today's research in the pharmaceutical industry. Many considerations can have significant impact by acting indirectly through this pressure. For instance, the development of RU 486 by major pharmaceutical companies in the United States was discontinued due to political opposition to the "morning-after pill" [10]. Major pharmaceutical companies have resisted pressure to market birth-control pills to prevent pregnancy as many as three days after unprotected sex [11 ].Vociferous outcries by ACTUP and other groups may have hastened the development of AIDS treatments. A 5-year, $100 million grant to treat AIDS in Africa speaks of altruism-and some feel a desire to develop long-term business contacts [12]. Merck has given away millions of dollars of ivermectin to treat river blindness in Africa [13]. Environmental impacts of chemicals and resulting legislation have curbed the use of solvents and reagents [14]. Continually developing resistance of bacteria to existing medicines promotes the development of new antibiotics [13]. Improving production yields of manufactured products by only a few percent results in significant cost savings. On a more personal level, companies apply various performance pressures, through promotions, raises, bonuses, awards, and perquisites. These pressures are felt down the managerial ladders. Cost-motivated considerations are key in all phases of process research and development.
Productivity during scale-up is therefore a major concern for efficiently getting an active compound to market. In scale-up operations, productivity is related to throughput, the amount of product that can be made per reactor volume per day. Sometimes this is referred to as space-time yield or volume efficiency [15].To increase productivity, conditions are developed to minimize reaction times, streamline operations, and simplify processing.
II. The Importance Of Simple Scale-Up Operations
The reliability of scale-up operations can have a significant impact on cost of the drug substances, and process conditions must be chosen wisely. Processes must provide suitable amounts of high-quality drug substances by or before the prescribed deadlines. If quality is not sufficiently high, additional time and drug substances will be lost through rework, thus increasing cost overall. A rugged or robust process must include three qualities: high-quality product must be prepared within the expected time cycle; the process must accommodate relatively broad purity ranges for the inputs, whether prepared or purchased; and the process must operate within parameter ranges, e.g., temperature and pH, which are readily obtainable during the expected process time cycle. Unless the process is rugged, additional time is incurred, and the quality of the drug substances may be jeopardized. Appropriate in-process controls (IPC) are necessary to maintain low operating costs. Processes must be as simple as possible, but superficially simple (simplistic) processes may be eventually prone to errors.
TIP: In developing processes, process chemists seek elegance in simplicity...
Table of Contents
Foreword by K. Barry Sharpless. Foreword by Jerome L. Moniot. Preface. About the Author. Approaches to Process Development. Route Selection. Reagent Selection. Solvent Selection. Running the Reaction. Effects of Water. In-Process Controls. Optimizing the Reaction by Minimizing Impurities. Optimizing Catalytic Reactions. Work-Up. Tools for Purifying the Product: Column Chromatography, Crystallization, and Reslurrying. Final Product Form and Impurity Considerations. Vessels and Mixing. Preparing for and Implementing the Scale-up Run. Troubleshooting. Chiral Syntheses. General Index. Reaction Type Index. Reagent Index.What People are Saying About This
Foreword by K. Barry Sharpless, The Scripps Research Institute, La Jolla, CA and Dr. Jerome Moniot, Bristol-Myers Squibb
Preface
This book has been developed primarily from my experiences at Bristol-Myers Squibb. The principles discussed are illustrated by examples from the chemical literature, patents, and my personal experience in the laboratory, pilot plants, and manufacturing plants. Many of the guidelines for implementing processes on scale (Chapter 14) were developed by the New Brunswick staff of BMS, and the thoughts there represent many collective years of experience.
I have selected examples from the literature primarily through the middle of 1999. Some reaction schemes are used in several chapters because they provide insights into different areas of process development. The interested reader could consult many of the process papers mentioned in this book for additional examples of successful process R&D. Some tips are repeated in the hope that readers who examine chapters out of sequence will not miss valuable points.