Practical Process Research and Development

A guide for Organic Chemists

Neal G. Anderson

• Publisher: Academic Press
• Year: 2012
• eBook ISBN: 9780123865380
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Inorganic Chemistry

Designed to provide a comprehensive, step-by-step approach to organic process research and development in the pharmaceutical, fine chemical, and agricultural chemical industries, this book describes the steps taken, following synthesis and evaluation, to bring key compounds to market in a cost-effective manner. It describes hands-on, step-by-step, approaches to solving process development problems, including route, reagent, and solvent selection; optimising catalytic reactions; chiral syntheses; and "green chemistry."Second Edition highlights: • Reflects the current thinking in chemical process R&D for small molecules• Retains similar structure and orientation to the first edition. • Contains approx. 85% new material• Primarily new examples (work-up and prospective considerations for pilot plant and manufacturing scale-up)• Some new/expanded topics (e.g. green chemistry, genotoxins, enzymatic processes)• Replaces the first edition, although the first edition contains useful older examples that readers may refer to- Provides insights into generating rugged, practical, cost-effective processes for the chemical preparation of "small molecules"- Breaks down process optimization into route, reagent and solvent selection, development of reaction conditions, workup, crystallizations and more- Presents guidelines for implementing and troubleshooting processes

Chapter 1

Introduction

Chapter Outline

I. Introduction

II. Equipment Considerations on Scale

III. Operations Preferred on Scale

IV. Patent Considerations

V. Summary and Perspective

References

The pharmaceutical industry develops medicines that maintain or improve the health and the quality of life for people, while providing a reasonable return for investors. The many unknowns of the business make for a high-risk environment, yet the rewards are high. Processes must be fit for purpose, that is, suitable for the current needs. Different depths of process knowledge and amounts of chemicals are needed depending on the stage of development of a drug candidate (new chemical entity or NCE) as it progresses to becoming a drug substance (active pharmaceutical ingredient or API) in a drug product. Guidelines for preparing toxicology batches are discussed. The capabilities and limitations of scale-up equipment are compared with routine laboratory operations. Batch, semi-batch, semi-continuous, and continuous operations are introduced. Efficient, cost-effective processes are developed through considering the factors of safety, environment, legal, economics, control, and throughput (SELECT). To speed the development of a drug candidate, process chemists and engineers must be adaptable and understand some of the needs of scientists involved in other aspects of drug development.

“The world doesn't move because of idealism…. [i]t moves because of economic incentives.”

– Fernando Canales Clariond, formerly Mexico's secretary of the economy [1]

“It is well-known that there are no technical optima in industry, only economic optima….”

– G. Guichon et al. [2]

“Today, green chemistry is simply a good business choice.”

– Paul Anastas [3]

I. Introduction

The driving forces of the pharmaceutical industry are to develop medicines that maintain or improve health and the quality of life for people, and to provide a reasonable return for investors. The many unknowns of the business, especially our imperfect understanding of biology, make for a high-risk environment. Yet the rewards are high as well. In Table 1.1 are presented some statistics associated with developing drugs, and these statistics explain some of the pressures of the business.

Significant financial gains are possible by developing drugs, as indicated by the penalties and fines levied against firms and people recently. For instance, in 2010 AstraZeneca was fined $520,000,000 for promoting Seroquel for off-label uses [4] and GlaxoSmithKline was fined $150,000,000 for violations of current Good Manufacturing Practices (cGMPs) [5]. In 2009, Pfizer was fined $2,300,000,000 for illegally promoting Bextra and three other medications [6], and Bristol–Myers Squibb (BMS) was fined $2,100,000 for making agreements with Apotex to delay the launch of generic Plavix [7]. In 2009, the FDA stopped reviewing applications from Ranbaxy and prohibited Ranbaxy from importing 30 generic drugs, due to falsified QC data [8]. In 2007, a former top official of China's state organization approving drugs was executed for taking bribes [9]. In 2004, BMS was fined $150,000,000 for “channel stuffing,” an accounting practice that artificially boosted the sale of drugs [10]. The reputation of the pharmaceutical industry has been sullied over the past few decades, but many people, including this author, enter this industry because they want to be able to help others.

TABLE 1.1

Some Statistics Relevant to the Pharmaceutical Industry

Value	Factor
$1,300,000,000	Cost to bring a drug to market (1)
5–20% of drug product price	CoG of API
30% of the CoG for drug product	Cost of QC (2)
Millions of dollars	Cost of failed drug formulation (3)
As high as market will bear	Price of drug product to consumer (higher for US than for most countries) (4)
$75,000	The value of one additional year of life, set in 2005 by health economists (5)
$200,000–$300,000	Annual cost of US chemist or engineer for an employer
About 95%	Portion of drug candidates that fail in pre-clinical or clinical studies
About 30%	Portion of approved drugs that recoup development costs (6)
8 years	Average time of development (goal is 5 years)
20 years	Period for exclusive sales of a patented drug (US)
20 – Development time	Years to recoup investment costs
$1,000,000	Sales lost for every day that a filing is delayed, if drug sales are $400 MM/year

⁽¹⁾ Undoubtedly includes the cost of advancing drug candidates that failed. Jarvis, L. M. Chem. Eng. News 2010, 88(23), 13. May be higher: Vertex developed Incivek (telaprevir) over 20 years at the cost of around $4,000,000,000: Jarvis, L. Chem. Eng. News 2011, 89(22), 8.

⁽²⁾ Mullin, R. Chem. E...

Table of contents

• Cover image
• Title page
• Table of Contents
• Dedication
• Copyright
• About the Author
• Preface to Second Edition
• Foreword
• Chapter 1. Introduction
• Chapter 2. Process Safety
• Chapter 3. Route Selection
• Chapter 4. Reagent Selection
• Chapter 5. Solvent Selection
• Chapter 6. Effects of Water
• Chapter 7. In-Process Assays, In-Process Controls, and Specifications
• Chapter 8. Practical Considerations for Scale-Up
• Chapter 9. Optimizing Processes by Minimizing Impurities
• Chapter 10. Optimizing Organometallic Reactions
• Chapter 11. Workup
• Chapter 12. Crystallization and Purification
• Chapter 13. Final Product Form and Impurities
• Chapter 14. Continuous Operations
• Chapter 15. Refining the Process for Simplicity and Ruggedness
• Chapter 16. Process Validation and Implementation
• Chapter 17. Troubleshooting
• Glossary
• General Index
• Reactions Index
• Reagents Index
• Drug Substance Index