Barbara H. Munk

The big leap

After more than two decades of school, it is finally time for you to venture out into the big wide world! Now what? Will you choose a traditional path, such as becoming a professor in academia or a research scientist in industry? Maybe instead you will pursue an alternative path within academia or business. How much will income level affect your thinking? Generally speaking, initial academic compensation will be lower than industry pay. Or possibly you will decide not to move immediately to outside employment, instead shifting your focus to a few more years of schooling, from a PhD to a postdoc or from one postdoc to another, or perhaps to become a patent attorney or to add a medical degree to your MS or PharmD or PhD. What an exciting time of your life this will be, but you will do well if you apply yourself. Remember, “the difficult we do immediately—the impossible takes only a little longer.”

Research and discovery

In this section, we have provided readers, including practitioners, students, and other interested parties, with perspectives on biotechnology, drug discovery, medicinal chemistry, pharmaceuticals, and pharmacology. Coverage of such an important business and research and development sector, so complicated, so expansive, and so expensive, can only be superficial in a treatise of any size. Leading references cited herein provide starting points for deeper dives. Other sections in this book cover key aspects of undergraduate, graduate, and professional training for careers in biomedical research and development. The final section addresses chemical development, manufacturing, and the path toward commercialization. Whether you are a clinician, a designer, an enzymologist, an organic chemist, a pharmacist, or a systems engineer, by now you should have gotten the picture that the healthcare sector and the biotech/pharma industry have jobs for you. If drugs are your medicines of choice to develop, remember that you must move from ideas into basic research, through discovery, and you must survive the rigors of preclinical and clinical development. Altogether you should expect 10+ year timelines. Some practitioners—even if they are true artisans—never see the fruits of their labors marketed during their lifetimes, primarily because of high rates of attrition. Even if they haven’t seen a drug to market, no doubt they have given the next drug hunter a head start. So many lives depend on us making the impossible possible. Unless we find a means to deal with the scourges of old age, like Alzheimer disease, it has been said that nations including the United States could struggle with bankruptcy by mid-century. We are depending on you to make a difference, discovering new affordable “billion dollar drugs” that prolong countless lives. Just one life saved is a miracle. Do it from an academic perch, advancing our basic understanding of disease and molecular mechanisms and pathways. Do it from a start-up venture as a founder or the first employee, making something out of nothing, the definition of an entrepreneur. Do it from an organic chemistry lab, designing and synthesizing novel blockbusters. Do it from a manufacturing plant. But please do it—we are counting on you!

Drug discovery: Standing on the shoulders of giants

We sit here today perched atop the shoulders of giants. Giants of medicinal chemistry and pharmacology who toiled hard, making and testing one compound each week, a very well-developed process when drug design utilizing computer graphics first came on the scene in the late 1970s. Preclinical development disciplines, including pharmacokinetics, drug metabolism, and toxicology, were also well in place by then. But soon a series of technological advances would rock the drug discovery world, with quantum leaps in the state-of-the-art, changing the face of drug discovery forever. This revolution included the preparation and high-throughput screening of larger and larger drug libraries, large-molecule biologics to compete with small-molecule drugs, and genomics and proteomics, thereby dramatically increasing the information available to drug hunters. But revolutions take time to settle in. As “Drug Discovery 2001: A Molecular Space Odyssey” dawned, pundits thought genomics would solve major healthcare problems overnight, relegating traditional pharmaceutical R&D methods to the waste bin. Reality prevailed and decades of iteration remain before genomics’ economic and social impact will change behavior fundamentally, nationally and internationally. Meanwhile, immuno-oncology moved cancer beyond “dying from” or “living with” to outright “cures” in selected cases. Resulting biotech financings and deals generated huge funds for R&D, employees, and investors, and importantly made possible new medical products for patients and caregivers, greatly improving the standard of care. Though today’s grand progress provides novel therapies to those in need, we still require the tools of neo-classical chemical biology—structure-based design, combinatorial synthesis, and high-throughput screening—along with the old-fashioned, laborious, one-drug-at-a-time art of science circa 1990. Biologics have made big headway into medical practice, saving countless lives and contributing greatly to industry profits, but small-molecule drugs still dominate scrips. Sadly, diminishing numbers of students will work the long, hard hours essential to mastering chemistry or pharmacology. Too many seek quick wins. For some it is about money. For others it is about achievement, adventure, and intellectual challenge. Finally, and most importantly, it is about helping others. Nothing feels better than “doing well by doing good.” Brilliant, dedicated scientists, please, make good health and longevity the norm. Pity the societies that don’t get this right!

Backgrounder: Medicinal chemistry: Research, discovery, art, science

This chapter will provide an introduction and overview to this book, covering biotechnology and pharmaceutical research and development at a high level from a medicinal chemist’s perspective. Our dialog will span topics including but not limited to healthcare-related education, research, discovery, development, and supporting technologies. We will familiarize readers with viewpoints that are grounded in the art and science of practitioners of medicinal chemistry, pharmacology, drug discovery, biotechnology (biotech), and pharmaceutical (pharma) sciences. To begin with, recognize that moving the biotech/pharma ideas from research to market can take decades. Proteins may move faster than small molecules; regardless, many individuals never see their ideas reach clinical trials. Then again, many of us have seen our contributions make a big difference in people’s lives. Historically, a bond forged between medicinal chemists and pharmacologists was essential. Not unexpectedly, as science advances, the key players are evolving. Whatever the disease and whatever their backgrounds, drug discovery scientists are still center stage, passionate about solving technical challenges, creating new products, and driving projects to success. Wouldn’t you feel good if “your” drug saved lives? Generations of drug hunters have led the way—witness early antibiotics like penicillin, and fast forward to lipid-lowering statins, huge winners. But have we lost our way with drugs priced

Chemical development: Analytical studies

1000 per pill? This too shall pass, because good health is so important, even if considered by some to be an entitlement that should be free. Biotech public offerings and pharma licensing deals have never been hotter, though ups and downs are inevitable. To make sense of all this, you only need one good idea… If you are doing good things, keep doing them until good things happen—they will.

Master’s degree programs

The analytical techniques used to fully characterize the active pharmaceutical ingredient are very important topics to address. While simple spectroscopic techniques and elemental analyses are sufficient in a medicinal chemistry laboratory, regulatory agencies require a much more elaborate data set to characterize a drug molecule for the registration of a drug. In this chapter, we explore the analytical studies required to validate a test method, test for impurities, to identify the polymorphic structure of the drug, and ensure stability of the drug throughout its life cycle.

FDA path and process: Sponsor‘s regulatory tasks for drug approval

So, you want to be a part of a drug hunting enterprise? Congratulations—saving lives is addictive! Most likely you will follow traditional educational routes, even in an age of creative destruction and innovation. Training in liberal arts is important, but if you plan to practice chemistry, study chemistry. Patent attorneys are another variation on the technical theme. The higher your degree, the more alternatives you are likely to have. The later the stage of your work, the more you will benefit from knowledge of project management and regulatory affairs. To practice medicine, you need a medical degree, but consider allied professions including pharmacy and nursing. People good at translating biology to chemists or vice versa, or similarly between the sciences and medicine or business, can be especially valuable team members and leaders. While chemical and biomedical training dominates laboratory-based biotech/pharma research and development divisions, economics and other financial degrees or sales and marketing experience are more common in business and operations. Ethics surfaces too, especially when patients are involved. Given a cast of thousands from idea to market, there must be a good role for you to play, whether it’s with a Master of Business Administration, a Master of Public Health, or one of the several possible Master of Science programs! And lifelong learning will be essential. From all of these perspectives, a Master’s degree may be just the right degree for what you want to do and what biotech/pharma research and development needs.

Two-year certification and degree programs

In this chapter, we review the major “modules” or parts of the New Drug Application covering the “drug substance” that are written by the Chemical Development team. The Common Technical Document follows the International Council on Harmonisation prescribed format and describes all elements in the manufacture of the drug substance including the chemical process, analytical methods, characterization of all relevant materials including impurities, and requirements of the cleaning processes. A well-organized and complete Common Technical Document permits effective review by both US and international agencies of the application for approval to market the drug.

Graduate and postgraduate education at a crossroads

In this chapter, we discuss career opportunities for technical support staff who play a key role in the development of new medicines. Job responsibilities, certificate programs, and 2-year academic degree programs for laboratory technicians, pharmacy technicians, and veterinary technicians are reviewed, and helpful links to key accreditation sites are provided. We conclude by reminding our readers of the need to be watchful of “degree mills”—organizations which promise a lot but deliver little, often at great expense.

Doctoral and professional programs

In this chapter we introduce the proverbial crossroads we have reached in graduate and postgraduate education and jobs. Many factors are at play, including an explosion of information, available now, at your fingertips, a move away from memorization toward critical thinking, the importance of learning by doing, and what has been called “the gathering storm.” Core drug discovery disciplines are discussed, such as medicinal and organic chemistry, especially in the context of academia–industry symbiosis. Challenges in making sure we continue to assemble the best and the brightest to tackle important biomedical problems are considered. Finally, we scratch the surface of how to navigate employers, employment, and careers.