Penicillin: A Paradigm for Biotechnology

Paperback  114 Pages  ISBN 1891545019      £25.00

Contents

The History of Penicillin Production

• Foreword
• Introduction
• The Role of the Government in the Penicillin Program
• The Development of Penicillin Strains
• The Evolution of Penicillin Manufacturing Processes
• Deep Tank Fermentation
• The Recovery of Penicillin by Extraction with a pH Gradient
• Centrifugal Solvent Extraction
• Freeze Drying
• The New Semisynthetic Penicillins
• The Importance of Innovation
• Meeting the Objective
• The Engineer and the Biologist

• Penicillin Update: Industrial
• Penicillin Biochemistry and Genetics

The implementation of large-scale production of penicillin in the early and mid-1940s was a major technological accomplishment. Not only was a remarkably effective life-saving drug produced, but this technology opened the way for the production of a succession of other important antibiotics and other valuable chemicals.

Although more than fifty years have passed since penicillin was first produced in volume, the biochemical engineer of today would immediately recognize the production plant and equipment used then: the stirred aerated reactor is still the standard; air is still sterilized by filtration; and the product is recovered by solvent extraction. In fact, the questions posed by Albert L. Elder in his December 29, 1943, memorandum to producers of penicillin could still usefully serve today as a check-list in developing an industrial fermentation.

In a number of instances, the unit operations developed and applied to penicillin production represented "firsts".

Penicillin was the first important commercial product produced by an aerobic, submerged fermentation. Acetone-butanol, which was a major product produced during and after World War 1, was produced in an anaerobic system and did not pose the oxygen transfer and heat transfer problems of the penicillin fermentation. In the 1930s, citric acid was produced by aerobic fermentation, but by surface fermentation in shallow trays and not by submerged fermentation in agitated deep tanks.

The instability of the penicillin molecule under acidic conditions and its low concentration in the fermentation broth required the development of extraction equipment that could efficiently contact the aqueous penicillin-containing broth with the water-immiscible extraction solvent, and then rapidly separate the two phases. This permitted rapid extraction of the penicillin from the acidified aqueous phase and rapid neutralization of the penicillin-rich solvent so as to minimize acid degradation of the penicillin. The multi-stage counter-current contactor developed by Walter Podbielniak for this purpose enjoyed wide usage for penicillin production, and for other systems as well.

The application of commercial scale lyophilisation (freeze drying) to penicillin opened the door to the use of this technique for the drying and preservation of sensitive biological products in general. This technique continues to this day to be a standard method for the preservation of bulk and sterile dosage forms of antibiotics and other small molecules, as well as many protein biologics, e.g., insulin, tissue plasminogen activator (tPa), human growth hormone.

The strain improvement technique of treatment with a mutagen followed by testing and selection is followed profitably to this day. Although techniques of genetic engineering are of use, they have supplemented rather than replaced the "classical" methods applied so effectively to Penicillium chrysogenum and many other organisms since.

When I first encountered "The history of penicillin production" in the early 1970s, I found it a fascinating tale of technology. Based on a 1966 symposium and written in large part by the scientists and engineers who were key participants in developing and applying the technology in industry, the slim volume was one that I returned to numerous times. As a teacher of biochemical engineering and applied microbiology at M.l.T., Hebrew University, and the University of Pennsylvania, I recommended it as background reading for my students. I believe that even today, anyone with an interest in biotechnology or industrial microbiology could profitably and pleasurably peruse this volume, which has been out of print. It has been a pleasant self-imposed duty to bring the book into print again, and through the collaboration with several scientists and engineers from industry and academe to bring the penicillin story to the present.

I would like to acknowledge the American Institute of Chemical Engineers for permission to reprint "The history of penicillin production," which was Number 100, Volume 66, 1970, of the Chemical Engineering Progress Symposium Series.

A.L. Demain, E. De Vroom, R.P. Elander, J. Krijgman, J.F. Martin, C. Oldenhof, and H.J.M. Van Nistelrooij kindly contributed chapters to bring the original volume to the present. Important information on the current production and consumption of penicillin and its derivatives was contributed by Michael Barber & Associates.

Jeff Karr, the Archivist of the American Society of Microbiology, willingly helped me search for biographical information and made available data from the Society's files to help complete the short biographies of the contributors to the original book.

Richard I. Mateles
Chicago, Illinois
August, 1998