REPORT FOR MANAGEMENT
The Pilot Plant Looks at the Analytical Departments The pilot plant is a key factor in translating research into profitable large scale production. This area of successful commercial chemical development is particularly well placed to see all the facets of the organization and operation of the analytical groups. Here a representative of a pharmaceutical and chemical company reports from the pilot plant view that industry is coming to depend more than ever before on the skill and thinking of the modern analytical chemist
FREDERICK A . BACHER Merck & Co., Inc., Rahway, N. J.
V O L U M E 2 8, NO. 5, MAY
1956
^ ^ N K of t h e dictionary definitions of " c o n t r o l " is " t o keep within limits." I n this sense of t h e word, as earlier reports in this series h a v e thoroughly established, analytical chemists control t h e chemical industry. We all know how often " c o n t r o l " is used in describing t h e functions of analysts—for example, "quality control," " p r o d u c t control," "process control." T h e very name "Chemical Control Division" reveals t h e power wielded b y the main analytical d e p a r t m e n t of Merck & Co., Inc. B u t nowadays analytical chemists m u s t play an active p a r t in blazing a new p a t h as %vell as in keeping industry from straying outside established limits. T h e way t o get maximum, benefit in b o t h kinds of activity from a staff of analysts is still being experimental^'· determined. T h e first part of this report shows briefly t h e main features of t h e plan Merck has developed for using analytical chemists. T h e n come a few principles of guidance, developed through the years in the pilot plant, on relations with analytical chemists. T h e final paragraphs describe our latest a t t e m p t t o come t o grips with pilot plant analytical problems. T h e pilot plant is particularly well placed t o see all t h e facets of the organization of analytical groups at Merck. As p a r t of t h e Research Division, t h e pilot plant deals for the most p a r t with research analytical groups and with its own Pilot P l a n t Control Laboratory. B u t t h e pilot plant often produces material for use outside the company— for example, in support of an extensive clinical research program. These activities bring it in contact with the Chemical Control Division a n d with those analysts otherwise known as p h a r macologists in the Merck I n s t i t u t e for Therapeutic Research.
The main analytical department at the Merck Rahway plant is the Chemical Control Division, "Control" for short. The group of analytical chemists assembled by Control literally controls the movement of materials throughout the several plants of the Chemical Division of Merck & Co., Inc. Finished products, raw materials, and key intermediates are subject to their skill and judgment. Except for analyses of raw materials and certain intermediates, however, Control is not responsible for manufacturing or process controls. Reporting to top management through an entirely separate chain of supervision. Control exercises its judgment unhampered by previous reports to the manufacturing division. As a result of this policy, every final product is tested twice—first by the factory which made it, as part of its process control, and then by Control for final release. The Chemical Control Division's Analytical Research Croup and especially its Quality Standards Department come closest to the pilot plant. These groups give most of their attention to new products, ranging from ultrapure inorganics for the electronics industry to the latest antibiotic. Ultimate responsibility for new product specifications rests with Control. Control's own research groups evaluate and supplement information from the research divisions and other sources for writing quality standards. Analytical Laboratories of Research Divisions
The research divisions maintain a separate group of analytical laboratories, including microbiological assay, physical measurements, elementary microanalysis, and pilot plant control. All 7A
REPORT FOR MANAGEMENT of these laboratories with their special ized, modern equipment inevitably serve the pilot plant, although their main efforts may be turned toward proj ects which may not get into production for several years, if ever. An especially important analytical service, frequently but erroneously classified otherwise, is given the pilot plant by the pharmacology group in the Merck Institute for Therapeutic Re search. Often in the early stages of a new product, no amount of chemical testing can replace the comfortable knowledge that toxicity and efficacy have been checked in animals. From the pilot plant point of view, the "analytical department" is mul tiple, almost all large subdivisions in the scientific area having an analytical group. This seldom leads to duplica tion because their regularly assigned problems are different. Their combined potential is high, however, as was demonstrated a few months ago when all were assigned the same problem. We needed within one week a method of detecting a potent veterinary drug at the level of 10 parts per billion in mixed animal feed. Ten parts per billion of anything, even in water, is bad enough, but the interference in mixed feeds made it seem hopeless. After a brief liaison meeting to rough out approaches and avoid identical experiments, all parties retired to their benches. Five days later, not one, but three feasible methods were in hand. The crisis was over, and, after a little polishing of procedures, each laboratory returned to its regular work. This example teaches the lesson of speed. It goes without saying that accuracy must be kept uppermost. Nevertheless, delay is usually costly and delay at the pilot plant stage in the highly competitive, fast-moving phar maceutical manufacturing industry can spell the difference between success and failure. Pilot plant production must move on schedule, but too often the time needed for testing is depressingly longer than a production man's dream. Part of the problem of speeding pilot plant operations can be solved by the tricks and tools of modern analysts— recording spectrophotometers, titrators, and the like. But the pace and variety of Merck pilot plant operations far out strip the automation experts' develop ment of specialized instruments. The best solution is to have adequate and generally accepted specifications and test methods ready. If the tests them selves can be carried out in a short time, so much the better. Each product pre sents a different set of problems and the best way of getting adequate control of V O L U M E 2 8, N O . 5, MAY 1 9 5 6
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world standard
a new product with minimum delay has probably not yet been found. Some principles are clear, however. 1. The analytical department is going to have the last word anyway. 2. Get an analyst into the problem early, so he will be ready with some answers when a new product is ready. 3. Analytical chemists sometimes have very good ideas. Many experts, especially analytical chemists, maintain that solving the analytical problem is three quarters of the job. The development chemist is at a loss to improve yield and reduce costs until the criteria for his product are known. Development problems and even so-called research problems often dissolve into routine application of statistical design of experiments, once the fundamental analytical re search has been completed. Discoveries made in attempting analysis often change the whole com plexion of a problem. An analyst was toying with methods of assay for a promising new drug. He found a new solvent for the hitherto almost insoluble substance. This observation made pos sible a research program which showed first that the new drug, although syn thetic, did not have the assigned struc ture and secondly that the drug was only one member of a new class of molec ular complexes. The original drug was replaced by a more potent, less expensive analog. Chicken raising today shows less risk and more profit because an analyst had his eyes open and shared what he saw with the rest of the team.
FISHER ^g£ φ ELECTROPHOTOMETER
...for colorimetric determinations • COMPACT • PRECISE • SELF C O N T A I N E D Biochemical determinations, chemi cal analyses and physical tests are simple as A-B-C with the Fisher Electrophotometer. Accurate colori metric analysis is quick and easy wherever solution color varies in a definite manner with the concentra tion of a constituent. Use it anywhere;line voltage fluctuations won't interfere.
Analytical Groups as Consultants An obvious administrative way of getting the most from analytical chem ists is to put one on each research team. But there simply are not enough trained analysts to go around. As a result, Merck research analytical groups work most effectively as consultants.
A 50-page manual of typical meth ods, and other useful data, is fur nished with the Electrophotometer.
The most recently organized consult ing laboratory, the process controls group, brings to bear a point of view slightly different from other analytical groups. Here is a little fable to show how this and other groups help bring a product through fundamental and developmental research to the pilot plant. A Fable. Let us suppose a new syn thetic drug has been discovered which gives promise of curing all known diseases. Because this is not the first promising drug and its chemical name is inconveniently long, it was named mesoheelol. By the time its wonderful medicinal properties were discovered, of course, a few bits of analytical data
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