Plant Looks at the mnaiyricai ueparrmenrs ilot 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
ONE
A. BACHER Io,,wv,
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V O L U M E 28, NO. 5, M A Y 1 9 5 6
of the dictionaiy definitions of “control” is “to keep within limits.” In this sense of the word, &s earlier reports in this series have thoroughly estabkhed, analytical chemists control the chemical industry. We all know how often “control” is used in desciibmg the functions of analysts-for example, “quality control,” “product control,” “process control.” The very name “Chemical Control Division” reveals the power wielded by the main analytical department of Rferck & Co., Inc. But nowadays analytical chemists must play an active part in blazing a new path as well as in keeping industiy from straying outside established limits. The way to get maximum benefit in both kinds of activity from a staff of analysts is still being experimentally determined. The first part of this report shows briefly the main features of the plan Merck has developed for using analytical chennsts. Then come a few principles of guidance, developed through the years in the pilot plant, on relations with analytical chemists. The final paragraphs describe our latest attempt to come to grips with pilot plant analytical problems. The pilot plant is particdaily well placed to see all the facets of the organization of analytical groups a t Merck. As part of the Research Division, the pilot plant deals for the most part with research analytical groups and with its own Pilot Plant Control Lahoiatoiy. But the pilot plant often produces material for use outside the companyfor example, in support of an extensive clinical research program. These activities bring it in contact with the Chemical Control Division and with those analysts otherwise known as pharmacologists in the Merck Institute foi Therapeutic Research.
The main analytical department a t 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 Group 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 snpplement infoimation 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 1A
Among chemists, t h e morning coffee-break is a well-established custom. During these informal symposia many worth-while data are exchanged. W e should like to sit in and tell you about some o f our 1,000 plus MERCKLABORATORY CHEMICALS. :JNIVERSAL ORGANIC SOLVENT
DIMETHYLFORMAMIDE MERCK,like money, has unusually wide appeal. Its low evaporation rate and ability to lure complex organics into solution have made it popular with all kinds of chromatographers. Feed Chemists on the other hand report Dimethylformamide is frankly indispensable in the determination of NiCarbazin, a new type of drug used to prevent coccidiosis in poultry. Also, protein chemists are intrigued-finding Dimethylformamide with its high dielectric properties dandy as a reaction solvent for amino acids. In fact, if it’s organic and tough to dissolve, reach for the Dimethylformamide and watch your fingers, Doctor! Skeptics should send for our technical data sheet. PULL-DOWN POWER
This is one for the biology boys. Trichloroacetic Acid’s major claim to fame is its ability to precipitate protein. So if you are looking for albumin in urine or non-protein
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This use of Methylene Chloride Spectro Grade will not make a hit with the stockroom guardians but we mention it solely for the romantically inclined, Every so often some histologist or realizing that speed is sometimes of the pathologist gets to wondering if the essence. Of course, what really makes tissue he’s looking a t under his micro- this Merck reagent attractive to specscope really contains fat. If doubt per- trographers is its superior transparency sists, a small bit of tissue is dunked in a a t wavelengths below 270 mp.This key MERCK advantage plus solvent properties that solution of OSMIUMTETROXIDE REAGENT and the fat comes up black. parallel chloroform without phosgene This proves that the cells contain fat formation, and a b.p. (4OoC)lower than and not some artifacts due to poor fix- chloroform makes it obvious why more ing technic. Other familiar uses include and more of you are reaching for METHhydroxylating lonesome double bonds Y L E N E CHLORIDEMERCKSPECTRO and catalyzing certain oxidations with GRADE. ceric sulfate. (A well-known example is speed-up of the balky reaction between MERCK arsenious acid and ceric sulfate.)OsMIUM L A B ORATORY TETROXIDE MERCKREAGENT is “the CHEMICALS most,” but keep its vapors out of eyes,
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of these laboratories with their specialized, modern equipment inevitably serve the pilot plant, although their main efforts may be turned toward projects 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 hlerck Institute for Therapeutic Research. 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 multiple, almost all large subdivisions in the scientific area having an analytical group. This seldom leads to duplication 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 lvithin 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 t o rough out approaches and avoid identical experiments, all parties retired to their benches. Five days later, not one, but three feasible methods mere 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. Severtheless, delay is usually costly and delay a t the pilot plant stage in the highly competitive, fast-moving pharmaceutical 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 analvstsrecording spectrophotometers, titrators, and the like. But the pace and variety of Rlerck pilot plant operations far outstrip the automation experts’ development of specialized instruments. The best solution is to have adequate and generally accepted specifications and test methods ready. If the tests themselves can be carried out in a short time, so much the better. Each product presents a different set of problems and the best way of getting adequate control of V O L U M E 28, N O . 5, M A Y 1 9 5 6
a nelv 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, EO 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 a t 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 research has been completed. Discoveries made in attempting analysis often change the whole complexion of a problem. An analyst mas toying with methods of assay for a promising new drug. He found a new solvent for the hitherto almost insoluble substance. This observation made possible a research program which showed first that the new drug, although synthetic, did not have the assigned structure and secondly that the drug was only one member of a new class of molecular 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. Analytical Groups a s Consultants
An obvious administrative way of getting the most from analytical chemists is to put one on each research team. But there simply are not enough trained analysts to go around. As a result, 1Ierck research analytical groups work most effectively as consultants. The most recently organized consulting 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 t o the pilot plant. A Fable. Let us suppose a nen- synthetic 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 mas named mesoheelol. By the time its wonderful medicinal properties were discovered, of course, a few bits of analytical data
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The process controls group was called in when the development team found yield variations apparently unrelated t o ieaction conditions. $fter consultation. an assay emerged to distinguish the two isomers of a key intermediate. Using this assay it was discovered that the only process controls needed a t this point were close pH control of the reaction mixture and melting point of the penultimate intermediate. In studying the final hydrogenation to produce niesoheelol, the process controls group devised a simple ultraviolet test to find how much unhydrogenated intermediate remained. The development team confirmed the analysts’ finding that the unhydrogenated intermediates could be readily removed by crystallization. -4s a result, hydrogenation time was cut from l i hours to 2 hours, leaving 0.57, unhydrogenated to be removed by final recrystallization. The quality standaids group was informed of this process change and added a maximum absorption limit a t 342 mp to ensure removal of this possibly objectionable impurity.
By this time the pilot plant had built up a supply of intermediates and the final reaction was run. The product passed all chemical controls, in both the pilot plant and control division laboratories, as well as animal safety testy. llesoheelol was sent on for extensive pharmacological and clinical study. The progress report that carried news of this accomplishment also carried a brief optimistic paragraph from fundamental research about a new discovery, to be knoivn as neoheelol. This fable gives some idea of the functions of the various groups as seen from the pilot plant. For greatest flexibility the pilot plant needs rapid and foolproof methods. But powerful techniques and elaborate apparatus are behind many of the apparently simple tests. Analytical chemists today are combining the progressive methods of all fields of science with their own traditional conservatism. This paper illustrates from the point of view of the pharmaceutical pilot plant how industry is coming to depend more than ever before on the skill and accurate thinking habits of the modern analytical chemist.
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