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 part icularly well placed to see all the facets of the organizat ion and operation of the analyt ical 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 analyt ical chemist

FREDERICK A. BACHER

^ ^ N K of the dictionary definitions of "control" is " to keep within l imits ." In this sense of the word, as earlier reports in this series have thoroughly established, analytical chemists control the chemical industry. We all know how often "contro l" is used in describ­ing the functions of analysts—for example, "qual i ty control ," "product control," "process control ." The very name "Chemical Control Division" reveals the power wielded by the main analytical depar tment of Merck & Co., Inc .

But nowadays analytical chemists must play an active pa r t in blazing a new pa th as %vell as in keeping industry from straying outside established limits. The way to get maximum, benefit in both kinds of activity from a staff of analysts is still being experimental^'· determined. The first part of this report shows briefly the main features of the plan Merck has developed for using analytical chemists. 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 a t t empt to come to grips with pilot plant analytical problems.

The pilot plant is part icularly well placed to see all the facets of the organ­ization of analytical groups at Merck. As par t of the Research Division, the pilot plant deals for the most par t with research analytical groups and with its own Pilot P lan t Control Laboratory. But the 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 and with those analysts otherwise known as phar­macologists in the Merck Ins t i tu te 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

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Merck & Co., Inc., Rahway, N. J.

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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 Merck 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 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 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 analysts— recording spectrophotometers, titrators, and the like. But the pace and variety of Merck 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

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 re­search has been completed.

Discoveries made in attempting analysis often change the whole com­plexion 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 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 as 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, Merck 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 to the pilot plant.

A Fable. Let us suppose a new 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 was named mesoheelol. By the time its wonderful medicinal properties were discovered, of course, a few bits of analytical data

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were already available. Measurements made by or at the request of the funda­mental research team gave us a frame­work for chemical control of mesoheelol. At this stage the development team took over. At the same time the physical chemistry and analytical re­search groups were designing methods for studying stability, for assaying pharmaceutical formulations, and for controlling the final product.

The process controls group was called in when the development team found yield variations apparently unrelated to reaction conditions. After 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 at this point were close pH control of the re­action mixture and melting point of the penultimate intermediate. In studying the final hydrogénation to produce mesoheelol, 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. As a result, hydrogénation time was cut fi'om 17 hours to 2 hours, leaving 0.5% unhydrogenated to be removed by final recrystallization. The quality stand­ards group was informed of this process change and added a maximum absorp­tion limit at 342 ταμ 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 tests. Mesoheelol 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 known 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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