Pfizer Looks at Analysis and Quality Control

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REPORT FOR

A New Analytical

Feature

MANAGEMENT

The role of analysis has grown increasingly important in the chemical process industries. In research, manufacturing processes, and quality control of products, the analyst has sparked phenomenal developments in new techniques and in the application of instrumentation. Because these advances have brought many benefits and also because much larger sums of money are being spent in the fields of analysis and control, management at all levels is more a w a r e of the role of the analyst. Yet in many ways there is need for better understanding of the over-all relationship of analysis în the o p e r a tion and management of a company. Consequently the editors of ANALYTICAL CHEMISTRY have planned a series of articles under the general heading "Report for Management." Beginning this month the articles will d e a l with management views of the* various questions associated with the operation of analytical departments and their relationships to other phases of company activities. The series will be authored by a top-flight group of men in positions to speak authoritatively.

JOHN E. McKEEN President and Chairman of the Board Chas. Pfizer & Co., Inc.

Pfizer Looks a t Analysis and Quality Control HiLIGH over the entrance to the administration building at Pfizer's Brooklyn plant is embossed a king-sized replica of the company seal. Its blue background stands in sharp relief to the red brick of the building and is a natural focal point. The gaze of one recent visitor, in fact, was drawn so irresistibly to the seal that he facetiously called it a "great unwinking eye." His phrase making was more apt than he knew, for apart from the corporate name, there is only one other word on the seal.

That word is "quality," an attribute that the Analytical Department guards as jealously in Pfizer products as if it were indeed a great unwinking eye. Thus, in the Pfizer philosophy, product quality and the Analytical Department are inseparably intertwined. That this philosophy has been more active than speculative shows in the record of the past 15 years. In 1940, the Analytical Department employed only six people; today, exclusive of control chemists and inspectors within each

V O L U M E 2 7, NO. 1 1 , N O V E M B E R

1955

production department, its roster includes more than 120 and has been expanding considerably faster than the Pfizer payroll as a whole. In 1940, the department ran an average of about 1100 tests a week; this week it will write nearly three times that number into its test notes. So large does the Analytical Department figure in the Pfizer philosophy, in fact, that all new production engineers are assigned to 2 weeks of study there before moving on to the posts for which 11 A

REPORT FOR M A N A G E M E N T

they were hired. This procedure, also followed with the sales staff, offers several important advantages. It impresses new men with the need for quality, underscores the fact that quality is indeed everybody's business, and, by placing them at what is truly a nerve center of the company, gives them an opportunity to become familiar with the raw materials that Pfizer uses and the entire line of products it produces. Pfizer's preoccupation with quality and quality control stems from a double root. The Pfizer seal is a guarantee that the company's industrial chemicals will live up to specifications. It is also a guarantee that the antibiotics, the vitamins, the hormones which the company manufactures will do what they are supposed to do—help the physician cure his patient. Morally there can be no greater compact than this, for life has not been laid in our hands to be treated lightly. Like most ethical considerations, this has a practical corollary. Essentially, a good reputation is based on quality and can spell the difference between growth or stagnation and, ultimately, even the fall of the auctioneer's hammer. A manufacturer who does not literally sweat over quality is unwittingly presiding over his own liquidation—and rightly so. Nowhere has this been better realized than in American mass production and particularly in the drug industry. In adapting our technology to their own needs, manufacturers overseas could pay us no higher form of flattery than to imitate our methods of statistical quality control. For the motto that "the cheapest thing to do with an unsatisfactory product is not to make it," is truly good business, as the Pfizer record—and the industry's—demonstrates. Thanks in part to the insurance provided by the Analytical Department and quality control, Pfizer's sales since 1945 have expanded from $27.5 million to $145.2 million. Given this kind of growth, the department has had to cover a lot of ground. Broadly, it is charged with: Developing and approving specifications of crude and finished materials for company-wide use Developing and publishing standard analysis and sampling techniques at all plants Providing technical supervision of analytical departments at all plants Providing analytical services and devising new test methods for research and development groups Organizing and staffing the headquarters Analytical Department and collaborating with other plant superintendents in the selection and training VOLUME

of Analytical Department personnel for both domestic and foreign operations Handling and satisfying customer product complaints Liaison with government control laboratories Maintenance of test notes on product batches In addition to its main plant at Brooklyn, Pfizer also manufactures at Groton, Conn., and Terre Haute, Ind. The Brooklyn and Groton installations produce a wide variety of industrial chemicals, antibiotics, vitamins, and steroids. At Terre Haute, in addition to antibiotics, Pfizer makes Vigofac, an animal growth factor, and other antibiotic and vitamin-fortified animal feed supplements. Analytical Department heads at all three plants report to the director of the department. The latter, through his assistant at Brooklyn, by far the largest of the company's control facilities, supervises the department's nine sections: antibiotics production, bulk chemicals, steroids, raw materials, analytical research, special testing, vitamins, office personnel, and product evaluation. Specifications for n e w products

More specifically, one of Analytical's key functions is to develop specifications for new products. In this area, the department has been kept busy, for last year, products not in existence in 1940 generated more than 80% of Pfizer's sales. In the past 3 years alone, the company has developed and brought to market 15 new major products in an even wider variety of dosage forms. All were turned out by one of the three methods around which Pfizer production revolves: fermentation, organic synthesis, and fermentation and synthesis combined. Long before it gets to the specification stage, however, the Analytical Department more often than not has been hard at work developing new tests for research. Thus, before Pfizer could begin producing streptomycin, for instance, Analytical devised methods which enabled research to differentiate streptomycin A from streptomycin B, and so helped to establish the salient fact that the former is far more active biologically than the latter. Development of assay methods

Similarly in the development of Terramycin, Analytical developed colorimetric and spectrophotometric assay methods by which that drug could be distinguished from other antibiotics then on the market. Likewise, the department devised identification tests for the drug reserpine. Useful in the

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treatment of both hypertension and mental illness, reserpine occurs in nature with several other closely related alkaloids. When Pfizer took the drug in hand, there existed relatively little literature on it and hence the Analytical Depart­ ment had to start virtually from scratch. The ultraviolet absorption pattern of the drug had been reported on, however. It had also been demon­ strated that the ester linkage between trimethoxybenzoic acid and reserpic acid is easily hydrolyzed. Pfizer found it logical to assume that both adds could be formed in reserpine, during production of either the alkaloid itself or its dosage forms. Both compounds, it was found, inter­ fere with quantitative measurement of the absorption of reserpine and must be removed before the measure­ ment can be made. This fact became the basis of one of the three identifica­ tion methods the department developed. By measuring the amount of reserpic acid or trimethoxybenzoic acid formed during the extraction process, the Analytical Department was able to determine the amount of decomposition that occurred. The amount of tri­ methoxybenzoic acid present, it found, is the best indication of decomposition, for reserpic acid is not very stable and decomposes to give products with greatlj' altered absorption spectra. One of these compounds, reserpic acid, is soluble in acid. The other is not. Hence after the reserpine is dis­ solved in chloroform, the mixture is extracted first with an aqueous acid and then with an aqueous base solution, to remove the reserpic acid and the tri­ methoxybenzoic acid. After transfer and dilution to a known volume in a volumetric flask, the absorbance of the chloroform was spectrophotometrically measured at several wave lengths (295 and 268 ηΐμ). The amount of reserpine present in the sample was then determined by compar­ ison to the absorbance of solutions containing known amounts of pure reserpine, and the identity of the com­ pound established by comparing its absorbance at different wave lengths. After devising tests for research, as the product moves into further develop­ ment stages, the Analytical Depart­ ment conducts a series of tests that are necessarily sweeping in scope. These include examination of crude materials, intermediates, and finished product with countercurrent distribution, chromato­ graphic, differential crystallization, and other complex exploratory techniques. All help the department to determine exactly the composition of the material under investigation, and they fre­ quently help production to increase ANALYTICAL

CHEMISTRY

REPORT FOR MANAGEMENT process yields. Though generally confined to development, these tests are also invoked when there is any serious doubt as to the quality of a product. Alany of the subsequent tests are routine. On the oral dosage form of one antibiotic, for instance, Analytical runs a total of 17 tests for such standard factor's as moisture, hydrogen chloride, ash content, pH, bulk, and particle size. Before final test notes are written on the finished dosage form, however, spot checks have been run at each stage of production for such factors as moisture, assay, and purity. Quality control

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In process and in packaging, Pfizerfinished products are gone over with a fine-toothed comb by a control task force made up of two statisticians, four chemists, and 150 technicians and inspectors. Control aspects apart, by reporting on and appraising the quality level of work in process, this team has proved to be an important adjunct to production supervision. Its observations blend into a dynamic picture of the history of any lot produced and together with final physical, chemical, and biochemical appraisals, form the basis on which shipment is ultimately released. This gives the Analytical Department a truly panoramic view of the manufacturing operation and access to all the necessary basic information it needs to stamp approval on a lot. These in-process controls enable Pfizer to detect and screen out contaminants before they actually get into production. Furthermore, they enable the company to take immediate action on substandard items at each stage of production, and thus result in a final product substantially free of impurities, at a point where correction would otherwise be extremely expensive. Quality control also scrutinizes all incoming packaging materials, compounding ingredients, and other supplies. Its probing begins with a random selection of cross-sectional samples which are checked for visual, physical, dimensional, and chemical characteristics and then either accepted or rejected according to a quality level agreed on by Pfizer and the vendor, based on the latter's best operating level consistent with economic considerations. Control of compounding, subdividing, and packaging operations is also a key to product uniformity and defectivefree production. Pfizer checks the high speed equipment used in these operations by the control chart methods developed and expounded by W. A. Shewhart. Maintained for both averages and range on every machine, these charts become part of the permanent ANALYTICAL

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record which details the character of the lot. Subsequently the finished product is retested for potency and far more extensively than when in process. This task falls within the province of the microbiological quality control group, which is divided into four test sections: bioassay, sterility, environmental, and pharmacological. Pfizer uses bioassay methods to support its chemical tests. Though more costly, they are required because chemical tests, of themselves, are not specific enough to establish biological activity and this is a factor that must be very carefully checked before the drugs can be released for shipment. A few antibiotics, in fact, cannot be satisfactorily tested by chemical means at all and these are checked entirety by microbiological assay. Apart from sterility tests on the finished product, the microbiological group at regular intervals also runs tests to ascertain that all sterile work areas are sterile in fact as well as designation. It periodically assays warehouse inventory to make sure that there has been no deterioration in the quality of the stored products and also tests finished dosage forms for toxicity in mice, pjTOgens in rabbits, and depressors—such as histamines—in cats. And in the case of some customer complaints on products, the microbiological group re-examines returned material. From its observations on these "rejects," the group sometimes gathers information, which when correlated with other data, can make for an improved product. Stability

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No product is really approved unless it is practically stable, however, and Pfizer tests for stability not only in process, finished product, and dosage form but also under accelerated conditions. This is necessary because many of the antibiotics and vitamins, to a lesser degree, are unstable and can go downhill rapidly. Meticulous testing ensures both company and customer that a given dosage form will live up to its specifications under a wide variety of climatological conditions all over the world, sometimes for as long as 3 to 5 years after it has gone into distribution. And in making its stability tests, Pfizer must consider not only the steaming humidity of Panama, say, but also far less predictable vagaries of the druggist who might inadvertently store his antibiotics just a little too close to a hot radiator, or where the sun can get at them. Consequently, the working equation is a complex one and is made even more so by a myriad of possible combinations. ANALYTICAL

CHEMISTRY

Bulk Terramycin, for instance, can be mixed with other antibiotics, inorganic chemicals, vitamin formulations—as in the case of the recently developed s t r e s s - f o r t i f i e d Terramycin-SF—and also with hormones and amino acids. Safety In the finished dosage form each of these components has to be tested for safety. Even though proved safe individually, when blended they must be again tested to make sure that none of the ingredients has been inactivated. This problem is literally compounded by the fact that many of the antibiotics, and many of the materials with which they can be blended, can in turn be fashioned into as many as 20 dosage forms requiring 15 tests each. This kind of complexity, of course, generates hydra-headed sampling problems. Like the rest of the industry, Pfizer's Analytical Department lias been able to resolve these only by immersing itself deep in statistics. Even the cold lucidity of the theory of probability is not entirely flawless, however, and sometimes must bow to a lightninglike flash of intuition. Recently, for instance, a batch of capsules tested completely out of pattern and at odds with in-process and finished product checks. After indicting bad sampling, the department validly exonerated itself by running the capsules through a Waring Blendor. This treatment shook up the capsules' distribution pattern and so enabled the department to take a new sample that tested well within allowable limits. To buttress its statistical controls, Pfizer has, of course, turned to instrumentation and, to ensure that it will remain up to technological snuff, encourages the Analytical Department to maintain close contact with all scientific groups in the field. The trend to instrumentation or automation, however, is a dynamic· one and the mass production industries owe a great deal to the analytical chemists and laboratories where the seeds of instrumentation first took root. Through tight liaison with the company's radiological laboratories, Pfizer's Analytical Department also has a stake in radioactive isotopes and trace elements. In a practical sense, these are still a little way over the testing horizon. But even if they are never joined to ultraviolet and infrared spectra, and colorimetric and polarographic test methods, Analytical will continue to function as an unwinking technical eye, charged with keeping the Pfizer name and quality as closely linked in reality as they are in the company seal.

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