Fifty Years of Publication: Hospital Pharmacy Anniversary

This year marks the 50th anniversary year for the publication of Hospital Pharmacy. As with most anniversaries, it is a time for celebration, reflection, and assessment.

Sidney Kahn, the Director of Pharmacy Services at Albert Einstein Medical Center, was the first Editor-in-Chief. Neil Davis, Director of Pharmacy Services at Temple University, was the first Assistant Editor. Neil would later step into the role of Editor-in-Chief. Together, these men built the foundation for the journal as we know it today. The Editorial Board was multidisciplinary with representation from nursing, pharmaceutical industry, and hospital pharmacy services. An annual subscription in 1966 for a print copy of the journal was $10. Now for less than $220 a year, an institution can have campus-wide digital access.

During my preparation for this editorial, I reviewed the first year of publication of Hospital Pharmacy. Issues facing the pharmacy profession in 1966 were not that dissimilar from those that we face today: the utilization of technology and electronic data, the provision of emergency services, the role of continuing education, financial considerations in managing pharmacy services, medication errors and their prevention, the art and substance of leadership and management, professional standards, the role of the pharmacy technician, the use of emergency drug boxes, the provision and safety of parenteral products, the importance of clinical research in the practice setting, strategic planning for the provision of pharmacy services in hospitals of all sizes, the use of antibiotics and resistance, and the review of rational therapy for several clinical conditions. As today, the background of authors was diverse, representing a variety of viewpoints from hospitals, academia, industry, and research. National and international perspectives were apparent.

Although some of the general issues affecting the profession may be similar, advancements in the practice of pharmacy in the last 5 decades are stunning. Make no mistake, 1966 was a very different world than it is today. The processes of unit dose distribution and generic product bioequivalency were in their infancy. The provision of 24-hour pharmacy services was not available in many hospital pharmacies participating in a national survey, and in 45% of the hospitals without a full-time pharmacist, drug services were provided by a nonpharmacist. In another 45% of these hospitals, pharmacy services were provided via an arrangement with a community pharmacy. ¹ During the early 1960s, less than 10% of the registered hospitals in the United States maintained some type of electronic data processing, with the majority of use devoted to bookkeeping purposes. Inventory control and documentation in the medication process were manual systems. ² In 1966, the creation of a newly designed service, a drug information division, was described at the Albany Medical Center. ³ Advertisements promoted the use of sodium cephalothin, meprobamate, injectable colistimethate sodium, and vitamin B complex. For an example of how far the profession has come, see the guest editorial from 1966 that is reprinted at the end of this article [Hosp Pharm. 1966;1(3):11–15].

What was apparent during my readings is that the advancement of the pharmacy profession and its practices, along with all health care practices, has been monumental. The role and presence of the pharmacist in patient care has expanded and positively influenced health outcomes. A culture of safety permeates our medication processes. And yet, our journey is a continuum; we have arrived at this moment through the cumulative experiences of our past. The journey will recreate itself over and over as we continue to build and improve practice and process, all directed to the optimization of patient care. And throughout this journey, the mission of Hospital Pharmacy has remained the same – to provide innovative information that illuminates and reflects the pulse of the pharmacy profession and its practices. We celebrate this anniversary. We celebrate the continued efforts of our authors, editors, editorial staff, and peer reviewers. And we look forward to future anniversaries with the hope of your continued participation.

Guest Editorial

Myth of Drug-product “Equivalency” by A.E. Slesser, PhD

I think that most pharmacists and physicians believe that drug products made by reputable knowledgeable capable manufacturers can be relied upon to work as they should and that so-called “generic equivalents,” sold on a price-appeal basis, cannot be so relied upon. But I also think that professional and lay people would like to know more than they do about the reason why this is so.

The purpose of this paper is to present the concept of drug quality and the drug quality control function in assuring therapeutically reliable drug products and to explain why so-called “equivalency” of cheaper products that purport to be the same is a myth. First, however, 2 terms must be differentiated.

The term drugs has been the source of much confusion. People say drug product—ie, tablets, capsules, injections, ointments, etc. A drug product consists of the chemical compound (the drug which produces the therapeutic effect) in combination with one or many other substances that must be used to make the tablet, capsule, injection, etc.

If people could be given the drug (the chemical compound) itself, there would be no question about therapeutic equivalency (or nonequivalency) between one drug and another because it would be easy to establish the physical and chemical specifications, which would assure that 2 chemical compounds were or were not the same. For many reasons, however, it is not possible to give the chemical compound itself to patients. The nature of the other substances which must be mixed with the drug (and there may be from one to 20 or more in a tablet, capsule, etc), the manner in which the mixing is done, the number and type of quality controls applied at each step of manufacture, all of these can affect the therapeutic efficacy of the dosage form.

The United States Phamacopeia (USP) gives recognition to this fact by stating on pages 785 and 786 of volume XVII:

The extent to which the therapeutic constituent [the drug] of a pharmaceutical dosage form [a drug product]…is available for absorption is influenced by a variety of factors…Among [these] are the manner of compounding; the crystal size and form of the therapeutic constituent; [and] the diluents, excipients and other compounding aids [the other substances with which the drug must be mixed to produce the tablet, capsule, etc]…The maintenance of a demonstrably high degree of “physiological availability” [therapeutic effectiveness] requires particular attention to all aspects of the production and testing process that may affect the … finished article.

In a drug product I feel that the most important quality is clinical effectiveness—the reliability that it will perform as it is expected to perform each time it is used. I do not think there will be much disagreement with this premise because, without clinical reliability, prescribing, dispensing or administering, the drug product may become a medical variation of “Russian Roulette.”

Now, there is only one way of assuring the therapeutic efficacy of a drug product and that is by properly designed and controlled clinical tests. Yet, despite this apparently simple concept, there is a widely prevalent tendency to confuse drug content of a drug product with drug potency or clinical effectiveness. A number of articles have appeared during the past 6 or 7 years that purport to show equivalency of tablets made by several manufacturers—each containing the same drug in the same quantity—and compared on the basis of the assay for drug content alone. Some of these studies are somewhat more comprehensive, and may also include comparisons of disintegration times and weight-variation tests. One must admit that there is a great tendency for the reader of such articles to reach conclusions concerning therapeutic equivalency on the basis of such comparisons because the reader may ask himself, “With all these data, what else is needed?”

One common and apparently logical sounding argument advanced to “prove” drug product therapeutic equivalency goes something like this: Generic X tablets are in the USP (or NF) and must meet USP (or NF) specifications. Therefore they must be clinically equivalent to the “Y” tablets (the brand name product containing the same drug and same amount, but manufactured by a reputable, knowledgeable, capable manufacturer). Parenthetically, it might be added that X tablets are almost always cheaper than “Y” tablets.

The fallacy in this seemingly logical argument is exposed by the chairman of the Committee on Revision of the National Formulary, Dr. Edward G. Feldmann.

In a speech before the Specialized Institute of Hospital Pharmacy held in Chicago in October 1962 (and reprinted in the American Journal of Hospital Pharmacy, 21:388, 1964), Dr. Feldmann stated:

Many people in pharmacy have the mistaken notion that if a product meets all the specific tests and requirements detailed for that article in the USP or NF monograph, then that particular product has to be perfectly satisfactory. While I wish this were true, I am sorry to say that it is not and the nature of the problem is such that we can never hope to develop compendia monographs which will give complete assurance of any product's absolute suitability.

Why do the USP and the chairman of the Revision Committee of the NF point up the limitations of these legal compendia in assuring therapeutic performance of drug products that appear in the compendia? The answer is simple and can be stated in 2 parts: (1) the performance function of a drug product cannot be spelled out in a USP or NF monograph because many factors other than the drug and amount are of vital importance in either assuring correct performance or negating it; (2) these “many factors” are of such a nature that they cannot be included in a compendium—nor should they be!

Refer to any tablet monograph in the USP or NF, for instance, and you will find no information concerning components (other than the drug itself) or method of manufacture or quality controls to be exercised during manufacture, or inspections, checks, tests, assays and other in-process controls to be exercised during manufacture, etc. Absence of such information is no adverse reflection on the USP and NF because information of this type (aside from the fact of impracticality of inclusion) is neither necessary nor indicated for the compendia to perform their valuable function.

However, knowledge and control of these factors should be the responsibility of the manufacturer of the drug products and the reputable and qualified manufacturer carries out this responsibility through the exercise of systematic effective quality control procedures.

As amplification of this point, I again quote Dr. Feldmann:

There is a very real and significant difference between compendia drug standards and manufacturing quality control procedures. Relatively few people are really aware of this difference, and even fewer understand the reasons for it.

The key difference between a drug product manufactured by the reputable and qualified manufacturer and the product that is sold on a price-appeal basis is quality control. Quality control is simply the systematic application of specification, sampling, testing and manufacturing controls to assure that each batch of the drug product produced, irrespective of when that is will be exactly like the clinically tested and clinically proved prototype lot—the lot that was established at the very outset as being clinically effective.

Under an effective quality control program that provides assurance of clinical performance reliability from batch to batch on a day-to-day basis 5 areas are important. These are based on the factors responsible for the clinical effectiveness of a clinically proved drug product, ie, certain specific ingredients meeting certain specific specifications, compounded according to a specific formula, by a certain specific procedure, using certain specific controls throughout the operations.

With this in mind, then, quality control first must control the components used in the drug product—both the drug itself and the added components. The reputable manufacturer makes sure that components all have pertinent, significant specifications and that these are in writing, that the components are purchased only from known reputable vendors, that written, detailed instructions describing the manner and method of sampling incoming shipments of components exist and are followed, that all analytical test methods are written, are complete, up-to-date, available to the analysts and are followed for establishing compliance with the written specifications. For example, an apparently trivial characteristic such as particle size of a component, whether the component is the active drug or not, may very well be a significant specification for which a test may be required prior to approving it for use in manufacturing the batch of drug product.

The second control factor is the formula. The formula must list each component and the amount that is to be used. The master formula should have been checked by no fewer than 3 capable competent people, independently and individually, for correctness. Each batch formula derived from this master formula is produced by a photocopy process which assures against errors in transcribing so that each batch formula will have to be correct if the master formula itself is correct.

The third factor is the manufacturing (or compounding) procedure. This is a written extremely exacting detailed description of every step of the manufacturing operation, including directions denoting the specific type of equipment to be used in each instance.

Fourth, are the various analytical tests, inspections and checks that must be carried out at certain stages during manufacture of the batch. These are important; all must be written; they must be detailed; there must be a lot of know-how in deriving what tests, inspections and checks are to be followed at the various stages of the manufacturing operation—with respect to raw material components, intermediates and at the finished product stage.

Finally, the application of what I call in-process controls is important. In-process controls are simply systemic controls which verify that all 4 of the preceding factors actually have been applied to assure batch-to-batch reproducibility of the clinically tested and proved prototype batch. They also assure that the quality results that the Analytical Control Laboratory gets on the sample of finished product tested, which of necessity is an extremely small fraction of the batch, is applicable to the entire batch as a whole.

Perhaps an easy-to-understand example may clarify the second function of in-process controls. In a prescription-compounding and dispensing course I taught at the University of Kentucky, I dictated prescriptions to the class, as a physician might do over the telephone; the students then compounded the prescriptions in the laboratory. Later I checked their work.

Let's suppose that on a particular day I had dictated a prescription calling for 20 capsules to be filled with a powder mixture consisting of 2 drugs and milk sugar. Let's also suppose that on the day that this prescription was being compounded I happened to be away from the laboratory. On my return the next day, suppose I stopped at Joe Jones' desk and saw his vial containing 20 nice, glistening capsules. Suppose that, at random, I picked out one of the 20 capsules and weighed it and found its weight to be correct. Assume also that the means for rapid analysis was available to me and that I found both drugs to be present in amounts reasonably close to the correct amounts.

Now, if I were to draw a conclusion about the quality of the entire 20 capsules based on the results of analyzing one capsule, how valid would such a conclusion be? Obviously, I would have one chance in 20 of being right because, just by chance alone, I might have picked out the only capsule of the 20 that was any good. Yet one out of 20 is a 5% sample—a very large sample as far as pharmaceutical manufacturing is concerned. Even a reputable manufacturer does not weigh and assay 50,000 capsules out of a batch consisting of as many as a million or more—and that's a 5% sample.

Now let's imagine that I had been present when Joe Jones filled this prescription and that I paused at his work-bench and observed him in every step of the compounding operation. In this case I would have noted the correctness of identity and weight of each ingredient, observed his mixing technique, and observed that his mixing was thorough, that as he filled each capsule and weighed it his balance had been zeroed and that there was an empty capsule on the right-hand pan as a tare. I would have seen that the filled capsule weights were very close to the theoretical weight.

If, in this instance I obtained the same results as in the previous example from one capsule selected at random, my conclusion with respect to the quality of the entire 20 would be based on an entirely different situation. Why? Because, in the second instance, in-process controls, which consisted of my observing every step in the compounding of the prescription, were operating. Therefore, with very little margin for error, I could very confidently extend my findings on the one capsule to the other 19.

Were I to give a capsule compounded under the first set of conditions and one compounded under the second set of conditions to an outside laboratory and request that they determine if the quality of the batch from which each capsule came was the same or different, the answer would come back: “The samples are from identical batches.” Why? Because until there is a laboratory that can, from a sample of a bottle or a sample of a shipment or of a batch, determine whether and what in-process controls were applied and their extent and validity, then the quality conclusions based on the results of such laboratory tests must of necessity be of questionable validity.

The reputable manufacturer (and the FDA!) recognizes the indispensability of in-process controls in assuring drug quality and assuring validity of sampling and test results throughout the manufacture of each batch. His in-process controls consist of such things as records and reports giving results of required tests and inspections—records, such as the results of tests on tablets at the time the batch is being compressed, control chart records of the fill accuracy of capsules as the batch is being encapsulated, signatures of operators and supervisors attesting to the double and triple weight and identity checks that have been made on each component in the compounding of the batch, signatures of operators and supervisors denoting that the correct working directions were used in compounding the batch, yield checks, analytical reports, etc. These are just a few examples.

Again, Dr. Feldmann corroborates these points by stating:

Obviously, a USP or NF momograph could never cover all these possibilities which might adversely affect the quality of a product. This then is an important function of the in-process quality control program. It is through such a program that products can be produced which have uniform, batch to batch purity and quality. It is because a particular manufacturer is known to employ a good program of this type that pharmacists and physicians can place greater reliability and confidence in the pharmaceuticals which he manufactures. But only his control department is in the position to know just what tests and checks should be run in their plant and on their product.

Further verification of the differences between “equivalent” drug products is afforded by Drs. Gerhard Levy and the late Eino Nelson, of the University of Buffalo School of Pharmacy (Journal of the American Medical Association, 177:689, 1961). These men warn that the case for generic-name prescribing has been overstated and that 2 products having the same generic name do not necessarily produce the same effects in patients.

They described how a drug product used in treating tuberculosis can be formulated with several types of coatings, some of which in time cause the medicine to lose its efficacy, and pointed out that “various brands of this drug are obviously not equivalent.” They reported that a sulfa drug product composed of fine particles was more readily absorbed than a similar formulation containing slightly larger particles, and thus exerted different effects.

As another example, they described an incident wherein the viscosity of solutions of a drug used in eye diseases played an important part in its therapy. Unless this ophthalmic medicine was carefully formulated, it thinned out in storage, causing the drug to lose its penetrating power.

An article summarizing 20 years' experience of 4 physicians with so-called “generic equivalents” that were cheaper than the brand-name product supplied by the reputable knowledgeable capable manufacturer can readily be understood in the light of the facts presented herewith. The article, which appeared in the February 1965 issue of the American Professional Pharmacist, was written by Dr. Max S. Sadove and 3 colleagues.

The doctors concluded that “generic equivalency is frequently a fable without basis in fact….” Time after time they found that supposedly identical drugs in actual clinical use had very different effects. For example, a generic-name local anesthetic was found to be less satisfactory than the trademark product formerly used. The effects of the generic anesthetic wore off more quickly and it deteriorated rapidly.

Did to the difference in cost justify this change to a generic product from the trademark product? Dr. Sadove and his colleagues said this:

In retrospect, it is obvious that the answer is no, but can this kind of error be prevented? We really don't know how it can. The specifications of the 2 products were identical. The clinical results were entirely different!

The experience of Dr. Sadove's group did not always bear out the claims of large savings through generic prescribing. “In one instance, the less expensive drug became more expensive, because of the amount that had to be discarded….” “In fact,” the Illinois physicians added, “we fear all low bids when they are sharply lower than the bids of the so-called ‘good companies’.”

It is true that the prices of certain manufacturer's generic-name “equivalent” drug products are sometimes much lower than those of trademark products made by reputable and qualified manufacturers because producers of the former are not innovators. They do not discover and develop new drugs through research. And most of them also economize by taking production, quality control and marketing shortcuts.

But, as many studies show, all drug products having the same generic name are not identical. Some generic-name drug products are of excellent quality; some are not. Unless the product (whether marketed under generic or brand name) is made by a reputable and qualified manufacturer, there is absolutely no way to tell which is good and which poor—before it is used—without the use of analytical and biological laboratory facilities more elaborate than most physicians, pharmacists and hospitals are likely to possess.

In summary—

• 1.The manufacturer most familiar with a given drug product (by virtue of having developed it, arranged for its clinical testing, etc) can and does build therapeutic performance reliability into each batch of the drug product he manufactures.
• 2.Therapeutic performance specifications for drug products (with one or 2 notable exceptions) cannot be and are not included in the USP or NF nor can USP or NF specifications or tests evaluate the therapeutic performance function.
• 3.For this reason therapeutic equivalency or nonequivalency between a drug product made by the reputable knowledgeable capable manufacturer and the price-appeal product containing the same dose of the same drug cannot be determined by laboratory testing and, in fact, may be vastly different.
• 4.For the above reasons most physicians are opposed to legislation that would compel them to prescribe by generic name only. Resolutions opposing such legislation have been adopted by a number of medical groups.
• 5.So far as drug quality is concerned, the public's best protection against substandard medications is still the trademark name of a reputable and qualified manufacturer.