rational policies for stability testing

CLIN. RESEARCH & REG. AFFAIRS, 10(3), 177-185 (1993)

RATIONAL POLICIES FOR STABILITY TESTING

J.T. Carstensen School of pharmacy

University of Wisconsin Madison, WI 53706

and

C.T. Rhodes Department of Pharmaceutics University of Rhode Island

Kingston, RI 02881

INTRODUCTION

The purpose of this paper is to present in a public forum ideas which the two authors have been advancing for discussion at various seminars and conferences in North America and Europe during the past few years. We do not claim that the concepts articulated in this paper are exclusively the product of our own experiences. We are aware that other pharmaceutical scientists have contributed substantially to the positions whch we define in this paper. Thus, we acknowledge with gratitude, many stimulating discussions with persons from academia, the industry, FDA and USP, and other regulatory bodies. Some of the points raised in t h s paper may not be accepted by all with an interest in drug product stability. We encourage response.

WHAT SHOULD BE MONITORED ON STABILITY TESTING OF PHARMACEUTICAL PRODUCTS?

The ruison d'etre of pharmaceutical stability testing should be to provide reasonable assurance that the "fitness for use" of our products remain at an acceptable level throughout the period during which they are in the marketplace available for supply to the patientkonsumer. (It is tempting to extend the above definition so that it

177

Copyright 0 1993 by Marcel Dekker, Inc.

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178 CARSTENSEN AND RHODES

covers the period until the last unit of product is used by the patient. However, since we are aware that a significant proportion of patients routinely store pharmaceuticals in a quite inappropriate manner, such an extension of the definition would, in our opinion, be unrealistically Utopian in nature. At present, the most likely method of improving storage of drug products by patients may well lie in individual counseling by pharmacists. This is surely a most important professional role.)

It is well established that a variety of the quality attributes which pertain to the safety, efficacy or consumer acceptability of pharmaceutical products can show a time-dependent decrease in value. Most commonly attention has been directed to loss of potency and many authorities would regard products which contain less than 90% of labeled claim as misbranded and of insufficient fitness for use. Thus, a great deal of stability testing is directed to quantifying the percentage of label claim in stability samples stored by the manufacturers under specified conditions. Such samples are often referred to as retained stability samples. Whilst in no way wishing to downplay the importance of potency determinations we strongly recommend that attention be given to changes in other quality attributes which, in some cases, may be more significant than loss of potency. Among the properties which may require monitoring for certain drug products are:

1. 2. change in bioavailability 3. 4. modification of microbiological status, 5. reduction in content uniformity 6.

7.

increase in concentration of active,

production of toxic decomposition products,

loss of pharmaceutical elegance, or change of any other attribute which may affect fitness for use.

Category seven of the above list is a catch-all group designed to cover a miscellany of possible problems. For example, if there is good reason to believe that a

transdermal product is liable to adhesion aging (the phenomenon whereby the ability of the patch to stick to the patient's skin becomes reduced on storage) then surely it is only prudent to monitor this parameter during stability testing.

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POLICIES FOR STABILITY TESTING 179

Some may object to the inclusion of pharmaceutical elegance in the above list. However, we would submit that a change in elegance may well reduce consumer/patient acceptability of a product and thus reduce patient compliance. For example, the slight yellow speckling sometimes observed when drugs containing amino functional groups are formulated into tablets containing spray-dried lactose may have no measurable significant effect on any safety or efficacy property, but if the patient loses confidence in the product because of this visual change, we believe that fitness for use has been impaired.

STABILITY INDICATING ASSAYS

Given the above-specified eclectic nature of potential stability problems, it is obviously apparent that we cannot restrict the definition of stability indicating assay to quantification of the active drug. For some pharmaceutical products other determinations may be equally, and in some cases more, important. However, we recognize that for many drug products the emphasis of stability testing will be

largely on measurement of active drug.

The amount of work in validating a stability indicating assay must depend inter alia on whether the drug is a new chemical entity (NCE) or a generic version of drug which is already on the market, such as would be appropriate for an Abbreviated New Drug Application (ANDA). For an NCE there are powerful arguments in favor of studies to elucidate degradation pathways and decomposition products although in some cases (particularly in the protein drGg class), such studies, because of our present technological limitations, cannot be reasonably expected to define the whole picture.

For drugs which are not NCE's, and for which an ANDA is an appropriate market license vehicle, there is usually far less justification for a requirement of studies of degradation mechanisms. In the same way as we do not require clinical trials per se of ANDA products but only bioequivalency studies, which build a bridge from the innovators products to the generic version, so for stability studies of ANDA products it is inappropriate to expect the sponsor to "re-invent the wheel" by elucidating decomposition mechanisms and identifying degradation products. (The

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only exception which we would make to this general statement is if there is reliable data which clearly indicates that a specific degradation product is known to be associated with serious toxicity. In such cases even for an ANDA we would insist on quantification of the offending degradation product if it was present in significant amounts.) Thus, for an ANDA product the validation of a stability indicating assay should consist of demonstrating that it is possible to quantify the parent drug in the presence of its degradation products. It should not normally be necessary to identify or quantify degradation products, if the ANDA sponsor can show that degraded specimens of their products show, qualitatively, the same degradation spectrum as the innovators product. Since most stability indicating assays used for quantification of drugs in ANDA products are based on ultra-violet detection of compounds separated on an HPLC, data from photo diode array detectors is usually quite sufficient for the purpose of demonstrating peak purity. Certainly testing of the product by light, heat, oxidative and acid/base stress is not unreasonable in demonstrating the stability indicating nature of an assay. However, it must be kept in mind that some drugs are inherently stable. How could one prove that an assay for gold in Auric Chloride injection is stability indicating? The medieval alchemists toiled for years to transmute base metals into gold, but unless our assays are to be conducted at Chernobyl, we could never prove that our assay for Auric Chloride is stability indicating. We cannot prove a negative.

RETAINED SAMPLE STABILITY TESTING

Although there are other methods of obtaining data on the stability of pharmaceutical products (test) distribution of product, simulation of market stress, examination of returned product, kinetic studies, etc.), the most important element in most stability testing of marketed pharmaceutical product is evaluation of retained stability samples.

The usual practice for such studies is that for every marketed product, for which stability data is required, the manufacturer selects stability samples for retained storage for at least one batch a year. Often when a new product is first introduced onto the market a manufacturer may decide to take stability samples of every batch. Later as increased confidence is gained in the stability of the product the number of batches kept on stability testing is likely to be progressively reduced so that only

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about two to five percent of marketed batches are designated as stability sample batches.

Stability samples are tested at predetermined intervals. Thus, if a product has a five-year shelf life it is conventional to test at: 3, 6, 9, 12, 18, 24, 36, 48 and 60 months. If a product is labeled for storage at controlled room temperature, it should be stored at a kinetic average temperature of 25OC although the product should be capable of sustaining occasional excursions to 300C. (Unfortunately, there are some persons at FDA who are fighting what appears to be a rearguard action to require that controlled room temperature stability samples shall be kept at 300C plus/minus 2OC.)

This conventional method of obtaining stability data on retained storage samples has generally worked well. However this method, which we term the Constant Interval Method, does have some disadvantages. Firstly, stability data from retained samples may, at least for some products, will give an unjustifiably optimistic view of the real life stability of our products in the marketplace since retained samples have been cosseted by storage under ideal conditions. They have never experienced the harsh reality of conditions in the market where product is subjected to abrupt changes in temperature, dropped off the edge of loading docks or transported in ill- sprung trucks over bumpy mountain roads. In a latter part of this paper we propose a radical new method of stability testing which addresses this fundamental problem in conventional stability testing.

Another problem with the Constant Interval Method is the burden which it places on the analytical testing facilities of many companies. In theory, stability samples must be tested on the exact day which the testing protocol would require. Even if for product X we only have one stability batch a year, the number of samples which require testing rapidly accumulates. For example, if the product has a five-year shelf life, we will eventually have about one stability sample per week which should be tested. The work involved in setting up an assay, running standard curves, etc. means that in reality many stability samples are in fact tested late. If the delay is only a week or two, we do not believe that this is likely to be a major problem. However, in recent years some FDA investigators have been issuing 483's for late stability testing even if the delay has only been a couple of days.

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We offer two possible solutions to the above problems. The first, the Fixed Date method of stability sample testing, is modest in nature and still uses conventional retained sample testing. The second method involves much more radical change. We term this method "Stability Testing by Evaluation of Market Samples."

THE FIXED DATE METHOD OF STABILITY TESTING

Using this method we designate four dates a year for stability testing of product X if it has a five-year shelf life. Thus, suppose we select the first working Tuesday in February, May, August and November, on such days we test all retained stability samples for product X if:

a. they are "freshmen" stability samples from batches which we manufactured after the last stability testing date for product X, providing that such samples are at least 4 weeks old.

or any stability sample within pludminus six weeks of the nominal stability testing interval as defined by the Fixed Interval method.

b.

The data obtained by this method is plotted on a stability graph or percent label claim as a function of real time with true sampling time being used for each sample tested.

This method has several advantages. Firstly, since stability testing for product X is concentrated to four days a year the number of stability samples tested on one occasion will increase by approximately at least an order of magnitude. This greatly reduces the cost per assay.

Secondly, this method by reserving, in advance, certain specified days for the stability testing of product X makes it far less likely that stability testing will be inadvertently overlooked.

Thirdly, the fact that stability data are generated in substantial quantities of four days a year for product X makes it much more likely that the results will be carefully reviewed and trends examined. When stability data are obtained in penny- packets, it is much less likely that time will be taken to interpret results.

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For OTC products, the constant data method could be used by a manufacturer right away. For NDA and ANDA products, prior approval is required.

STABILITY TESTING BY EVALUATION OF MARKET SAMPLES

As has been previously pointed out by the present authors, conventional retained sample stability testing does have significant disadvantages (1,2). Not only are the storage conditions idealistic rather than realistic, but also the number of batches tested in small, usually only about two to five percent of the universe. The argument is sometimes advanced that since parts of the United States are not in climate zones one or two (temperate or Mediterranean), we should use 300 plus/minus 20 for the kmetic average storage temperature. Manufacturers and distributors are, of course, under an obligation to store USP products in accordance with USP requirements. However, we fully recognize that even in temperate areas

of the country pharmaceutical products can, on occasion, be exposed to excessively high temperatures during transport or storage. Recognizing that storage instructions on a product label may sometimes have little effect and be no more than pious platitudes, we propose that renewed attention be directed to stability testing by sampling product which is available on the market. This is not an entirely new concept; we are aware that some companies, e.g., Lederle Laboratories, used a

form of marketplace testing (gang testing) up until the mid-nineteen fifties.

Our proposal envisages two phases in the stability testing of pharmaceutical products. When new products are introduced onto the market as a result of a successful NDA or ANDA, application retained sample testing shall be conducted for one shelf life period on at least two to five percent of all marketed batches (Thus, for a product with a five-year shelf life this phase would last five years.). If at the end of this phase the manufacturer could document that there have been no product recalls due to stability problems, then retained sample testing for the product could be drastically reduced or possibly entirely discontinued and stability testing would be concentrated on the evaluation of marketplace samples. It might well be appropriate to require an increased rigor to be shown in the testing of products which had shown stability problems. Depending on the frequency and severity of the stability problems, manufacturers might be required to test a larger percentage of marketed batches.

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For those products which have a clean stability record at the end of phase one, phase two testing which would involve sampling of product form the market to monitor stability. Once a year (or more frequently for products with short shelf lifes), samples would be obtained from warehouses, hospital and community pharmacies, and for OTC products from supermarkets, etc., located at representative locations throughout the United States.

It is realized that different samples harvested would have different ages, and the totality of results could be subjected to linear regression of potency as a function of time. In this case, of course, batch-to-batch variation would have to be considered by appropriate statistical analysis.

The fitness for use of the samples would be determined by a battery of tests appropriate for the particular product. Testing would include such attributes as label adhesion, label legibility, and torque on screw caps. This type of testing is inherently more rigorous since it challenges the product not just in he idealized retained sample storage conditions, but also in the real marketplace. We recognize that even for well-formulated, essentially stable products there would probably be occasions when market samples would be found to be wanting in one or more quality parameters. Thus, in the evaluation of the data a simple "no fail" criterion would be unrealistic. A reliable statistical test would have to be used. We would recommend that careful consideration be given to the Tolerance Interval concept developed by our colleague, Dr. Sanford Bolton.

We recommend that the testing of market stability samples should be performed at a small number of selected, certified laboratories which would specialize in this type of work. Perhaps USP, FDA, PMA, or NAPM might play roles in coordinating this testing.

This proposal has, we believe, many advantages. It provides a more realistic method of monitoring the fitness for use of pharmaceutical products in that it monitors the quality of product as it is supplied to patients. The nature of this testing is such that we may be able to identify "bad boys" in the distribution and storage network and then be able to take effective remedial action.

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This plan is flexible and responds to peculiar needs of different products. For stable products the amount of stability testing would be greatly reduced. (Surely one of the most depressing sights in the pharmaceutical industry is to visit a stability testing facility of a company which makes a range of well-formulated, stable products and see the large stocks of samples being exhaustively tested by well- trained analysts. When such products have a record of impressive stability for

many years, we wonder if the stability samples might not be better employed in treating patients and the analysts more productively engaged on assisting in the evaluation of new products.)

We realize that the above outlined proposal would need to be fleshed out in considerable detail if it were to be implemented. Perhaps a first step would be to develop a pilot scale study which would evaluate the feasibility of this approach.

It is our considered professional opinion that the above proposal merits serious consideration by all concerned with the cost and quality of drug products whch are supplied to the U.S. public. I t offers a way of more realistically evaluating the quality of pharmaceutical products as they are supplied to the patient, while at the same time allowing the manufacturers of stable products to dramatically reduce costs.

REFERENCES

1. J.T. Carstensen and C.T. Rhodes, Drug Development and Industrial Pharmacy 9 (401) (1991).

2. J.T. Carstensen and C.T. Rhodes, Drug Development and Industrial Pharmacy 14 1765 (1988).

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rational policies for stability testing

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