NEW DRUGS AND THE COSMETIC CHEMIST 465 Idrug application, samples of the dosage forms the applicant proposes to Imarket representative of the drug employed in clinical studies, of the drug Iproposed for initial marketing, and of commercial scale production, to- igether with samples of the new drug substances used in producing the Ibatches of the drug represented by the foregoing samples, and such refer- lence standards and blanks as may be required to perform the assay proce- Idures described in the application. The new drug sample regulations were designed for the purpose of check- iing the adequacy of the proposed methods in a new drug application to Idetermine whether or not these methods to be employed are adequate Ito preserve the identity, strength, quality, and purity of the article to Ibe marketed, and to verify specifications, especially for new drug sub- Istances. Our experience to date with the drug sample regulations has brought •out some common faults which arise to cause difficulty in complying with Ithese regulations. We have received insufficient and inadequately identi- Ified samples. In some instances, applicants fail to submit their results ion the batches represented by their samples. As to the methods submitted Iby the applicant for the laboratory test procedures of the samples, many •are not given in sufficient detail. We can evaluate the adequacy of pro- Iposed drug controls only when an applicant submits adequately described Imethods and unambiguous laboratory reports. We would recommend Ithat you submit methods that can be employed routinely by our labora- Itories to assay your product without the necessity of having the blanks iinvolved in a particular batch. A demonstration of the stability of a proposed preparation should be isubmitted as a part of a new drug application. The potency of a drug is •most important at the time it is consumed. This suggests that prolonged 'stability may be even more important for an over-the-counter drug that may be used intermittently over a long time until exhausted than in the tcase of a prescribed drug entirely consumed as directed during a short I period of illness. There are a number of significant factors affecting the stability that I should be considered in designing studies of the shelf life of a formulation I but which are not always given the full consideration that they deserve. I For example, temperature, pH, particle size, moisture, air oxidation, dilu- lents, preservatives, containers, closures, light and the presence of certain I trace metals, are some of the important factors. It is most important in this day of new and different containers and t closures for packaging drugs that the samples for stability study be taken 'from material stored as it will be in the market package. Once the stability of a formulation of a drug in a specific market container I has been established, it does not follow that a change in formulation or

466 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS container, no matter how minor, will not change the stability of the prepar- ation. Changes in the container, closure, excipients, flavor and manufac- turing and processing operations may affect the stability adversely, requir- ing additional studies of stability. It should be emphasized that almostl any changes in process or composition require evaluation as to their effect l on the stability of the product. In interpreting the results of stability studies many firms have found to• their disadvantage that the carrying over of stability data from one formu-I lation to another is not acceptable. In general, the results of any stabilityl study are applicable only to the formulation under the test conditions im-i posed, such as temperature, diluents, container, moisture, pH, closures,I etc., employed on a particular article. The chemical assay methods on which stability studies are based shouldl be sufficiently specific to differentiate between the unaltered drug and itsl possible degradation products. A method that does not differentiate thel original product from the degradation products is of no value in reaching I a conclusion that the preparation is stable. Too often we are expected to evaluate the stability of a product on thel basis of data derived from a single batch. In addition, we are continually I being asked by members of firms about how long their firm should run--orl be required to run--stability studies of a preparation for acceptance in al new drug application. They seem to ignore the fact that we must be as. guided as they by what the data indicate. A preparation may be stable, apparently, in the hands of one pharma- ceutical firm under the conditions of his own manufacture. The prepara- tion of the same composition in another's hands, using different raw mater- ials, different equipment, different containers, and variation in technique, may not be stable. Frequently, we find that an applicant, when his formu- lation is the same as that of another firm, relies entirely on the other firm's stability studies. He finds to his disadvantage that studies of the stability of his formulation are an essential part of his own new drug application. I do not propose to discuss in detail all the requirements in Part Six of the new drug application which deals with labeling. A drug must be safe for use as labeled, so that evaluation of labeling is another vital step in the consideration of the safety of a new drug. The information derived from the animal and clinical Studies provides knowledge regarding the indica- tions, dosage, contraindications, precautions and side effects of a newl drug. Generally the labeling of cosmetic-type drug preparations will be similar' to the pattern of labeling'employed on other drugs, with perhaps a fewl unique characteristics. If the drug is to be sold over-the-counter, that is, without prescription, the package should includ• among'other things ade- quate directions for use in self-medication and adequate warnings. The