The American Medical Association has questioned whether expiration dating markedly underestimates the actual shelf life of drug products. Results from the shelf life extension program (SLEP) have been evaluated to provide extensive data to address this issue. The SLEP has been administered by the Food and Drug Administration for the United States Department of Defense (DOD) for 20 years. This program probably contains the most extensive source of pharmaceutical stability data extant. This report summarizes extended stability profiles for 122 different drug products (3,005 different lots). The drug products were categorized into five groups based on incidence of initial extension failures and termination failures (extended lot eventually failed upon re-testing). Based on testing and stability assessment, 88% of the lots were extended at least 1 year beyond their original expiration date for an average extension of 66 months, but the additional stability period was highly variable. The SLEP data supports the assertion that many drug products, if properly stored, can be extended past the expiration date. Due to the lot-to-lot variability, the stability and quality of extended drug products can only be assured by periodic testing and systematic evaluation of each lot.

We have completed 2 26-wk studies to evaluate the hemizygous transgenic Tg.AC mouse, which has been proposed as an alternative short term model for testing carcinogenicity. We attempted to evaluate the response to the known rodent carcinogens cyclophosphamide, phenolphthalein, and tamoxifen and to the noncarcinogen chlorpheniramine following topical application. In the first study, a weak response (2/17 animals) was observed to the positive control 12-0-tetradecanoylphorbol 13-acetate (TPA in ethanol, 1.25 pg). and no response was observed to cyclophosphamide, phenolphthalein, or chloeheniramine, despite evidence for skin penetration. The second study compared 1.25 pg and 6.25 pg of TPA in ethanol and acetone solutions. Tamoxifen was also evaluated in both solvents and orally. No significant response was observed to tamoxifen by skin paint or oral routes. Over 60% of the high dose TPA-treated animals showed no (0 or 1) papilloma response, and 30% of the animals each developed more than 32 papillomas. The heterogenous response to high dose TPA may be related to variability in the responsiveness of hemizygous animals. In light of these findings, further Tg.AC studies should employ homozygous animals, and the underlying cause for heterogeneity in the tumorigenic response of Tg.AC mice should be identified and eliminated.Papillomagenesis; cyclophosphamide; chlorpheniramine; phenolphthalein; skin: tamoxifen; 12-o-tetradecanoylphorbol Keyvords.13-acetate; zeta-globin INTRODUC~IONThe testing of pharmaceuticals for potential carcinogenicity has traditionally been performed using 2-yr dosing studies in both mice and rats. Recently, an agreement has been reached stimulating revisions to this process. The document entitled "Testing for Carcinogenicity of Pharmaceuticals" was recently signed by representatives to the International Committee for Harmonization and published in' the Federal Register (5). This agreement, among the U.S. Food and Drug Administration (FDA), the European Union, the Japanese Ministry of Health and Welfare, and the three pharmaceutical manufacturer groups for these regions, allows 1 short-or medium-term rodent carcinogenicity model to replace 1 of the species from the 2-yr rodent bioassay. The confidence behind the FDA's agreement to use data from alternative assays is primarily based on a knowledge base from the Center for Drug Evaluation and Research (3) showing that the rat data are primarily predictive and are relied on more heavily than the mouse data for predicting human carcinogenicity. The rat model will continue to be used in a 2-'yr bioassay format while allowing the use of 1 shorter term alternative to expand the knowledge base on these models.Several different animal models have been identified as possible candidates for the short-term test. The Tg.AC, Tg-rasH2, p53 heterozygote, XPA-deficient, and newborn mouse models are the subjects of a more recent collaborative effort organized by the International Life Sciences Institute (ILSI) to address this question. The early data suppo...

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Considerable amounts of aflatoxins were produced when mycelium of Asperg i h s parasiticus ~~~1 , 3 2 4 0 grown for 4 days in a synthetic medium (SL medium) or a semi-synthetic medium (YES medium) were resuspended in either medium for 2 days, but not when resuspended in media lacking sucrose, or in buffers. Acetate[~-l*C] was incorporated efficiently on addition to cultures grown in YES medium or on addition to mycelium grown and resuspended in SL medium. Changes in pH within the range of 3.5 to 6.5 did not have any pronounced effect on aflatoxin production or on incorporation of labelled acetate by resuspended mycelia.