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This article was originally published in The Tan Sheet

Executive Summary

ADVIL, ANACIN, PREPARATION H, TODAY SPONGE CITED IN FDA WARNING LETTER to Whitehall outlining violations of current good manufacturing practices. In the March 19 letter, FDA Newark District Director Matthew Lewis said that FDA inspectors found cGMP deficiencies during a Feb. 3-March 1 inspection of Whitehall's Hammonton, N.J. facilities that involved "the manufacture, processing, packaging, testing and distribution of Advil tablets, Dristan gel capsules, Anacin tablets, Maximum Strength Anacin tablets, Arthritis Pain Formula caplets, Preparation H suppositories and [the] Today contraceptive sponge." Whitehall said it is working with FDA compliance officials to resolve questions raised by the warning letter. Among the GMP problems cited in the nine-page warning letter were "inadequate/deficient" annual product reviews conducted by Whitehall. The warning letter states that "annual product reviews were found to be inadequate/deficient for each drug product to determine the need for changes in drug product specifications, manufacturing and/or control procedures." Specifically, the annual reviews "do not include a review of investigation of all product failures of batches or components to meet specifications or recommendations to correct deficiencies for future batches," FDA said. The annual product review for Dristan gelcaps uncoated cores, for instance, showed no product rejects. "However, Dristan Uncoated Tablets, Batch #100304, failed content uniformity," which resulted in the rejection of Batch #106617 of Dristan gel caps on Dec. 23, 1992 for failing content uniformity," FDA explained. Similarly, the annual product review for Preparation H Ointment showed that five batches were rejected in 1992, but "does not identify all batch failures" for the product, FDA charged. A batch of Dristan gelcaps uncoated cores also was "found to fail specifications for content uniformity," FDA said, adding that the investigation report into this failure was inadequate "because there was no mention of the possible cause of the failure and no reference to any review of other batches." In addition, a batch production record for Dristan gelcaps was "ambiguous and nonreflective of the batch in that it was rejected for content uniformity yet was released by [quality assurance]. No reason was listed on the batch record to justify the release," the agency pointed out. Regarding Advil, FDA found that packaging date codes "to identify dates of stability testing [are] inaccurate because stability batches revealed that packaging date codes are not truly representative of the product age." The letter adds that the procedure currently in effect "for requesting and receiving stability samples from the Richmond, Va. facility is inadequate in that there is very little correlation and coordination between QA personnel to ensure that the correct dated samples are pulled for testing." Also, there is "no reconciliation between the products manufactured and the stability samples collected," FDA determined. On deficiencies associated with Aspirin Free Anacin, FDA discovered that a batch of an acetaminophen and starch mixture that was used to manufacture Aspirin Free Anacin uncoated core tablets contained 800 parts per million of para-aminophenol when no more than 5 ppm is allowed. Yeast and mold also were found in that batch, which was subsequently rejected. "However, the analysis of remaining lots [of the acetaminophen/starch] only included analysis for . . . mold and yeast" and not for the overabundance of para-aminophenol. The warning letter also mentions the contamination of certain batches of Arthritis Pain Formula, which was the subject of a recent Class II recall by Whitehall ("The Tan Sheet" March 22, p. 16). FDA faulted the "design of the chilsonator," which was found to be "inadequate to prevent foreign matter from contaminating the batch." In a separate section outlining Preparation H-related deficiencies, FDA charged that batch production records for Preparation H suppositories were deficient "in that mixing times for ingredients were not always specific." For example, there was no specific time indicated for: the addition of "'remelt' leftovers from previous batches which were added to the blend of current batches prior to molding"; and the addition of "'PMN' glycerin solution added to preweighted skin respiratory factor," FDA said. "Adequate procedures for tracking investigation of product failures and subsequent release" also have not been established by Whitehall for Preparation H, the agency said. For instance, a certain batch of the product was packaged into three date codes, FDA explained. The three packaged codes were retested and two codes were released. "There was no written rationale why these codes were released and [the third code] was rejected," the letter maintains. In addition, Whitehall did not validate the "Z" stock formulation for Preparation H,nor did it perform preservative effectiveness testing for the "Z" stock formulation after a new preservative was added. Validation protocols for the Preparation ointment and suppository formulation also "were not formally approved prior to the manufacture of the validation batches," FDA continued, and validation reports do not address the failure of certain validation batches. Addressing batch production records for Preparation H, FDA cited the firm for being nonspecific about "mixing times, temperature and speed controls." The batch production record also "does not list any time for the temperature required for molded suppositories to be stored in the refrigerator for drying purposes prior to packaging," the agency noted. The FDA letter also assigns a separate section for cGMP violations related to the Today contraceptive sponge. Specifically, the agency cited Whitehall for not having any reject parameters for the Today sponge nor any investigation instructions for product failures. In addition, "production line logs do not accurately identify the defects of the rejected sponges," FDA asserted. In a section of the warning letter on the "quality control laboratory," FDA charged that the "gas chromatograph used in the analysis of Advil tablets, Dristan gelcaps, Anacin tablets, and Arthritis Pain Formula caplets have not been validated with respect to integration of peak areas on chromatograms obtained during analysis of the various OTC drug products." Quality control laboratory notebooks also "contained data that was incomplete, prerecorded and inadequate," and the standard operating procedure for finished product testing was found to be deficient with regard to investigation of product failure in that a written report of investigation is not required if, on retest, a product meets specification." In addition to the recent Arthritis Pain Formula recall, Whitehall's OTC brands have been the subject of several recalls in the last few years. In January 1992, Whitehall initiated a Class II recall of Anacin because of the presence of metal particles due to the contamination of Rhone-Poulenc's bulk product ("The Tan Sheet" March 1, p. 20). The firm also conducted a Class III recall of Preparation H in 1989 due to mold contamination and a Class III recall of the Clearplan Easy ovulation predictor kit in late 1991. Whitehall parent American Home Products also recently received a warning letter from FDA citing the absence of sterility assurance and inadequate validation procedures in Elkins-Sinn's production of diazepam and tobramycin.

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