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This article was originally published in The Tan Sheet

Executive Summary

DRUG IMPURITY INTERNATIONAL STANDARDS MAY BE APPLIED TO OTCs and generic drugs following a recommendation by an FDA ad hoc advisory committee on June 22. The ad hoc group was convened to discuss the second draft of an International Conference on Harmonization guideline, which addresses how drug companies should handle impurities in new molecular entities. However, the advisory group suggested that the guidelines should also be applied to over-the-counter drugs and generics. In written questions to the committee, which included several members of the agency's Generic Drugs Advisory Committee, FDA asked whether the same standards for identifying impurities in NMEs also should be applied to generic and OTC drugs. Committee member Gordon Amidon, PhD, University of Michigan College of Pharmacy, commented: "I don't see how we can set up a double standard, so consequently I think the same standard [for NMEs] should apply" to OTCs and generics. Addressing the guideline's limited focus on NMEs, FDA Office of Generic Drugs Director Roger Williams said: "I don't think we can make rational public policy that . . . applies to only one segment of life." At a June 23 meeting sponsored by the National Association of Pharmaceutical Manufacturers, FDA Office of Generic Drugs Associate Director of Chemistry Robert Jerussi, PhD, said the ad hoc committee's decision to apply the same impurity standards to OTCs and generics "is a big thing," especially for OTCs. "For generic drugs," he said, "it's probably not too bad. For OTC products, it's probably not so good because those are not treated very rigorously today." At NAPM's annual meeting in January, Jerussi emphasized that the ICH's impurity standards would be "a major change" for the U.S. At the June 22 advisory committee meeting, Williams and Chelsea Labs VP-Scientific Affairs Tony Amann (on behalf of the generic drug industry) predicted that the impurities testing requirements would be burdensome. In general, the ICH guideline calls for the isolation and identification of unknown impurities in NMEs that are present "at a level of .1% or greater." FDA's current practice is to evaluate impurities on a case-by-case basis. The agency does not have a defined threshold for identification of impurities. The ad hoc committee agreed that there should be a threshold for identification of impurities when the route of synthesis of a drug product changes. However, the committee was initially uncertain whether it should recommend a specific threshold given the possibility that lower levels of impurities could cause adverse events. The committee eventually decided that the identification threshold for impurities in drug products should be at the .1% level as in the ICH document. Committee member Christopher Rhodes, University of Rhode Island, summarized: "For want of a number . . . I would be prepared to go with [.1%]; however, I hope that it would be borne in mind that there will be cases where that number would indeed be far too high." Committee members also concluded that regardless of the percentage threshold, if the total daily intake of an impurity exceeds a certain amount, then the impurity should be identified. The committee suggested a range of 100 mcg to 1 mg as an appropriate daily intake threshold for an impurity. The ICH guideline provides two alternatives for defining the threshold limit. One method would use an impurity percentage as a threshold that increases as the daily dose increases. The .1% threshold would be used when the daily dose of an NME exceeds 10 mg. The second option "is based on a concept that levels below .1% would not need qualification for drugs with daily doses exceeding 1,000 mg per day, whereas the qualification of impurities for drugs administered at a daily dose of less than 1,000 mg per day would not require qualification unless the daily intake of the impurity exceeds 1 mg," the guideline states. FDA Division of Oncology and Pulmonary Drugs Supervisory Pharmacologist Alan Taylor, PhD, informed the committee that the agency's "experience with the database suggests that depending on the [impurity in] the drug product, . . . the toxic dose can be quite low." He noted that "it's going to be difficult to not simply arbitrarily assign a dose; at the same time, we do think that that is worth doing . . . having the percent level and a maximum intake." Taylor also is ICH coordinator for the Center for Drug Evaluation and Research's safety working group. FDA Division of Cardio-Rental Drugs Medical Officer Charles Ganley, MD, provided examples of cases where low percentage levels of impurities in drug products can cause serious adverse health effects. Ganley described the 1989 case in which contaminated L- tryptophan manufactured in Japan resulted in over 1,500 reports of eosinophilia myalgia syndrome and more than 30 deaths. "One impurity . . . has been implicated as a potential impurity responsible for EMS," Ganley said. "The median amount of this impurity in lots examined is .0089%" and if the substance is "responsible for EMS, affected individuals ingested approximately 200 mcg per day." FDA is evaluating the ICH draft guideline on impurities in preparation for the ICH II conference in Orlando, Fla. on Oct. 27-29, where the document will be the subject of further discussion.

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