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ICH REQUIREMENTS FOR QUALIFICATION OF IMPURITIES IN NEW MOLECULAR ENTITIES SHOULD APPLY TO GENERIC AND OTC DRUGS, FDA AD HOC ADVISORY CMTE. AGREES

Executive Summary

International requirements for qualification of unknown impurities in new molecular entities should apply to generic drugs and over-the-counter drugs, an FDA ad hoc advisory committee concluded June 22. The ad hoc committee was convened to discuss a second draft guideline by the International Conference on Harmonization, which addresses how drug companies should handle impurities in NMEs. FDA is currently evaluating the draft guideline in preparation for the ICH II conference in Orlando, Fla. on Oct. 27-29, where the guideline will be the subject of further discussions. The second draft guideline was completed in March. 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. 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, 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 generics and OTCs]." Concerns about the scope of the guideline were voiced by FDA Office of Generic Drugs Director Roger Williams, who said: "I don't think we can make rational public policy that maybe applies to only one segment of life [NMEs]." Summarizing the ad hoc committee's findings, Committee Chairman Leslie Benet, PhD, University of California at San Francisco, said: "If a generic product shows more than .1% of an impurity [then] that .1% would have to be isolated and characterized." Addressing the impact of the impurities testing requirements, Williams said: "I think we're talking about a series of, I would say fairly horrendous pharm/tox studies that are quite expensive. It's burdensome [to generic companies], no question about it." The guideline specifies that when the level of an unknown impurity goes above the threshold, "if data or literature references are not available on the safety of a new impurity, toxicity studies may be required." Representing generic drug associations, Chelsea Labs VP Scientific Affairs Tony Amann warned that "the impact on the whole [generic] industry is going to be phenomenal. Certainly we can expect reduced competition...delays...unnecessary duplication of testing...and increased cost." Amann queried: "Are we getting more and more to an NDA system rather than to an ANDA system under the present guideline?" The following day at the National Association of Pharmaceutical Manufacturers' mid-year meeting in Washington, D.C., Office of Generic Drugs Associate Director of Chemistry Robert Jerussi, PhD, said the ad hoc committee's decision that the same impurity standards should hold for NMEs, generics and OTCs "is a big thing; for generic drugs, 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, major, major change" for the U.S. ("The Pink Sheet" Feb. 15, T&G-3). The ad hoc committee agreed that there should be a threshold for identification of impurities when the route of synthesis for drug products changes. However, the committee was initially uncertain whether it should recommend a specific number for the threshold given the possibility that lower levels of impurities could cause adverse events. The committee eventually determined that the identification threshold for impurities in drug products should be the .1% level. Committee member Christopher Rhodes, University of Rhode Island, said: "I think it's reasonable...In [the] best of all possible worlds, each case would be considered by its separate scientific merits." But, Rhodes pointed out, "we live in a world where we do at least have to have some guidelines." He concluded: "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. The ICH guideline gives two alternate proposals for defining the threshold limit. Alternative I uses an impurity percentage as a threshold that increases as the daily dose increases. The .1% threshold is used when the daily dose of an NME exceeds 10 mg. "Alternative II 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. The guideline notes that identification of impurities below levels of .1% "is generally not considered necessary. However, where there is evidence to suggest the presence of formation of toxic impurities, there may then be a need to identify them at lower levels." FDA Division of Oncology and Pulmonary Drugs Supervisory Pharmacologist Alan Taylor, PhD, informed the committee that "our experience with the data-base 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 & Research safety working group. FDA Division of Cardio-Renal 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. One case came to light in 1988, when FDA was notified that many batches of Warner-Lambert's Cholybar (cholestyramine) were contaminated with DDT-like pesticides. "In some lots, the amount of DDE and DCBP were as high as .092% and .073%, respectively," Ganley said. "If resin from these lots were ingested at the highest recommended doses of cholestyramine, which is 24 gms per day, a patient would have ingested 22 mgs of DDE and 18 mgs of DCBP per day." 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." At the open public hearing, Canadian Health Protection Branch Drugs Directorate Pharmaceutical Division Chief Peter Jeffs, PhD, told the committee that Canada has used the .1% threshold for seven years. Jeffs noted that the policy also applies to generic drugs. "As a matter of fact, that was probably a major reason that we went into looking at impurities at that level," Jeffs said. He added that "if we found an impurity that was above .1%, normally what would happen is the company would go back and clean it up . . . What's happening now is that these studies are all done before the product comes in."
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