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ICH LATEST IMPURITIES DRAFT SUGGESTS DRUGS WITH DAILY DOSE ABOVE 500 MG

This article was originally published in The Tan Sheet

Executive Summary

ICH LATEST IMPURITIES DRAFT SUGGESTS DRUGS WITH DAILY DOSE ABOVE 500 MG may require a qualification of impurities since the proposed .1% standard would allow for impurities above 500 mcg per day. The fourth and current draft of the impurities guideline (dated Nov. 1), which was released at the Second International Conference on Harmonization Oct. 27-29 in Orlando, Fla., states: "For a drug administered at a dose of greater than 500 mg/day, qualification of impurities which individually would give rise to a dose of more than 500 mcg/day should be considered." The draft generally requires that drug firms identify impurities above .1%. "This consideration would take into account factors such as manufacturing reproducibility and/or analytical capability, duration of therapy and route of administration, and any evidence to suggest that low levels of impurities in certain drug or therapeutic classes have been associated with adverse drug reactions in specific patient populations," the draft document says. The guideline also contains a decision tree for deciding what types of safety studies should be conducted when an impurity level exceeds the threshold. In general, "identification of all impurities at or above the .1% level" is required for all "batches used in safety studies, clinical studies and as manufactured by the proposed commercial process," according to the draft. Impurities observed in stability studies also should be identified, the guideline adds. Although the current impurities guidelines applies only to new drugs, an ad hoc FDA advisory committee suggested at a June meeting that requirements for qualification of unknown impurities in new molecular entities should also apply to OTC drugs and generics ("The Tan Sheet" June 28, p. 13). More recently, FDA Center for Drug Evaluation and Research Associate Director Roger Williams, MD, told a Nonprescription Drug Manufacturers Association conference that FDA is considering adopting the ad hoc committee's recommendation ("The Tan Sheet" Oct. 11, p. 18). The impurities guidance is one of seven such documents being prepared by ICH working groups. Most of the guidances are expected to become consensus guidelines ready for consultation in early 1994. Another ICH draft guideline that deals with dose selection for carcinogenicity studies states that use of a maximum tolerated dose, which was developed for genotoxic substances, may not be appropriate for non-genotoxic agents. There is concern that "exposures in rodents greatly in excess of the intended human exposures may not be relevant to human risk because they so greatly alter the physiology of the test species [and] the findings may not reflect what would occur following human exposure," the draft says. During a wrap-up session of the conference, FDA Division of Genetic Toxicology Director Daniel Casciano, PhD, discussed the dose selection guideline and provided a summary of what the Expert Working Group on Safety recommended during technical symposia. The expert working group reached agreement on when carcinogenicity studies are required, Casciano noted. "It is generally agreed that studies are not required if a product is to be given once or less than three month's duration," the FDAer said. "There is general agreement that carcinogenicity studies are required if the product is to be given for over six-month's duration." In addition, Casciano said, "there has been agreement that if carcinogenicity data is available in two species, additional studies will not be required if there is a change in the clinical route of administration or if there is a change of the chemical form administered. For example, salt to an acid base." This would be acceptable "if adequate evidence is provided that there is no significant alteration in metabolic or pharmacokinetic [profiles]," Casciano stated. Five other consensus draft guidelines were distributed during the ICH conference, including "Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies" and "Toxicokinetics: Guidance for Repeated-Dose Tissue Distribution Studies."
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