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BULK DOXORUBICIN 97% PURITY LEVEL ACCEPTED BY FDA

Executive Summary

BULK DOXORUBICIN 97% PURITY LEVEL ACCEPTED BY FDA in response to a citizen petition originally submitted by Adria Labs to the agency in 1987. In a May 7 letter to Adria's lawyers, Kleinfeld, Kaplan and Becker, Center for Drug Evaluation and Research Director Carl Peck, MD, said "the agency believes that these proposed modifications to the subject monographs reflect an adoption of all the recommended changes submitted both in Adria's request for hearing and its previous Feb. 26, 1987 petition." The proposed modifications appear in a May 3 Federal Register notice. The proposal would amend the antibiotic monograph for doxorubicin published in September 1988, which allowed for 90% purity levels for bulk doxorubicin. In its petition and in a subsequent lawsuit filed in February 1989, Adria argued that the 90% purity levels required for bulk doxorubicin in the monograph set an unacceptably low standard for generic products since Adria's bulk product was 97% pure and a new assay methodology was available to assure such a purity level ("The Pink Sheet" March 27, T&G-12). Cetus-Ben Venue, which received the first generic doxorubicin approval in 1989, is not expected to be affected by the requirement for higher purity standards. Ben Venue, which buys its bulk product from SICOR (Societa Italiana Corticosteroidi), said at the time of the approval that its product meets the specifications sought by Adria. FDA's ANDA approval list states that SICOR's bulk product has purity limits of 97% to 102%. The amendments being proposed to the bulk doxorubicin monograph "revise the doxorubicin hydrochloride content limits from 900 to 1,100 micrograms per milligram on the anhydrous base to 970 to 1,020 micrograms per milligram on the anhydrous and solvent-free basis." FDA is also proposing to: "revise the high-pressure liquid chromatography (HPLC) test currently specified for determining the content of doxorubicin hydrochloride; revise the pH limits from a range of 3.8 to 6.5 to a range of 4.0 to 5.5; add a total solvent residue test with an upper limit of not more than 2.5%; and add a chromatographic purity test with a total impurity specification of not more than 3.0%." The regulation for doxorubicin hydrochloride for injection (lyophilized powder) and doxorubicin hydrochloride injection (aqueous solution) will also be amended under the FDA proposal. For the lyophilized powder, FDA is revising the pH range from 3.8 to 6.5 to a range of 4.5 to 6.5 and adding a provision to the product description allowing methylparaben. In both the powder and aqueous solution regulations, the pyrogen test will be replaced with the USP endotoxin Test with an upper limit of not more than 2.2 USP endotoxin units per milligram of doxorubicin and the HPLC test will be revised.
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