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Executive Summary

Excipients in new dosage forms should be examined for safety and the data presented in NDA submissions, FDA Chemist Stuart Zimmerman, Div. of Cardio-Renal Drug Products said in comments on the FDA draft guideline on NDA submissions. Zimmerman emphasized that "any one set of experiments that may be designed to show a lack of potential toxicity for a drug in one context may not be completely extrapolatable to another drug product having been designed to be administered in another manner." Citing the example of an oral dosage versus a transdermal system, the FDA reviewer advised that "caution must be used to accurately extrapolate" the toxicity results. The FDAer maintained that the agency's drug product guideline does not address fully the issue of how an NDA applicant should treat excipients for which there are no established set of specifications, or for which the official sanctions were established for a different usage or dosage form. Zimmerman's comments may be interpreted as a practical addendum to the drug product guideline. His comments reflect the view of an FDA reviewer toward the type of data regarding excipients which review staffers want to see in NDA submissions. The first step for the sponsor should be to identify to what extent there have been prior safety sanctions for the usage of a proposed excipient, Zimmerman suggested. If the NDA proposed to rely on a previously approved sanction, the basis for this reliance should then be given. Of concern, particularly for new drug delivery systems, Zimmerman said, are such factors as "(a) design of the study aimed to develop any sanction concerned with safeness (b) validity of the methodologies used to measure toxic effects, (c) specific types of toxic effects considered; such as, tissue-specificity for adverse effects and (d) specific barriers involved that may limit migration of the excipient, and/or known endogenous transport systems that may have effects." A hypothetical example highlighting the difficulties that can arise interpreting toxicity data, Zimmerman suggested, would be a firm proposing to use a particular excipient as an enhancer to help transport a drug across a skin barrier in a transdermal system. "The firm may not have considered that in this application the excipient may have the risk of degrading the skin whereas it may not have shown toxic effects when taken orally or in a test animal in some previously conducted study that allowed that excipient to be classified as safe under some CFR [Code of Federal Regulations] sanction." Whatever conclusions are stated in the NDA by the firm regarding the excipient, Zimmerman maintained, "should be fully justified by taking all the relevant similarities and differences between reliantly used sanctions and their own application for usage into account. Any conditional assumptions made, aims of protocols involved, and limits of methodologies involved should be explained." Zimmerman added that "only by this kind of assessment can the reviewer feel confident that the scientific facts have been appropriately discussed for a reasonable assessment to be made." For excipients having no official FDA sanction, such as GRAS status or CFR food additive status, Zimmerman said, a key question to address is the excipient's potential for reaching systemic circulation. If an excipient shows that potential, the FDA reviewers would be likely to ask the extent to which it may attain levels that could cause toxic effects. Again citing the case of a transdermal system, Zimmerman noted that "if a substance showed a high potential for migration through the skin, then it may be more suspect for causing subsequent toxic reactions than if it was blocked by the skin layers."

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