EA Review #1, NDA 20-358

Page 11

Half-lives were presented at 54, 11, and 30 hours at pH 5, 7, and 9, respectively.

The half-life presented are experimental values in the presence of a xenon arc lamp.  Considerably longer half-lives were obtained from calculations which normalized these results to flat bodies of water at various seasons and latitudes (see page 177).  Since many of these half-lives exceed the threshold of 5 days, the statement that the drug substance is subject to rapid photodegradation in aqueous media (page 14) is misleading.  Photodegradation cannot be considered a primary depletion mechanism unless the longer half lives can be shown to be irrelevant to the locations or seasons where the substance may be released.

DEFICIENT.

8.

Environmental Effects of Released Substances

Microbial inhibition was conducted by (whited out) according to EATAD 4.02 in compliance with FDA Good Laboratory Practice regulations (see Attachment 4).  No inhibition of soil bacteria or nitrogen-fixing bacteria was observed.  An MIC of 1000 mg/L was determined for fungi, ascomycetes, and blue-green algae.

Adequate.

Search literature and report available test data in format items 7 and 8 and also report any mammalian toxicity information.  A computerized structure/activity relationship modeling program could be used to supplement the literature information.

9.

Use of Resources and Energy:

a.       Use of Water and Energy:

          The Wellcome Foundation Limited (UK)

          It is estimated that less than 10% of the facilities energy use and less than 0.1% of the water will           be associated with drug substance production.

          Adequate.

          Burroughs Wellcome Co. (USA)

          Drug Substance