November 18, 1991

PMF 5351-A000

Arthur L. Craigmill, PhD
Animal Drug Coordinator
Western Region IR-4
Environmental Toxicology
University of California
Davis, CA 95616

Dear Dr. Craigmill:

We refer to your submission dated April 2, 1991, to the Public Master File (PMF) 5351 providing for the use of procaine penicillin G and novobiocin sodium suspension as a dry-doe treatment for mastitis in dairy goats. The submission contains efficacy, target animal safety and milk depletion data, an environmental assessment and the freedom of information (FOI) summary.

We have completed our review of the submission and offer the following comments:

1 . Efficacy

We are unable to complete a review of the efficacy study results because of inadequate data submission. Since there was a very low incidence of bacterial udder infection in the herds of dairy goats used in the study, additional information is needed to verify the results presented in summary tables for the drug's treatment and control claims as follows:

A. In order to determine the actual incidence of udder infection with various organisms in each herd before treatment and their response after treatment, we need the complete "Case Report Form" described in Table 2 for the pre- and post-treatment bacterial milk culture status of each treated and untreated control animals from each herd.

B. From the above information, prepare separate tables for each herd indicating isolation of each organism from the udder of an animal sampled (both treated and control) pre- and post-treatment.

The summary tables which were submitted do not indicate the source of each animal and its udder health status. Also, no explanations were provided for the asterisk used in the table (raw data) for several animals.

C. Appropriate explanations are needed to decipher and verify the data presented in Table 5. It is not clear how the animals were selected and categorized under treated and control claims. There appears to be some error in the numbers shown across the lines 12-14; these need to be verified.

D. We need complete data (including raw data) with proper explanations so that data presented in Tables 6 and 7 can be verified. This is essential to account for each animal which is identified as either failure or cure in support of the treatment and control claims.

2. Target Animal Safety

We are not convinced that the intramammary product (Albadry Plus®) is safe as the target animal safety study indicates for the following reasons:

The data indicate that intramammary infusion of 200,000 IU procaine penicillin G plus 400 mg novobiocin sodium suspension into the udders of goats caused irritation which was not palpable during the observation period. Immediately after treatment, the somatic cell count (SCC) was greatly elevated and then declined but not to the pre-treatment level by 6 days post-treatment indicating persistence of irritation. Other adverse reactions observed included the presence of clots and flakes in the foremilk of all treated does by the 4th milking (approximately 2 days post-treatment) and blood tinged milk from 2/3 of the does by the 6th milking which persisted for 6 milkings. However, the report has failed to indicate when these conditions cleared up and the udders of the affected animals became normal.

Since the above adverse reactions were observed in does which were milked twice a day following treatment, it is believed that in normal use conditions as a dry-doe therapy, the product (Albadry Plus®) may cause more irritation to the udders of does not being milked out. Therefore, we suggest that you submit any additional safety information you may have to address our concerns.

3. Milk Depletion

The standard curves used to assay the peniciliin content of goat milk in the milk depletion study did not reach the necessary detection level. Therefore, it cannot be determined if there were penicillin residues at the working harmonized tolerance level of 0.008 u/mL for penicillin G procaine. The penicillin portion of the study should be repeated. The recoveries for penicillin in milk were very low, which increases the detection level. Consideration should be given to the use of a standard curve diluted in milk, which would eliminate the need for recovery factors. If this study is repeated, we will require comparability data to show that the modifications of method from the original "Greenbook" method for penicillin do not affect the accuracy and precision of the method. Comparability data should also be provided for the novobiocin assay.

We remind you that a sponsor requesting approval of an NADA in dairy goats will need to provide a residue depletion study in edible tissues for establishing a withdrawal period. If IR-4 decides to initiate such a study, we suggest that a protocol be provided to us for review before study initiation.

4. Environmental Assessment (EA)

We have reviewed the submitted EA and have determined that the use of Albadry Plus® Suspension in dairy goats is not expected to have a significant impact on the environment.

When an NADA or supplemental NADA for the proposed use is submitted, it will be necessary for the sponsor to provide information concerning the potential environmental impacts of the manufacturing process. Specifically, for any domestic bulk drug and premix production site(s), the sponsor should submit a list of substances expected to be emitted, the mission controls exercised, a citation of and signed statement of compliance with applicable emission requirements (including occupational) at the Federal, state and local level, and a discussion of the effect the approval will have upon compliance with current emission requirements. The same type of information should be provided for any foreign production of the drug or, alternatively, the sponsor can provide letters from the appropriate office(s) of the foreign government stating that the manufacture of the product that is the subject of the application has been evaluated by that government and that it meets their requirements for emission and occupational controls. The letter(s) should specify the drug manufacturing facility, the drug product that would be manufactured under the NADA and the government's emission and occupational requirements.

The manufacturing information will be evaluated along with the information provided in the PMF EA for Albadry Plus® Suspension for use in dairy goats and, if appropriate, a finding of no significant impact (FONSI) will be prepared for the approval of the NADA.

5. FOI Summary

We will provide detailed comments on your FOI summary when the concerns with the efficacy, target animal safety and microbiological results noted above are addressed.

Should you have any questions concerning the above comments, please contact us.

Future correspondence regarding this submission to the file for your public master file (PMF) should be addressed by this submission's correspondence date and our file number, PMF 5351-A000.

Sincerely yours,

/s/
Andrew J. Beaulieu, DVM
Director, Division of Therapeutic Drugs for Food Animals
New Animal Drug Evaluation
Center for Veterinary Medicine