[Federal Register Volume 59, Number 198 (Friday, October 14, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-25398]


[[Page Unknown]]

[Federal Register: October 14, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 452

[Docket No. 94N-0296]

 

Antibiotic Drugs; Azithromycin for Oral Suspension

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the 
antibiotic drug regulations to provide for the inclusion of accepted 
standards for a new drug dosage form of azithromycin, azithromycin for 
oral suspension. The manufacturer has supplied sufficient data and 
information to establish its safety and efficacy.

DATES: Effective on November 14, 1994; written comments, notice of 
participation, and request for a hearing by November 14, 1994; data, 
information, and analyses to justify a hearing by December 13, 1994.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: James Timper, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-6714.

SUPPLEMENTARY INFORMATION: FDA has evaluated data submitted in 
accordance with regulations promulgated under section 507 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 357), as amended, with 
respect to a request for approval of a new dosage form of azithromycin, 
azithromycin for oral suspension. The agency has concluded that the 
data supplied by the manufacturer concerning the new antibiotic drug 
dosage form are adequate to establish its safety and efficacy when used 
as directed in the labeling and that the regulations should be amended 
in 21 CFR part 452 to provide for the inclusion of accepted standards 
for this product.

Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

Submitting Comments and Filing Objections

    This final rule announces standards that FDA has accepted in a 
request for approval of a new antibiotic drug dosage form. Because this 
final rule is not controversial and because when effective it provides 
notice of accepted standards, FDA finds that notice and comment 
procedure is unnecessary and not in the public interest. This final 
rule, therefore, becomes effective on November 14, 1994. However, 
interested persons may, on or before November 14, 1994, submit written 
comments to the Dockets Management Branch (address above). Two copies 
of any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. Received comments may be seen 
in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday 
through Friday.
    Any person who will be adversely affected by this final rule may 
file objections to it and request a hearing. Reasonable grounds for the 
hearing must be shown. Any person who decides to seek a hearing must 
file (1) on or before November 14, 1994, a written notice of 
participation and request for hearing, and (2) on or before December 
13, 1994, the data, information, and analyses on which the person 
relies to justify a hearing, as specified in 21 CFR 314.300. A request 
for a hearing may not rest upon mere allegations or denials, but must 
set forth specific facts showing that there is a genuine and 
substantial issue of fact that requires a hearing. If it conclusively 
appears from the face of the data, information, and factual analyses in 
the request for a hearing that no genuine and substantial issue of fact 
precludes the action taken by this order, or if a request for a hearing 
is not made in the required format or with the required analyses, the 
Commissioner of Food and Drugs will enter summary judgment against the 
person(s) who request(s) the hearing, making findings and conclusions 
and denying a hearing. All submissions must be filed in three copies, 
identified with the docket number appearing in the heading of this 
document and filed with the Dockets Management Branch.
    The procedures and requirements governing this order, a notice of 
participation and request for a hearing, a submission of data, 
information, and analyses to justify a hearing, other comments, and 
grant or denial of a hearing are contained in 21 CFR 314.300.
    All submissions under this order, except for data and information 
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 
1905, may be seen in the Dockets Management Branch (address above) 
between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 452

    Antibiotics.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
452 is amended as follows:

PART 452--MACROLIDE ANTIBIOTIC DRUGS

    1. The authority citation for 21 CFR part 452 continues to read as 
follows:

    Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 357).

Sec. 452.160a  [Redesignated from Sec. 452.160]

    2. Section 452.160 is redesignated as Sec. 452.160a and new 
Secs. 452.160 and 452.160b are added to subpart B to read as follows:


Sec. 452.160  Azithromycin oral dosage forms.


Sec. 452.160b  Azithromycin for oral suspension.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Azithromycin for oral suspension is a 
dry mixture of azithromycin with a suitable and harmless buffer 
substance, sweetener, diluent, anticaking agent, and flavorings. The 
dry mixture is packaged in single dose packets each containing 1,000 
milligrams of azithromycin. The azithromycin content is satisfactory if 
it is not less than 90 percent and not more than 110 percent of the 
number of milligrams of azithromycin that it is represented to contain. 
Its moisture content is not more than 1.5 percent. When constituted as 
directed in the labeling, the pH of the suspension is not less than 9 
and not more than 11. It gives a positive identity test for 
azithromycin. The azithromycin used conforms to the standards 
prescribed by Sec. 452.60(a)(1).
    (2) Labeling. It shall be labeled in accordance with the 
requirements of Sec. 432.5 of this chapter.
    (3) Requests for certification; samples. In addition to complying 
with the requirements of Sec. 431.1 of this chapter, each such request 
shall contain;
    (i) Results of tests and assays on:
    (A) The azithromycin used in making the batch for potency, 
moisture, pH, residue on ignition, heavy metals, specific rotation, 
crystallinity, and identity.
    (B) The batch for content, moisture, pH, and identity.
    (ii) Samples, if required by the Director, Center for Drug 
Evaluation and Research:
    (A) The azithromycin used in making the batch: 10 packages, each 
containing approximately 1,000 milligrams.
    (B) The batch: A minimum of 30 packages.
    (b) Tests and methods of assay--(1) Azithromycin content. Proceed 
as directed in Sec. 452.60(b)(1), preparing the dissolving solvent and 
sample solution and calculating the azithromycin content as follows:
    (i) Dissolving solvent. Dissolve 2.2 grams of potassium phosphate 
monobasic in 1,590 milliliters of ultrapure deionized or high-
performance liquid chromatographic-grade water. Add 600 milliliters of 
2-propanol, 480 milliliters of ethanol, and 330 milliliters of 
acetonitrile, adjust to pH 8.4 with 10M potassium hydroxide and shake 
on a reciprocating shaker for 30 minutes. The dissolving solvent is 
0.01M monobasic potassium phosphate:2-propanol:ethanol:acetonitrile 
(53:20:16:11, by volume).
    (ii) Preparation of sample solution. Quantitatively transfer the 
contents of one package into a 500-milliliter volumetric flask. Add 
about 350 milliliters of dissolving solvent and shake on a 
reciprocating shaker for 30 minutes. Dilute to volume with dissolving 
solvent, stopper the flask, and mix well. Place 40 milliliters of the 
resulting suspension into a suitably sized centrifuge tube. Stopper the 
tube and centrifuge the suspension (about 20 minutes at 1,000 
revolutions per minute). Pipet 10.0 milliliters of the diluted solution 
into a 50-milliliter volumetric flask and dilute to volume with mobile 
phase (described in Sec. 452.60(b)(1)(i)). Pipet 2.0 milliliters of the 
diluted solution into a 50-milliliter volumetric flask and dilute to 
volume with mobile phase. The final dilution of the sample and standard 
must be identical. The final concentration of azithromycin in the 
sample solution is 0.003 milligram per milliliter (estimated).
    (iii) Calculations. Calculate the azithromycin content as follows: 

                                                                        
     Milligrams of                                    AU X PS X d       
   azithromycin per               =            -------------------------
       package                                         AS X 1,000       
                                                                        

where:
AU = Area of the azithromycin peak in the chromatogram of the 
sample (at a retention time equal to that observed for the 
azithromycin standard);
AS = Area of the azithromycin peak in the chromatogram of the 
azithromycin working standard;
PS = Azithromycin activity in the azithromycin working standard 
solution in micrograms per milliliter; and
d = Dilution factor of the sample = 500 X 50/10 X 50/10 X 50/2.
    (2) Moisture. Proceed as directed in Sec. 436.201 of this chapter.
    (3) pH. Proceed as directed in Sec. 436.202 of this chapter, using 
the drug constituted as directed in the labeling. Allow the constituted 
suspension to sit for 10 minutes undisturbed before making the 
measurement.
    (4) Identity. Using the high-performance liquid chromatographic 
procedure described in paragraph (b)(1) of this section, the retention 
time for the peak of the active ingredient must be within 2 percent of 
the retention time for the peak of the corresponding reference 
standard.

    Dated: September 28, 1994.
David B. Barr,
Deputy Director, Office of Compliance, Center for Drug Evaluation and 
Research.
[FR Doc. 94-25398 Filed 10-13-94; 8:45 am]
BILLING CODE 4160-01-F