[Federal Register Volume 59, Number 35 (Tuesday, February 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-3856]


[[Page Unknown]]

[Federal Register: February 22, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 442, 444, 448, and 455

[Docket No. 93N-0364]

 

Antibiotic Drugs; Updates, Technical Changes, and Corrections

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 by updating, making noncontroversial 
technical changes, and making corrections in accepted standards of 
antibiotic and antibiotic-containing drugs for human use. These changes 
will result in more accurate and usable regulations.

DATES: Effective February 22, 1994; written comments, notice of 
participation, and request for a hearing by March 24, 1994; data, 
information, and analyses to justify a hearing by April 25, 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: Peter A. Dionne, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-0335.

SUPPLEMENTARY INFORMATION: FDA is amending the antibiotic drug 
regulations by updating, making noncontroversial technical changes, and 
making corrections in certain antibiotic drug regulations that provide 
for accepted standards of antibiotic and antibiotic-containing drugs 
intended for human use.
    In Sec. 442.216a(a)(1) (21 CFR 442.216a(a)(1)), separate limits for 
the pyridine content are being given for the L-arginine formulation and 
the sodium carbonate formulation. Separate limits are needed because 
the current limits allow the L-arginine formulation to contain up to 
5.2 milligrams (mg) of pyridine per gram (g) of ceftazidime activity, 
while the sodium carbonate formulation may not contain more than 4.4 mg 
of pyridine per g of ceftazidime activity.
    In Sec. 442.216a(b)(1)(ii)(a), different loss on drying procedures 
are given for the L-arginine formulation and the sodium carbonate 
formulation. This is necessary because the procedure in the current 
monograph would not remove all of the water from the sodium carbonate 
formulation of the product (some water is ``trapped'' as sodium 
hydrogen carbonate), and the procedure will thus lead to falsely high 
potency values. Because the two formulations contain differing amounts 
of ceftazidime pentahydrate as a percent weight by weight of the powder 
blend, different loss on drying limits are now being given for each 
formulation. The loss on drying limits are now not more than 12.5 
percent if it contains L-arginine and not more than 13.5 percent if it 
contains sodium carbonate. The asymmetry of the arginine peak is also 
revised from the current limit of 2.5 to a limit of 4.0. This limit is 
more realistic of the values obtained in this assay.
    Revisions are being made in the descriptions of certain ophthalmic 
products (21 CFR part 444) and peptide products (21 CFR part 448). FDA 
has discovered that some of these monographs contain errors that would 
allow formulation without preservatives and other essential inactive 
ingredients to fit the monographs. FDA has not reviewed any of these 
products without these ingredients and does not know if they are safe 
and effective. The agency is, therefore, revising certain ophthalmic 
monographs to correct these errors.
    In Sec. 455.185a(a)(1) (21 CFR 455.185a(a)(1)), FDA is making a 
revision to allow vancomycin hydrochloride for oral solution to contain 
a suitable stabilizing agent. The agency has reviewed this formulation 
and found it to be safe and effective.

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

    These amendments institute changes that are corrective, editorial, 
or of a minor technical nature. Because the amendments are not 
controversial, and because when effective they provide notice of 
accepted standards, FDA finds that notice, public procedure, and 
delayed effective date are unnecessary and not in the public interest. 
This final rule, therefore, becomes effective February 22, 1994. 
However, interested persons may, on or before March 24, 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 March 24, 1994, a written notice of participation 
and request for a hearing, and (2) on or before April 25, 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 Parts 442, 444, 448, and 455

    Antibiotics.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
442, 444, 448, and 455 are amended as follows:

PART 442--CEPHA ANTIBIOTIC DRUGS

    1. The authority citation for 21 CFR part 442 continues to read as 
follows:

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

    2. Section 442.216a is amended by revising paragraphs (a)(1), 
(b)(1)(ii)(a), and (b)(4) to read as follows:


Sec. 442.216a  Ceftazidime pentahydrate for injection.

    (a) Requirements for certification--(1) Standards of identity, 
strength, quality, and purity. Ceftazidime pentahydrate for injection 
is a dry mixture of ceftazidime pentahydrate and sodium carbonate or L-
arginine. Its ceftazidime potency is satisfactory if each milligram of 
ceftazidime pentahydrate for injection contains not less than 900 
micrograms and not more than 1,050 micrograms of cefazidime activity 
when corrected for both loss on drying and its sodium carbonate or L-
arginine content, as appropriate for the formulation. Its ceftazidime 
content is satisfactory if it is not less than 90 percent and not more 
than 120 percent of the number of milligrams of ceftazidime that it is 
represented to contain. It is sterile. It is nonpyrogenic. Its loss on 
drying is not more than 12.5 percent if it contains L-arginine and not 
more than 13.5 percent if it contains sodium carbonate. The pH of its 
aqueous solution is not less than 5.0 and not more than 7.5. Its 
pyridine content, if it contains sodium carbonate, is not more than 0.4 
percent, except that for the issuance of a certificate for each batch 
of the sodium carbonate formulation, the pyridine content is not more 
than 0.12 percent. Its pyridine content, if it contains L-arginine, is 
not more than 0.3 percent, except that for the issuance of a 
certificate, the pyridine content of the L-arginine formulation is not 
more than 0.10 percent. The ceftazidime pentahydrate conforms to the 
standard prescribed by Sec. 442.16a(a)(1).
* * * * *
    (b) * * *
    (1) * * *
    (ii) Calculations--(a) Ceftazidime potency (micrograms per 
milligram). Calculate the micrograms of ceftazidime per milligram as 
follows:

                                                                        
                                                      Au X Ps X 100     
  Micrograms of ceftazidime per milligram    =  ------------------------
                                                  As X Cu X (100-m-S-A) 
                                                                        

where:
Au = Area of the ceftazidime peak in the chromatogram of the 
sample (at a retention time equal to that observed for the 
standard);
As = Area of the ceftazidime peak in the chromatogram of the 
ceftazidime working standard;
Ps = Ceftazidime activity in the ceftazidime working standard 
solution in micrograms per milliliter;
Cu = Milligrams of sample per milliliter of sample solution;
m = Percent loss on drying (determined as directed in 
Sec. 436.200(h) of this chapter if the formulation contains sodium 
carbonate and determined as directed in Sec. 436.200(g) of this 
chapter if the formulation contains L-arginine);
S = Percent sodium carbonate content of the sample (determined as 
directed in Sec. 436.357 of this chapter); and
A = Percent L-arginine content of the sample (determined as directed in 
Sec. 455.204 of this chapter, except use ceftazidime instead of 
aztreonam in the working standard solution and use water instead of 
mobile phase). Prepare the sample solution by diluting an accurately 
weighed portion of the contents of a vial with water to 0.2 milligram 
per milliliter (estimated). The resolution between the ceftazidime peak 
and the arginine peak is not less than 6.0, the asymmetry factor for 
the arginine peak is not more than 4.0).
* * * * *
    (4) Loss on drying. Proceed as directed in Sec. 436.200(h) of this 
chapter if the formulation contains sodium carbonate and as directed in 
Sec. 436.200(g) of this chapter if the formulation contains L-arginine.
* * * * *

PART 444--OLIGOSACCHARIDE ANTIBIOTIC DRUGS

    3. The authority citation for 21 CFR part 444 continues to read as 
follows:

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

    4. Section 444.320c is amended by revising the second sentence of 
paragraph (a)(1) to read as follows:


Sec. 444.320c  Gentamicin sulfate-prednisolone acetate ophthalmic 
suspension.

    (a) * * *
    (1) * * * It contains suitable and harmless chelating agents, 
tonicity agents, buffers, and preservatives. * * *
* * * * *
    5. Section 444.342a is amended by revising the first sentence of 
the undesignated paragraph under paragraph (a)(1)(v) to read as 
follows:


Sec. 444.342a  Neomycin sulfate- -------------------- ophthalmic 
suspension; neomycin sulfate- -------------------------- ophthalmic 
solution (the blanks being filled in with the established name(s) of 
the other active ingredient(s) present in accordance with paragraph 
(a)(1) of this section).

    (a) * * *
    (1) * * *
    (v) * * *
It contains suitable and harmless buffers, dispersants, and 
preservatives. * * *
* * * * *
    6. Section 444.342c is amended by revising the first sentence of 
the undesignated paragraph under paragraph (a)(1)(ii) to read as 
follows:


Sec. 444.342c  Neomycin sulfate-gramicidin -------------------------- 
ophthalmic solution; neomycin sulfate-gramicidin ------------------ 
ophthalmic suspension (the blanks being filled in with the established 
name(s) of the other active ingredient(s) present in accordance with 
paragraph (a)(1) of this section).

    (a) * * *
    (1) * * *
    (ii) * * *
It contains suitable and harmless buffers, dispersants, irrigants, and 
preservatives. * * *
* * * * *
    7. Section 444.342d is amended by revising the first sentence of 
the undesignated paragraph under paragraph (a)(1)(iv) to read as 
follows:


Sec. 444.342d  Neomycin sulfate-polymyxin B sulfate ------------------
---- ophthalmic suspension (the blank being filled in with the 
established name(s) of the other active ingredient(s) present in 
accordance with paragraph (a)(1) of this section).

    (a) * * *
    (1) * * *
    (iv) * * *
It contains suitable and harmless buffers, dispersants, irrigants, and 
preservatives. * * *
* * * * *
    8. Section 444.342i is amended by revising the second sentence of 
paragraph (a)(1)(ii) to read as follows:


Sec. 444.342i  Neomycin sulfate-polymyxin B sulfate ophthalmic 
solution.

    (a) * * *
    (1) * * *
    (ii) * * * It contains suitable and harmless buffers, dispersants, 
irrigants, and
 preservatives. * * *
* * * * *
    9. Section 444.342j is amended by revising the second sentence of 
paragraph (a)(1) to read as follows:


Sec. 444.342j  Neomycin sulfate-polymyxin B sulfate-dexamethasone 
ophthalmic suspension.

    (a) * * *
    (1) * * * It contains suitable and harmless buffers, dispersants, 
irrigants, and
 preservatives. * * *
* * * * *
    10. Section 444.380a is amended by revising the second sentence of 
paragraph (a)(1) to read as follows:


Sec. 444.380a  Tobramycin ophthalmic solution.

    (a) * * *
    (1) * * * It contains suitable and harmless buffers, dispersants, 
preservatives, and tonicity agents. * * *
* * * * *
    11. Section 444.380c is amended by revising the second sentence of 
paragraph (a)(1) to read as follows:


Sec. 444.380c  Tobramycin-dexamethasone ophthalmic suspension.

    (a) * * *
    (1) * * * It contains suitable and harmless buffers, dispersants, 
preservatives, and tonicity agents. * * *
* * * * *

PART 448--PEPTIDE ANTIBIOTIC DRUGS

    12. The authority citation for 21 CFR part 448 continues to read as 
follows:

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

    13. Section 448.330 is amended by revising the second sentence of 
paragraph (a)(1) to read as follows:


Sec. 448.330  Polymyxin B sulfate-trimethoprim hemisulfate ophthalmic 
solution.

    (a) * * *
    (1) * * * It contains suitable and harmless buffers and 
preservatives. * * *
* * * * *

PART 455--CERTAIN OTHER ANTIBIOTIC DRUGS

    14. The authority citation for 21 CFR part 455 continues to read as 
follows:

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

    15. Section 455.185a is amended in paragraph (a)(1) by adding a new 
sentence after the first sentence to read as follows:


Sec. 455.185a  Vancomycin hydrochloride for oral solution.

    (a) * * *
    (1) * * * It may contain a suitable stabilizing agent. * * *
* * * * *

    Dated: February 9, 1994.
Stephanie R. Gray,
Acting Director, Office of Compliance, Center for Biologics Evaluation 
and Research
[FR Doc. 94-3856 Filed 2-18-94; 8:45 am]
BILLING CODE 4160-01-F