[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
