Antibiotics Drugs; Rifabutin and Rifabutin Capsules

DEPARTMENT OF HEALTH AND HUMAN SERVICES

21 CFR Parts 430, 436, and 455

[Docket No. 94N-0184]

Antibiotics Drugs; Rifabutin and Rifabutin Capsules

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 include accepted standards for a new

antibiotic drug, rifabutin, and the use of the antibiotic drug in a

dosage form, rifabutin capsules. The manufacturer has supplied

sufficient data and information to establish its safety and efficacy.

DATES: Effective September 9, 1994; written comments, notice of

participation, and requests for a hearing by September 9, 1994; data,

information, and analyses to justify a hearing by October 11, 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 (1) a new antibiotic drug,

rifabutin, and (2) its use in a dosage form, rifabutin capsules. The

agency has concluded that the data supplied by the manufacturer

concerning these antibiotic drugs are adequate to establish their

safety and efficacy when used as directed in the labeling and that the

regulations should be amended in 21 CFR parts 430, 436, and 455 to

include accepted standards for these products.

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 an antibiotic drug. 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,

is effective September 9, 1994. However, interested persons may, on or

before September 9, 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 September 9, 1994, a written notice of

participation and request for a hearing, and (2) on or before October

11, 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

21 CFR Part 430

Administrative practice and procedure, Antibiotics.

21 CFR Parts 436 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

430, 436, and 455 are amended as follows:

PART 430--ANTIBIOTIC DRUGS; GENERAL

1. The authority citation for 21 CFR part 430 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 507, 701 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,

355, 357, 371); secs. 215, 301, 351 of the Public Health Service Act

(42 U.S.C. 216, 241, 262).

2. Section 430.4 is amended by adding new paragraph (a)(69) to read

as follows:

Sec. 430.4 Definitions of antibiotic substances.

(a) * * *

(69) Rifabutin. Rifabutin is an antibiotic substance having the

chemical structure described by the following name:

(9S,12E,14S,15R,16S,17R,18R,19R, 20S,21S,22E, 24Z)-6,16, 18,20-

tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-

heptamethylspiro[9,4-(epoxypentadeca[1,11,13]trienimino)-2H-

furo[2',3':7,8]naphth[1,2-d]imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-

trione-16-acetate.

* * * * *

3. Section 430.5 is amended by adding new paragraphs (a)(104) and

(b)(106) to read as follows:

Sec. 430.5 Definitions of master and working standards.

(a) * * *

(104) Rifabutin. The term ``rifabutin master standard'' means a

specific lot of rifabutin that is designated by the Commissioner as the

standard of comparison in determining the potency of the rifabutin

working standard.

(b) * * *

(106) Rifabutin. The term ``rifabutin working standard'' means a

specific lot of a homogeneous preparation of rifabutin.

4. Section 430.6 is amended by adding new paragraph (b)(106) to

read as follows:

Sec. 430.6 Definitions of the terms ``unit'' and ``microgram'' as

applied to antibiotic substances.

* * * * *

(b) * * *

(106) Rifabutin. The term ``microgram'' applied to rifabutin means

the rifabutin (potency) contained in 1.022 micrograms of the rifabutin

master standard.

PART 436--TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-

CONTAINING DRUGS

5. The authority citation for 21 CFR part 436 continues to read as

follows:

Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 357).

6. Section 436.215 is amended by alphabetically adding a new entry

to the table in paragraph (b) and by adding new paragraph (c)(18) to

read as follows:

Sec. 436.215 Dissolution test.

* * * * *

(b) * * *

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Dosage form Dissolution medium Rotation rate\1\ Sampling time(s) Apparatus

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* * * * * * *

Rifabutin capsules 900 mL 0.01N hydrochloric acid 100 45 min 1

* * * * * * *

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\1\Rotation rate of basket or paddle stirring element (revolutions per minute).

(c) * * *

(18) Rifabutin--(i) Preparation of the working standard solution.

Accurately weigh approximately 45 milligrams of the rifabutin working

standard into a suitable-sized volumetric flask. Dissolve and dilute to

volume with 0.01N hydrochloric acid (prepared by diluting 5.0

milliliters of hydrochloric acid (37 percent) to 6 liters with

distilled water) to obtain a concentration of approximately 13

micrograms rifabutin activity per milliliter.

(ii) Preparation of sample solutions. Forty-five minutes after the

beginning of the rotation, withdraw a 10-milliliter aliquot from the

vessel. Dilute a 2-milliliter portion of the sample to 25 milliliters

with 0.01N hydrochloric acid.

(iii) Procedure. Using a suitable spectrophotometer and 0.01N

hydrochloric acid as the blank, determine the absorbance of each

standard and sample solution at the absorbance maximum at approximately

280 nanometers. Determine the exact position of the absorbance maximum

for the particular instrument used.

(iv) Calculations. Determine the total amount of rifabutin

dissolved as follows:

AU X c X d X 900

T = -------------------------

AS X 1,000

where:

T = Total milligrams of rifabutin activity dissolved;

AU = Absorbance of sample;

AS = Absorbance of the standard;

c = Rifabutin activity of the working standard solution in

micrograms per milliliter; and

d = Dilution factor of the sample filtrate.

* * * * *

7. New Secs. 436.369 and 436.370 are added to subpart F to read as

follows:

Sec. 436.369 Thin layer chromatography test for free N-

isobutylpiperidone content in rifabutin.

(a) Equipment--(1) Chromatography tank. A rectangular tank,

approximately 23 X 23 X 9 centimeters, with a glass solvent trough on

the bottom and a tight-fitting cover.

(2) Iodine vapor chamber. A rectangular tank, approximately 23 X 23

X 9 centimeters, with a suitable cover, containing iodine crystals.

(3) Plates. Use 20 X 20 centimeter thin layer chromatography plates

coated with silica gel 60F 254 or equivalent to a thickness of 250

microns.

(b) Reagents--(1) Developing solvent. Mix petroleum ether (b.p. 60

to 80 deg.C) and acetone in volumetric proportions of 100:30,

respectively.

(2) Spray solution. Prepare a 1 percent solution of soluble starch

in water (containing 0.01 percent mercuric iodide).

(c) Preparation of spotting solutions--(1) Sample solution. Prepare

a solution of the rifabutin sample in 1:1 chloroform/methanol to

contain 10 milligrams per milliliter.

(2) Standard solution. Prepare a solution of N-isobutylpiperidone

standard in 1:1 chloroform/methanol to contain 1 milligram per

milliliter. Transfer aliquots of 0.5, 1.0, 2.0, 5.0, and 10.0

milliliters into separate 100-milliliter volumetric flasks and dilute

to volume with 1:1 chloroform/methanol. These solutions contain,

respectively, the equivalent of 0.05, 0.1, 0.2, 0.5, and 1.0 percent of

N-isobutylpiperidone.

(d) Procedure. Pour 100 milliliters of developing solvent into the

glass trough on the bottom of the unlined chromatography tank. Cover

and seal the tank. Allow it to equilibrate while the plate is being

prepared. Prepare a plate as follows: on a line 2.0 centimeters from

the base of the thin layer chromatography plate, and at intervals of

2.0 centimeters, apply 10 microliters of each of the standard solutions

and the sample solution prepared as directed above. After the spots are

thoroughly dry, place the plate into the trough in the bottom of the

tank. Cover and tightly seal the tank, allow the solvent front to

travel about 15 centimeters from the starting line and then remove the

plate from the tank. Air dry the plate. Warm the iodine vapor chamber

to vaporize the iodine crystals and place the dry plate in the iodine

vapor chamber until the spots are visible (usually about 5 minutes).

Remove the plate from the iodine vapor chamber and spray with 1 percent

starch solution.

(e) Evaluation. Measure the distance the solvent front traveled

from the starting line and the distance the spots are from the starting

line. Calculate the Rf value by dividing the latter by the former.

N-isobutylpiperidone has an Rf value of about 0.3. Rifabutin has

an Rf value of about 0.1. Compare the size and intensity of any N-

isobutylpiperidone spots in the sample lane with the N-

isobutylpiperidone spots in the standard lanes, and report the

percentage of N-isobutylpiperidone in the sample.

Sec. 436.370 Spectrophotometric identity test for rifabutin capsules.

(a) Equipment. A suitable spectrophotometer capable of recording

the ultraviolet spectrum in the 200 to 400 nanometer range, using

suitable quartz cells of 1 centimeter pathlength.

(b) Preparation of working standard and sample solution--(1)

Working standard solution. Suspend approximately 200 milligrams of

rifabutin working standard in 20 milliliters of methanol and sonicate

for approximately 5 minutes. Filter the resulting solution through a

suitable 0.5 micrometer filter. Transfer a 2-milliliter aliquot of the

filtered solution to a 100-milliliter volumetric flask and fill to

volume with methanol. Further dilute with methanol to obtain a solution

containing 20 micrograms of rifabutin activity per milliliter.

(2) Sample solution. Empty and combine the contents of five

capsules. Suspend a quantity of the capsule contents equivalent to 200

milligrams of rifabutin in 20 milliliters of methanol. Sonicate for

about 5 minutes and then filter through an appropriate 0.5 micrometer

filter. Transfer a 2-milliliter aliquot to a 100-milliliter volumetric

flask and dilute to volume with methanol. Further dilute with methanol

to obtain a solution containing 20 micrograms of rifabutin activity per

milliliter (estimated).

(c) Procedure. Using a suitable spectrophotometer equipped with 1.0

centimeter cells and methanol as the blank, determine the absorbance

spectra of the working standard and sample solutions over the

ultraviolet range of 250 to 300 nanometers.

(d) Evaluation. Compare the spectrum of the sample to that of the

working standard. The identity of the rifabutin capsules is confirmed

by quantitative comparison of the two spectra with an absorbance

maximum being observed at about 275 nanometers.

PART 455--CERTAIN OTHER ANTIBIOTIC DRUGS

8. 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).

9. New Sec. 455.88 is added to subpart A to read as follows:

Sec. 455.88 Rifabutin.

(a) Requirements for certification--(1) Standards of identity,

strength, quality, and purity. Rifabutin is an amorphous red-violet

powder. It is (9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,

22E,24Z)-

6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-

7,9,15,17,19,21,25-heptamethylspiro[9,4-(epoxypentadeca

[1,11,13]trienimino)-2H-furo[2',3':7,8] naphth[1,2-d]imidazole-2,4'-

piperidine]-5,10,26-(3H,9H)-trione-16-acetate. It is very slightly

soluble in water, sparingly soluble in ethanol, and soluble in

chloroform and methanol. It is so purified and dried that:

(i) Its potency is not less than 950 micrograms and not more than

1,020 micrograms of rifabutin activity per milligram on an anhydrous

basis.

(ii) Its content for the four major related substances detected by

high-performance liquid chromatography (HPLC) is not more than 1.0

percent each. All other unknown related substances are not more than

0.5 percent. The total of all related substances is not more than 3.0

percent.

(iii) Its moisture content is not more than 2.5 percent.

(iv) Its N-isobutylpiperidone content is not more than 0.5 percent.

(v) It gives a positive identity test.

(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 the batch for rifabutin potency,

related substances, moisture, N-isobutylpiperidone, and identity.

(ii) Samples, if required by the Director, Center for Drug

Evaluation and Research: 10 packages each containing approximately 300

milligrams.

(b) Tests and methods of assay--(1) Potency. Proceed as directed in

Sec. 436.216 of this chapter, using ambient temperature, an ultraviolet

detection system operating at a wavelength of 254 plus-minuss> 1

nanometers, an 11 centimeters X 4.7 millimeters (i.d.) column packed

with microparticulate (5 to 7 micrometers in diameter) packing material

such as octylsilane chemically bonded to porous silica (U.S.

Pharmacopeia designation L7), a flow rate of about 1.0 milliliter per

minute, and a manual or automatic injector capable of injecting 10

microliters. The retention time for rifabutin is between 9 and 11

minutes. Reagents; working standard, sample, and resolution solutions;

system suitability requirements; and calculations are as follows:

(i) Reagents--(A) Hydrochloric acid, 2N. Dilute 85 milliliters of

hydrochloric acid (37 percent) with distilled water to 500 milliliters.

(B) Potassium dihydrogen phosphate, 0.1M. Prepare a solution

containing 15.4 grams of potassium dihydrogen phosphate monohydrate

(potassium phosphate monobasic) per liter of distilled water.

(C) Sodium hydroxide, 2N. Dissolve 8 grams of sodium hydroxide

pellets in 100 milliliters of distilled water.

(D) Mobile phase. Acetonitrile:phosphate buffer, pH 6.5, 50:50. Mix

equal quantities of acetonitrile and 0.1M potassium dihydrogen

phosphate and adjust to an apparent pH of 6.5 plus-minuss> 0.1 by

dropwise addition of 2N sodium hydroxide. Filter through a suitable

filter capable of removing particulate matter 0.5 micron in diameter

and degas it just prior to its introduction into the chromatograph.

Slight adjustments of the mobile phase components ratio may be made in

order to meet the system suitability requirements described in the

system suitability tests in paragraph (b)(1)(iii) of this section.

(ii) Preparation of working standard, sample, and resolution test

solution--(A) Working standard solution. Accurately weigh approximately

25 milligrams of the rifabutin working reference standard into a 50-

milliliter volumetric flask. Add 5 milliliters of acetonitrile.

Dissolve and dilute to volume with mobile phase and mix to obtain a

solution having a known concentration of about 0.5 milligram of

rifabutin per milliliter.

(B) Sample solution. Accurately weigh approximately 25 milligrams

of sample into a 50-milliliter volumetric flask. Add 5 milliliters of

acetonitrile. Dissolve and dilute to volume with mobile phase and mix

to obtain a solution containing 0.5 milligram of rifabutin per

milliliter (estimated).

(C) Resolution test solution. Dissolve approximately 10 milligrams

of rifabutin in 2 milliliters of methanol and add 1 milliliter of 2N

sodium hydroxide. Allow to stand for 3 to 4 minutes and then add 1

milliliter of 2N hydrochloric acid. Mix and dilute to 50 milliliters

with mobile phase. Store aliquots of this solution in the frozen state

for future use.

(iii) System suitability requirements. Using the apparatus and

conditions described in this section, test the chromatographic system

by injecting the resolution test solution. The chromatogram shows one

major degradation peak and two minor degradation peaks eluting at

relative retention times (RRT) of 0.5-0.6, 0.65-0.75, and 0.8-0.9,

respectively, followed by the rifabutin peak.

(A) Asymmetry factor. The asymmetry factor (AS) is

satisfactory if it is not less than 1.0 and not more than 4.0 for the

rifabutin peak.

(B) Efficiency of the column. The absolute efficiency (hr) is

satisfactory if it is not more than 11 for the rifabutin peak,

equivalent to 2,000 theoretical plates for a 11-centimeter column of 5-

micrometer particles.

(C) Resolution factor. The resolution factor (R) between the peak

for rifabutin and its closest eluting degradation product (generated in

situ as described in paragraph (b)(1)(iii) of this section and eluting

at RRT of 0.8-0.9) is satisfactory if it is not less than 1.3.

(D) Coefficient of variation (relative standard deviation). The

coefficient of variation (SR in percent of 5 replicate injections

of the rifabutin working standard solution) is satisfactory if it is

not more than 2.0 percent. If the system suitability parameters have

been met, then proceed as described in Sec. 436.216(b) of this chapter.

(iv) Calculations. Calculate the micrograms of rifabutin per

milligram of sample on an anhydrous basis as follows:

AU X PS X 100

Micrograms of rifabutin = -----------------------

per milligram AS X CU X (100-m)

where:

AU = Area of the rifabutin peak in the chromatogram of the

sample (at a retention time equal to that observed for the

standard);

AS = Area of the rifabutin peak in the chromatogram of the

rifabutin working standard;

PS = Rifabutin activity in the rifabutin working standard

solution in micrograms per milliliter;

CU = Milligrams of sample per milliliter of sample solution;

and

m = Percent moisture content of the sample.

(2) Related substances. Proceed as directed in paragraph (b)(1) of

this section for potency using the sample prepared as described in

paragraph (b)(1)(ii)(B) of this section and calculating the amounts of

related substances as follows.

(i) Calculations. Calculate the percentage of related substances as

follows:

Ai x 100

Percent individual HPLC- = -----------------------

related substance At

A x 100

Percent total HPLC- = -----------------------

related substances At

where:

Ai = Area of the individual related substance peak;

A = The sum of areas of all peaks minus the area due to the

rifabutin peak and solvent front peak; and

At = The sum of areas of all peaks in the chromatogram

excluding the solvent peak.

(ii) [Reserved]

(3) Moisture. Proceed as directed in Sec. 436.201 of this chapter.

(4) N-Isobutylpiperidone. Proceed as directed in Sec. 436.369 of

this chapter.

(5) Identity. (i) Proceed as directed in Sec. 436.211 of this

chapter, using the sample preparation method described in paragraph

(b)(1) of that section using a 1 to 2 percent mixture in potassium

bromide.

(ii) The identity of rifabutin is confirmed by the qualitative

comparison of the HPLC of the sample to the rifabutin working standard

as directed in paragraph (b)(1) of this section.

10. New Sec. 455.188 is added to subpart B to read as follows:

Sec. 455.188 Rifabutin capsules.

(a) Requirements for certification--(1) Standards of identity,

strength, quality, and purity. Rifabutin capsules are gelatin capsules

containing rifabutin with a suitable and harmless filler and with or

without binders, lubricants, and stabilizers. Each capsule contains

rifabutin equivalent to 150 milligrams of rifabutin. Its rifabutin

content is satisfactory if it is not less than 90 percent and not more

than 110 percent of the number of milligrams of rifabutin that it is

represented to contain. Its content of the four major related

substances detected by high-performance liquid chromatography (HPLC) is

not more than 1.0 percent each. All other unknown related substances

are not more than 0.5 percent. The total of all related substances is

not more than 4.5 percent. It passes the dissolution test if the

quantity (Q) dissolved is 75 percent at 45 minutes. It passes the

identity test. The rifabutin used conforms to the standards prescribed

by Sec. 455.88(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 rifabutin used in making the batch for potency, related

substances, moisture, N-isobutylpiperidone, and identity.

(B) The batch for content, related substances, dissolution, and

identity.

(ii) Samples, if required by the Director, Center for Drug

Evaluation and Research:

(A) The rifabutin used in making the batch: 10 packages, each

containing approximately 300 milligrams.

(B) The batch: A minimum of 30 capsules.

(b) Tests and methods of assay--(1) Rifabutin content. Proceed as

directed in Sec. 455.88(b)(1), preparing the sample solution and

calculating the rifabutin content as follows:

(i) Preparation of sample solution. Empty 20 capsules, collecting

the contents quantitatively. Weigh the powder and determine the average

capsule fill weight. Mix the powder and accurately weigh a portion

containing the equivalent of about 25 milligrams of rifabutin into a

50-milliliter volumetric flask. Add 5 milliliters of acetonitrile.

Dilute to volume with mobile phase and mix to yield a solution

containing 0.5 milligram of rifabutin per milliliter (estimated).

Filter through a suitable filter capable of removing particulate matter

0.5 micron in diameter prior to injection into the chromatographic

system.

(ii) Calculations. Calculate the rifabutin content as follows:

AU X CS X PS X Wa

Milligrams of rifabutin = -----------------------

per capsule AS X CU X 1,000

where:

AU = Area of the rifabutin peak in the chromatogram of the

sample (at a retention time equal to that observed for the

standard);

AS = Area of the rifabutin peak in the chromatogram of the

rifabutin working standard;

CS = Milligrams of rifabutin working standard per milliliter of

standard solution;

CU = Milligrams of sample per milliliter of sample solution;

PS = Rifabutin activity in the rifabutin working standard

solution in micrograms per milliliter; and

Wa = Average capsule fill weight in milligrams.

(2) Related substances. Proceed as directed in paragraph (b)(1) of

this section for rifabutin content using the sample prepared as

described in paragraph (b)(1)(i) of this section and calculating the

amounts of related substances as follows.

(i) Calculations. Calculate the percentage of related substances as

follows:

Ai x 100

Percent individual HPLC- = -----------------------

related substance At

A x 100

Percent total HPLC- = -----------------------

related substances At

where:

Ai = Area of the individual related substance peak;

A = The sum of areas of all peaks minus the area due to the

rifabutin peak and solvent front peak; and

At = The sum of areas of all peaks in the chromatogram

excluding the solvent peak.

(ii) [Reserved]

(3) Dissolution test. Proceed as directed in Sec. 436.215 of this

chapter. The quantity (Q) (the amount of rifabutin activity dissolved)

is 75 percent within 45 minutes.

(4) Identity. (i) The retention time of the rifabutin response in

the HPLC procedure described in paragraph (b)(1) of this section as

applied to the sample solution compares qualitatively to that of the

rifabutin reference standard.

(ii) The identity of rifabutin capsules is also confirmed by the

spectrophotometric identity test described in Sec. 436.370 of this

chapter.

Dated: August 1, 1994.

Stephanie R. Gray,

Acting Director, Office of Compliance, Center for Drug Evaluation and

Research.

[FR Doc. 94-19484 Filed 8-9-94; 8:45 am]

BILLING CODE 4160-01-F