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d=Dilution factor of the sample.

(B) The batch for idarubicin hydrochloride content, sterility, bacterial endotoxins, moisture, pH, and identity.

(ii) Samples required if requested by the Director, Center for Drug Evaluation and Research:

(A) The idarubicin hydrochloride used in making the batch: 14 packages, each containing approximately 40 milligrams.

(B) The batch:

(1) For all tests except sterility: A minimum of 34 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay. Idarubicin hydrochloride is toxic. It must be handled with care in the laboratory. Transfer all dry powders into a suitable hood while wearing rubber gloves. Avoid inhaling fine particles of powder. Solutions should not

be pipetted by mouth. If the substance contacts the skin, wash with soap and water. Dispose of all waste material by dilution with large volumes of dilute sodium hypochlorite (bleach) solution.

(1) Idarubicin hydrochloride content (HPLC). Proceed as directed in § 450.30(b)(1), preparing the sample solution and calculating the idarubicin hydrochloride as follows:

(i) Sample solution. Prepare the sample solution by rinsing the contents of the vial into an appropriate-sized volumetric flask with sufficient diluent to obtain a concentration of 0.5 milligram of idarubicin hydrochloride per milliliter (estimated).

(ii) Calculations. Calculate the idarubicin hydrochloride content per vial as follows:

(2) Sterility. Proceed as directed in $ 436.20 of this chapter, using the method described in $436.20(e)(1).

(3) Bacterial endotoxins. Proceed as directed in the U.S.P. Bacteria endotoxin test. The specimen under test contains not more than 8.93 U.S.P. endotoxin units per milligram of idarubicin hydrochloride.

(4) Moisture. Proceed as directed in $ 436.201 of this chapter, using the sample preparation method described in $ 436.201(d)(4).

(5) PH. Proceed as directed in $436.202 of this chapter, using the sample obtained after reconstituting the drug as directed in the labeling, except use distilled water instead of saline.

(6) Identity. The high-performance liquid chromatogram of the sample determined directed in paragraph (b)(1) of this section compares qualitatively to that of the idarubicin hydrochloride working standard.

as

(58 FR 26665, May 4, 1993]

$ 450.240 Plicamycin for injection.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Plicamycin for injection is a dry mixture of plicamycin and mannitol with or without a suitable buffer substance. Each immediate container contains 2.5 milligrams of plicamycin, Its plicamycin content is satisfactory if it contains not less than 90 percent and not more than 110 percent of the number of milligrams of plicamycin that it is representated to contain. It is sterile. It is nonpyrogenic. Its moisture content is not more than 2.0 percent. It contains no depressor substances. Its pH when reconstituted as directed in the labeling is not less than 5.0 and not more than 7.5. It passes the identity test for plicamycin. The plicamycin used conforms to the standards prescribed by $ 450.40(a)(1).

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5 of this chapter. In addition, each package shall bear on its label or labeling the following as indicated:

(i) On the outside wrapper or container the statement “Store below 10° C. (50° F.)”.

Micrograms of

A, XP, X100 plicamycin

per milligram A, XC, X(100-m) where: Au-Area of the idarubicin hydrochloride

peak in the chromatogram of the sample (at a retention time equal to that ob

served for the standard); As-Area of the idarubicin hydrochloride

peak in the chromatogram of the idarubicin hydrochloride working stand

ard; Ps=Idarubicin hydrochloride activity in the

idarubicin hydrochloride working standard solution in micrograms per milliliter; and

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(ii) On the outside wrapper or container and on the immediate container the statement “Mandatory: Before using read enclosed professional information carefully for dosage instructions and warnings”.

(iii) On the outside wrapper or container the statement “Warning: For hospital use only. To be used under direct supervision of a physician”.

(3) Requests for certification; samples. In addition to complying with the requirements of $ 431.1 of this chapter, each such request shall contain:

(i) Results of tests and assays on:

(a) The plicamycin used in making the batch for plicamycin content, loss on drying, absorptivity, pH, identity, and crystallinity.

(6) The batch for plicamycin content, sterility, pyrogens, moisture, Ph, depressor substances, and identity.

(ii) Samples required:

(a) The plicamycin used in making the batch: 3 packages, each containing not less than 50 milligrams; and 2 packages, each containing not less than 100 milligrams.

(6) The batch:

(1) For all tests except sterility: A minimum of 21 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay. Plicamycin is more toxic than the average drug and must be handled with care in the laboratory. Avoid inhaling fine particles of powder. If the substance contacts the skin, wash with soap and water. Plicamycin is hygroscopic and care should be exercised during storage and weighing of samples. Dispose of all waste materials by dilution with larger volumes of trisodium phosphate solution. The samples should be stored at 10° C. or less in a sealed light-resistant container with a dessicant. Solutions should not be pipetted by mouth.

(1) Plicamycin content. Proceed as directed in § 436.341 of this chapter, except prepare the sample solution and calculate the plicamycin content as follows:

(i) Preparation of sample solution. Place approximately 5 milligrams of the sample, accurately weighed, into a 50-milliliter, amber volumetric flash

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(2) Sterility. Proceed as directed in $ 436.20 of this chapter, using the method described in paragraph (e)(1) of that section, except use the entire contents of each of the immediate containers tested.

(3) Pyrogens. Reconstitute the sample as directed in the labeling and proceed as directed in $ 436.32(b) of this chapter, using

solution containing 50 micrograms of plicamycin per milliliter.

(4) Moisture. Proceed as directed in $ 436.201 of this chapter, using the total contents of three to five vials.

(5) pH. Proceed as directed in $436.202 of this chapter, using the drug reconstituted as directed in the labeling. Allow the solution to remain in contact with the electrodes until a steady reading is obtained or for 5 minutes.

(6) Depressor substances. Proceed as directed in $436.35 of this chapter.

(7) Thin layer chromatography identity test for plicamycin-(i) Equipment-a) Plates. Use 20 by 20 centimeter or 15 by 20 centimeter

thin layer chromatographic plates coated with Silica Gel Mixture, Chromatographic, U.S.P., to a thickness of 250 microns. Activate the plates by heating at 110° C. for 75 minutes. Place the plates in a desiccator until cooled to room temperature. Plates may be stored in a desiccator for 7 days.

(6) Chamber (chromatographic). A suitable chamber, equipped for thin layer chromatography.

(ii) Preparations of solutions-(a) Sol- mannitol. Measure the distance the vent. Mix reagent grade chloroform solvent front traveled from the startwith reagent grade absolute methanol ing line and the distance the fluoresin volumetric proportions of 1:1.

cent spots are from the starting line. (6) Spray A. Mix 50 milliliters of Calculate the Rf value by dividing the freshly prepared 1.0 percent ferric chlo- latter by the former. The plicamycin ride in water (weight per volume), just standard should have an Rf value of 0.7. before spraying, with 50 milliliters of If the standard has an Rf value greater freshly prepared 1.0 percent potassium than 0.8, the mobility of the standard ferricyanide in water (weight per vol- may be decreased by increasing the ume).

ratio of the chloroform to methanol in (c) Spray B. Dissolve 2.28 grams of the solvent to 3:2 or 3:1. Plicamycin apperiodic acid in 100 milliliters of water. pears as a single major component with Dilute one volume of this periodic solu- the same Rf value as the plicamycin tion with 10 volumes of acetone.

standard. It may show trace compo(d) Spray C. Dissolve 184 milligrams nents at Rf values of about 0.5 and 0.4, of benzidine in a solution of 0.6 milli- and at the origin, which shall not be liter of acetic acid, 4.4 milliliters of more intense than those shown by the water, and 95 milliliters of acetone.

plicamycin standard. (iii) Preparation of spotting solutions

(39 FR 19145, May 30, 1974, as amended at 40 (a) Plicamycin standard solution. Weigh 5

FR 1512, Jan. 8, 1975; 46 FR 60568, Dec. 11, milligrams of plicamycin working

1981; 47 FR 9396, Mar. 5, 1982; 48 FR 11427, standard and dissolve in 10 milliliters Mar. 18, 1983; 49 FR 5097, Feb. 10, 1984; 49 FR of methanol. Use the solution the same 24019, June 11, 1984; 50 FR 19676, May 10, 1985) day it is prepared. (0) Plicamycin for injection sample solu

8 450.245 Mitomycin for injection. tion. Dilute with methanol to a con- (a) Requirements for certification (1) centration of 0.5 milligram of Standards of identity, strength, quality, plicamycin per milliliter. Centrifuge and purity. Mitomycin for injection is a and use the supernatant for spotting. dry mixture of mitomycin

and (c) Mannitol reference solution. Sus- mannitol. Its potency is satisfactory if pend 100 milligrams of mannitol in 5 it contains not less than 90 percent and milliliters of methanol. Centrifuge and not more than 120 percent of the numuse the supernatant for spotting.

ber of milligrams of mitomycin that it (iv) Procedure. Fill the chamber to a is represented to contain. It is sterile. depth of 0.6 centimeter with freshly It is nonpyrogenic. It contains no deprepared solvent. Spot duplicate plates pressor substances. Its moisture conas follows: On a line 2.5 centimeters tent is not more than 5 percent. Its PH, from the base of the silica gel plate, when reconstituted as directed in the and at intervals of 2.0 centimeters, spot labeling, is not less than 6.0 and not 100 microliters (in four 25-microliter more than 8.0. It passes the identity aliquots) of the standard solution, the test for mitomycin. The mitomycin sample solution, and the mannitol ref- used conforms to the standards preerence solution. Allow each aliquot to scribed by $450.45(a)(1). dry before applying subsequent vol- (2) Labeling. It shall be labeled in acumes. After all spots are thoroughly cordance with the requirements of dry, place the silica gel plates in the $ 432.5 of this chapter. chromatographic chamber and develop (3) Requests for certification; samples. by the ascending technique for approxi- In addition to complying with the remately 60 minutes. Allow several min- quirements of $431.1 of this chapter, utes for the plates to air dry. On one each such request shall contain: plate, locate and record the position of (1) Results of tests and assays on: fluorescent spots by examining under (a) The mitomycin used in making long wave ultraviolet light. Apply the batch for potency, moisture, pH, spray A and record the position of blue absorptivity, identity, and crystallinspots on the yellow-green background. ity. On the other plate, locate the mannitol (6) The batch for potency, sterility, by first applying spray B, followed by pyrogens, depressor substances, moisspray C. The spots appearing white are ture, pH, and identity.

PART 452-MACROLIDE ANTIBIOTIC

DRUGS

Subpart A-Bulk Drugs

Sec.
452.10 Erythromycin.
452.15 Erythromycin estolate.
452.25 Erythromycin ethylsuccinate.
452.25a Sterile

erythromycin ethylsuccinate. 452.30a Sterile erythromycin gluceptate. 452.32a Sterile erythromycin lactobionate. 452.35 Erythromycin stearate. 452.50 Clarithromycin. 452.60 Azithromycin. 452.75 Troleandomycin.

Subpart B-Oral Dosage Forms

(ii) Samples required:

(a) The mitomycin used in making the batch: Five packages, each containing approximately 100 milligrams.

(6) The batch:

(1) For all tests except sterility: A minimum of 25 immediate containers.

(2) For sterility testing: 20 immediate containers, collected at regular intervals throughout each filling operation.

(b) Tests and methods of assay-(1) Potency. Proceed as directed in $ 436.105 of this chapter, preparing the sample for assay as follows: Reconstitute as directed in the labeling. Using a suitable hypodermic needle and syringe, remove all of the withdrawable contents from each container if it is represented as a single dose container; or if the labeling specifies the amount of potency in a given volume of the resultant preparation, remove an accurately measured representative portion from each container. Dilute the solution thus obtained with sufficient 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to give a stock solution of convenient concentration. Further dilute the stock solution with solution 1 to the reference concentration of 1 microgram of mitomycin per milliliter (estimated).

(2) Sterility. Proceed as directed in $ 436.20 of this chapter, using the method described in paragraph (e)(1) of that section.

(3) Pyrogens. Proceed as directed in $436.32(a) of this chapter, using a solution containing 0.5 milligram of mitomycin per milliliter.

(4) (Reserved]

(5) Depressor substances. Proceed as directed in $436.35 of this chapter.

(6) Moisture. Proceed as directed in $ 436.201 of this chapter.

(7) PH. Proceed as directed in 8436.202 of this chapter using the drug reconstituted as directed in the labeling.

(8) Identity. Proceed as directed in $ 436.310 of this chapter.

452.110 Erythromycin oral dosage forms. 452.110a Erythromycin tablets. 452.110b Erythromycin enteric-coated tab

lets. 452.110c Erythromycin capsules. 452.110d Erythromycin particles in tablets. 452.115 Erythromycin estolate oral dosage

forms. 452.115a Erythromycin estolate tablets. 452.115b Erythromycin estolate capsules. 452.1150 Erythromycin estolate oral suspen

sion. 452.115d Erythromycin estolate for oral sus

pension. 452.115e Erythromycin estolate for pediatric

drops. 452.115f Erythromycin estolate chewable

tablets. 452.115g Erythromycin estolate and

sulfisoxazole acetyl oral suspension. 452.125 Erythromycin ethylsuccinate oral

dosage forms. 452.125a Erythromycin ethylsuccinate

chewable tablets. 452.125b Erythromycin ethylsuccinate oral

suspension. 452.125c Erythromycin ethylsuccinate for

oral suspension. 452.125d Erythromycin ethylsuccinate tab

lets. 452.125e Erythromycin ethylsuccinate

sulfisoxazole acetyl for oral suspension. 452.135 Erythromycin stearate oral dosage

forms. 452.135a Erythromycin stearate tablets. 452.135b Erythromycin stearate oral suspen

sion. 452.135c Erythromycin stearate for oral sus

pension. 452.150 Clarithromycin oral dosage forms. 452.150a Clarithromycin tablets. 452.150b Clarithromycin granules for oral

suspension.

(39 FR 19145, May 30, 1974, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19920, May 13, 1985)

452.160 Azithromycin oral dosage forms. 452.160a Azithromycin capsules. 452.160b Azithromycin for oral suspension. 452.175 Troleandomycin oral dosage forms. 452.175a Troleandomycin capsules. 452.175b Troleandomycin oral suspension. 452.175€ Troleandomycin for oral suspen

sion. 452.175d Troleandomycin chewable tablets.

Subpart C-Injectable Dosage Forms

452.225 Erythromycin ethylsuccinate injec

tion. 452.230 Sterile erythromycin gluceptate. 452.232 Erythromycin

lactobionate injectable dosage forms. 452.232a Erythromycin lactobionate for in

jection. 452.232b Sterile erythromycin lactobionate.

Subpart D-Ophthalmic Dosage Forms

452.310 Erythromycin ophthalmic ointment.

Subpart E [Reserved)

Subpart F-Dermatologic Dosage Forms

452.510 Erythromycin dermatologic dosage

forms. 452.510a Erythromycin ointment. 452.510b Erythromycin topical solution. 452.510d Erythromycin-benzoyl peroxide

topical gel. 452.510e Erythromycin topical gel.

(ii) [Reserved]

(iii) Its moisture content is not more than 10 percent.

(iv) Its pH is not less than 8.0 or more than 10.5.

(v) Its residue on ignition is not more than 2.0 percent.

(vi) Its heavy metals content is not more than 50 parts per million.

(vii) It gives a positive identity test for erythromycin.

(viii) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of $ 432.5 of this chapter.

(3) Requests for certification; samples. In addition to the requirements of $ 431.1 of this chapter, each such request shall contain:

(i) Results of tests and assays on the batch for potency, moisture, residue on ignition, heavy metals, pH, identity, and crystallinity.

(ii) Samples required: 10 packages, each containing not less than 500 milligrams.

(b) Tests and methods of assay-(1) Potency. Proceed as directed in $436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient methyl alcohol to give a concentration of 10 milligrams of erythromycin base per milliliter (estimated). Dilute this solution further with sufficient 0.1M potassium phosphate buffer, pH 8.0 (80lution 3), to give a stock solution containing 1.0 milligram of erythromycin base per milliliter (estimated). Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

(2) [Reserved]

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

(4) PH. Proceed as directed in 8 436.202 of this chapter, except standardize the pH meter with pH 7.0 and pH 10.0 buffers and prepare the sample as follows: Dissolve 200 milligrams of sample in 5 milliliters of reagent grade methyl alcohol. Add 95 milliliters of water and mix. Record the pH when an equilibrium value has been reached.

(5) Residue on ignition. Proceed as directed in $436.207(a) of this chapter.

(6) Heavy metals. Proceed as directed in $ 436.208 of this chapter.

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