Yttrium Y90Ibritumomab Tiuxetan Injection
»Ibritumomab Tiuxetan is the immunoconjugate resulting from a stable thiourea covalent bond between the monoclonal antibody ibritumomab and the linker-chelator tiuxetan [N-[2-bis(carboxymethyl)amino]-3-(p-isothiocyanatophenyl)propyl]-[N-[2-bis(carboxymethyl)amino]-2-(methyl)ethyl)glycine.This chelate provides a high-affinity,conformationally restricted chelation site for 90Yand 111In.The approximate molecular weight of Ibritumomab Tiuxetan is 148kD.
Ibritumomab is a murine IgG1kappa monoclonal antibody directed against the CD20antigen,which is found on the surface of normal and malignant Blymphocytes.Ibritumomab is produced in Chinese hamster ovary cells and is composed of two murine gamma 1heavy chains of 445amino acids each and two kappa light chains of 213amino acids each.
Yttrium Y90Ibritumomab Tiuxetan Injection is a sterile,nonpyrogenic preparation of the immunoconjugate of ibritumomab and tiuxetan that is labeled with 90Yand is suitable for intravenous administration.It contains not less than 90.0percent and not more than 110.0percent of the labeled amount of 90Yas the ibritumomab complex,expressed in megabecquerels (or millicuries)per mLat the time indicated in the labeling.It may contain buffers and stabilizers.It contains no antimicrobial agents.Other chemical forms of radioactivity do not exceed 5percent of the total radioactivity.The immunoreactive fraction,as determined by a validated method,is not less than 90percent.
Packaging and storage— Preserve in single-dose containers,and store in a refrigerator for not more than 8hours.[NOTE—Translucent protein particles may develop,which are removed by filtration prior to administration using a 0.22-µm low-protein-binding filter.]
Labeling— Label it to include the following in addition to the information specified for LabelingunderInjections á1ñ:the time and date of calibration;the amount of Yttrium Y90ibritumomab tiuxetan as total MBq (or mCi)and concentration of yttrium 90Yibritumomab tiuxetan,in MBq (or mCi)per mL,at the time of calibration;the expiration date and time;the storage temperature;and the statement,“Caution—Radioactive Material.”The labeling indicates that,in making dosage calculations,correction is to be made for radioactive decay,and also indicates that the radioactive half-life of 90Yis 64.1hours.
Radionuclide identification (see Radioactivy á821ñ)—
A: The beta radiation of the Injection shows a mass absorption coefficient within 5%of the value found for a known standard of the 90Ywhen tested under the same counting conditions.
B: The beta-ray spectrum,obtained on an energy calibrated beta spectrometer,is identical to that of the spectrum of 90Yof known purity,showing a maximum beta particle energy (Emax)at about 2280keV.[NOTE—Because of the inherent difficulty in measuring beta radiation,a second comparative test should be performed.]
Bacterial endotoxins á85ñ— The limit of endotoxin content is not more than 175/VUSP Endotoxin Units per mLof the Injection,when compared with the USP Endotoxin RS,in which Vis the maximum recommended total dose,in mL,at the expiration date or time.
pHá791ñ: between 5.5and 7.5.
Radiochemical purity—
Adsorbent: 1-×8-cm instant silica gel strip.
Test solution: the Injection.
Application volume: 10µL.
Developing solvent system: 0.9%sodium chloride solution.
Procedure— Proceed as directed for Thin-Layer Chromatographyunder Chromatography á621ñby ascending chromatography.Determine the distribution of radioactivity on the chromatogram by scanning with a suitable collimated radiochromatogram strip scanner,and determine the percentage of radiochemical purity of the test specimen.Not less than 95%of the 90Yactivity is present as a band between the RFvalues of 0.0and 0.1.
Radionuclidic purity (Content of 90Sr in an yttrium Y90chloride solution)— Prepare a strontium/yttrium carrier solution containing 0.34mg of yttrium chloride (YCl3·6H2O)and 0.30mg of strontium chloride (SrCl2·6H2O)per mLof 0.1Nhydrochloric acid.Apply about 50µLof this solution at the origin of a 2-×19-cm cellulose phosphate chromatographic strip (see Chromatography á621ñ),and allow to dry.Apply about 5µLof the yttrium Y90chloride radiolabeling solution at the origin,and develop the chromatogram by ascending chromatography over a period of about 1.25hours,using 3Nhydrochloric acid as the developing solvent,until the solvent front migrates to the 15-cm mark.Allow to dry.Cut the strip at the 8-cm mark,and place the upper section (solvent front)in a suitable liquid scintillation solvent.Using a suitable counting assembly (see Beta-Emitting Radionuclidesin the Assaysection of Identification and Assay of Radionuclidesunder Radioactivity á821ñ),determine the radioactivity,in KBq (or µCi)per mLof yttrium Y90chloride solution.The total radioactivity of 90Sr is not greater than 740KBq per 37GBq (or 20µCi per Ci)of 90Yat the expiration date as stated on the labeling.
Other requirements— It meets the requirements under Injections á1ñ,except that the radioactive component may be distributed or dispensed prior to completion of the test for Sterility,the latter test being started on the date of manufacture.
Assay for radioactivity á821ñ— Using a suitable counting assembly (see Scintillation and Semiconductor Detectorsin Identification and Assay of Radionuclides),determine the total radioactivity,in MBq (or µCi),of the unshielded Injection,using a calibrated system.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(RMI)Radiopharmaceuticals and Medical Imaging Agents
USP28–NF23Page 2044
Pharmacopeial Forum:Volume No.29(3)Page 681
Phone Number:1-301-816-8305