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Working document QAS/07.243 September 2007 RESTRICTED

Monographs for individual radiopharmaceutical preparations

(September 2007)

DRAFT FOR COMMENT

© World Health Organization 2007

All rights reserved.

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations’ concerned staff and member organizations) without the permission of WHO. The draft should not be displayed on any website.

Please send any request for permission to:

Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mail: [email protected].

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.

Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall not be liable for any damages incurred as a result of its use.

Please send any comments on the revision of this draft document to Dr S. Kopp with a copy to Ms M.-L. Rabouhans, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or e-mail: [email protected] and [email protected] by 10 November 2007.

Working document QAS/07.243 page 2

SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/07.243


Date

Draft revision of general monograph mailed out for comments

September-October 2007

Collation of any comments received

October 2007

Presentation to WHO Expert Committee on Specifications for Pharmaceutical Preparations

October 2007

Further follow-up action as required

October 2007 - …


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RADIOPHARMACEUTICALS Introduction The World Health Organization and the International Atomic Energy Agency (IAEA) have been working jointly on specifications for Radiopharmaceuticals. Following consultation and discussion, it was agreed that this work should include inter alia revision of the general monograph in The International Pharmacopoeia and the preparation of monographs for individual radiopharmaceuticals. Meanwhile, for the main volumes of the Fourth edition of The International Pharmacopoeia, published in December 2006, the section on Monographs for Radiopharmaceuticals consists of the general monograph for Radiopharmaceuticals as included in the 3rd edition. A draft revised general monograph for Radiopharmaceuticals has now been prepared by the IAEA together with a first set of individual draft monographs for about 30 radiopharmaceutical preparations (more drafts are in preparation) for addition to the 4th edition of The International Pharmacopoeia. These texts are now being circulated by WHO for comment in line with the usual consultative process for monograph development. As noted within the documents however, the WHO Secretariat has not, as yet, adapted these texts to the format and style of The International Pharmacopoeia. This will be carried out at a later stage. Meanwhile, a "skeleton text" has been prepared to provide an indication of the format and style that will be used for the monographs for the individual radiopharmaceutical preparations (working document QAS/07.244). Comments are therefore invited on the technical content of the draft monograph texts. In addition to publishing these monographs in the section on Radiopharmaceuticals in a future Supplement to The International Pharmacopoeia, it is intended that they also form part of a joint IAEA/WHO publication that would also include other texts relevant to the manufacture and use of radiopharmaceuticals. In including the monographs in such a "stand-alone" publication, it would be necessary to supplement them with relevant supporting texts from The International Pharmacopoeia. These would include, for example, the General Notices, the general monographs for Parenteral Preparations and Capsules, selected Methods of Analysis (such as 1.13 Determination of pH, 1.14.4 High performance liquid chromatography, 3.4 Test for bacterial endotoxins).


RADIOPHARMACEUTICALS


Draft monographs are provided in this document for the radiopharmaceutical preparations included in List 1 below; draft monographs for the radiopharmaceuticals included in List 2 are in preparation and when received will form an addendum to this document.

List 1: Draft monograph provided

Fludeoxyglucose (18F) injection.

Gallium Citrate (67Ga) injection

Iobenguane (123I) injection

Iobenguane (131I) injection Samarium ethylene diamine tetramethylene phosphonate complex (153Sm) injection Sodium Iodide (131I) capsules

Sodium Iodide (131I) injection

Sodium Iodide (131I) solution

Sodium iothalamate (125I) injection

Sodium Pertechnetate (99mTc) injection

Sodium Phosphate (32P) injection

Strontium Chloride (89Sr) injection

Technetium (99mTc) Bicisate complex injection

Technetium 99mTc Exametazime complex injection.

Technetium (99mTc) labelled Macrosalb (99mTc MAA) injection

Technetium (99mTc)- Mebrofenin complex injection

Technetium (99mTc) Mertiatide injection Technetium(99mTc) Methylene Diphosphonate (MDP) complex injection

Technetium (99mTc) Nanocolloid injection


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Technetium (99mTc) Pentetate complex injection

Technetium(99mTc ) Pyrophoshate tin complex injection

Technetium (99mTc) labelled Red Blood Cells injection

Technetium(99mTc) Sestamibi complex injection

Technetium (99mTc) Succimer complex injection

Technetium (99mTc) Sulphur Colloid injection

Technetium (99mTc) Tetrofosmin complex injection

Technetium [99mTc] Tin colloidal injection

Thallous Chloride (201Tl) injection

Yttrium silicate (90Y) colloid injection

List 2: Draft monographs in preparation

(Will form addendum to this document)


Draft monographs for individual radiopharmaceutical preparations

Note from the Secretariat: Before inclusion in The International Pharmacopoeia these draft monographs will be adapted to the format, layout and editorial style shown in the "skeleton text" provided in working document QAS/07.244. This "skeleton text" indicates the order of headings and provides examples of the usual form of wording and of cross-reference to method texts. The requirements of the general monograph for Radiopharmaceuticals and of the general monograph for the relevant dosage form will be invoked by means of a compliance statement included immediately below the heading "Requirements". Cross reference to the general monograph for Radiopharmaceuticals will therefore be made under specific section headings only where necessary; for example, under Bacterial endotoxins to highlight that the general method of analysis (3.4) is modified.

Fludeoxyglucose (18F) injection Latin name. Fludeoxyglucosi solution iniectabilis Chemical name. 2-[

18F] fluoro-2-deoxy-D-glucopyranose (2-[

18F] fluoro-2- deoxy -D-

glucose) Other names.

18F-FDG

Graphic formula.

Description. Fludeoxyglucose (

18F) injection (

18F-FDG) is a colourless or slightly yellow and

sterile solution. Radionuclide production.

18F is a radioisotope of fluorine and may be prepared by proton

irradiation of 18

O deuteron irradiation of 20

Ne or alpha irradiation of 16

O and processed in a manner that

18F obtained is carrier free.

Radiochemical synthesis 1. Target materials Each batch of target material must be tested in special production runs before its use in routine fluorine-18 production and manufacture of the preparation, to ensure that under specified conditions, the target yields fluorine-18 in the desired quantity and quality.


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2. Precursors for organic synthesis It is recommended to test the precursors in production runs before their use for the manufacture of the preparation, to ensure that under specified production conditions, the precursors yield the preparation in the desired quantity and quality. 1,3,4,6 tetra-O-acetyl-2- O -trifluoromethanesulphonyl-β-D-mannopyranose examine by infrared absorption spectrophotometry comparing with reference spectrum. Melting point 119°C to 122°C. 3,4,6 tri-O-acetyl-D-glucal. examine by infrared absorption spectrophotometry comparing with reference spectrum. Melting point 53°C to 55°C. Production systems and their performance complies with the requirements set by the competent authority. 2-[18F]Fluoro-2-deoxy-D-glucose may be prepared by various chemical synthetic pathways, which lead to different products in terms of specific radioactivity, by-products and possible impurities. Most widely used is the method of phase transfer catalysed nucleophilic substitution of 1,3,4,6 tetra-O-trifluoromethanesulphonyl-β-D-mannopyranose with [18F]fluoride. Generally [18F]fluoride is absorbed on an anion-exchange resin and eluted with a solution of potassium carbonate which is then evaporated to dryness. Addition of a phase transfer catalyst such as an aminopolyether in dry acetonitrile may be used to enhance the nucleophilicity of the [18F]fluororide. Hydrolysis using hydrochloric acid may lead to the formation of 2-chloro-2-deoxy-D-glucose. Hydrolysis under alkaline conditions may lead to the formation of 2-[18F]fluoro-2deoxy-D-mannose as a by-product. Variations of the method substitute the aminopolyether by a tetra-alkyl ammonium salt, or use solid phase catalysed nucleophilic substitution on derivatized anion-exchange resin, e.g. derivatized with 4-(4-methylpiperidiono)pyridine. Electrophilic pathways for production of 2-[18F]fluoro-2-deoxy-D-glucose proceed by the reaction of molecular [18F]fluorine or [18F]acetylhypofluorite with 3,4,6-tri-O-acetyl-D-glucal. [18F]Acetylhypofluorite is obtained by conversion of molecular [18F]fluorine on a solid complex of acetic acid and potassium acetate. The production of molecular [18F]fluorine requires the addition of small amounts of fluorine to the neon target gas, usually from 0.1 per cent to 1 per cent, resulting in the reduction of the specific radioactivity of the end-product. Hydrolysis of the O-acetyl protected [18F]fluorinated sugar yields 2-[18F]fluoro-2-deoxy-D-glucose and usually small amounts of 2-[18F]fluoro-2-deoxy-D-mannose. The preparation can be purified by serial chromatography on combinations of ion-retardation resin, ion-exchange resin, alumina and octadecyl derivatised silica gel. Removal of the phase transfer catalyst can be achieved by different methods, all using combinations of separation cartridges.


The injection is preferably prepared by sterilization by autoclave method Ph. Int. This is the preferred method especially for those centres which are likely to serve beyond their own institute. The product may contain preservatives and/or stabilizing agents. Category. Diagnostic radiopharmaceutical Storage. Complies with the general requirements for storage. See radiopharmaceutical preparation. FDG injection should be stored at room temperature (below 30°C) and is for immediate use. Labelling. Complies with the general requirements for labelling. See radiopharmaceutical preparation. Additional Information. Complies with the general requirements for additional labelling. See radiopharmaceutical preparation. (e.g. dilutions, concentration etc) Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Fludeoxyglucose (

18F) injection (

18F-FDG) is a colourless or slightly yellow and

sterile solution of 2-deoxy-2-fluoro-D-glucose in which a portion of the molecules contain radioactive fluorine

18F in the molecular structure. The content of

18F is not less than 90.0 %

and not more than 110.0 % of the content of 18

F stated on the label at the reference date and hour stated on the label.Not less than 95% of total

18F is present as

18F-fluoro 2-deoxy D

glucose and 18

F-fluoro 2-deoxy D mannose. The later should not exceed 10% limit. The specific activity of

18F FDG is not less than 55MBq per mg or 9990MBq per mmol (1.5mCi

per mg or 270 mCi per mmol). The radioactive half life of 18

F is 109.8 minutes and emits positrons with a maximum energy of 633keV, followed by annihilation gamma radiation of 511 keV. Identification Either test A or B in addition to C.

A. The gamma ray spectrum recorded measured in a suitable instrument with a sample of 18F FDG, suitably diluted if needed, is identical to that of a specimen of 18F in that it exhibits a major peak at 511 keV, maximum at 633 keV and possibly a sum peak at 1020 keV depending on geometry and detector efficiency.

B. The half-life determined using a suitable detector system is between 105 and 115

minutes.


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C. Confirm the principal peak in radiochromatogram obtained with the test solution is the same as retention time (Rf) as the principal peak in the chromatogram obtained with reference solution.

Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between 4.5 to 8.5. Radionuclidic purity. See radiopharmaceutical preparation. Complies with general assessment for radionuclide purity. Record the gamma-ray spectrum using suitable instrument and half life measured by methods described. The injection may be released for use before completion of test. Radiochemical Purity. See radiopharmaceutical preparation. Carry out thin-layer chromatography (TLC) as described in Ph. Int. Apply about 5 µl of sample of 18F FDG injection, appropriately diluted to get optimum count rate, to activated silica gel plate ( or thin layer silica gel plate, 1.5 X 15 cm) and develop with a mixture of acetonitrile and water (95:5). 18F FDG has an Rf value of about 0.4 in this system. Allow to dry and determine the radioactivity distribution by a suitable method. Not less than 90% of the total radioactivity is in the spot corresponding to 18F FDG. Chemical purity. 18F-FDG may be synthesized by a nucleophilic or electrophilic pathway and hence may contain different impurities. It is necessary to demonstrate the absence or lack of physiological effect of any unlabelled starting ingredients and reagent chemicals employed in the synthetic process that may be present. Toxic substances or by products including kryptofix (aminopolyether), tetra alkyl ammonium salts and 2-chloro-3 deoxy-D-Glucose are to be controlled at appropriate limits. Conformance with these limits is to be demonstrated by the use of one or more limit tests using known separation chromatographic techniques. Chemical purity. Particular tests for chemical purity may be omitted if the substances mentioned are not used or cannot be formed in the production process.

(a) 2-Fluoro-2-deoxy-D-glucose and 2-chloro-2deoxy-D-glucose. Examine by liquid chromatography Test solution. The preparation to be examined. Reference solution (a) Dissolve 10 mg of glucose R in water R and dilute to 100 ml with the same solvent. Reference solution (b) Dissolve 10 mg of 2-fluoro-2deoxy-D-glucose R in water R and dilute to V with same solvent, V being the maximum recommended dose in millilitres. Reference solution (c) Dissolve 1.0 mg of 2-choloro-2-deoxy-D-glucose CRS in water R and dilute to 2ml with the same solvent. Dilute 1ml of this solution to V with the same solvent, V being the maximum recommended dose in millilitres.


The chromatographic procedure may be carried out using: – a column 0.25 m long and 4.0 mm in internal diameter packed with strongly basic anion-

exchange resin for chromatography R (10µm), – as mobile phase at a flow rate of 1ml/minutes 0.1M sodium hydroxide protected against

contamination by carbon dioxide, – a suitable radioactivity detector for radiochemical purity testing, – a detector suitable for carbohydrates in the required concentration range, – a loop injector, maintaining the column at a constant temperature between 20oC and 30oC. Equilibrate the column with the mobile phase until a stable baseline is achieved. Inject separately reference solutions (a), (b) and (c). If the validation studies exclude the formation of 2-chloro-2-deoxy-D-glucose inject separately reference solutions (a) and (b). Continue the chromatography for twice the retention time of D-glucose, 2-fluoro-2-deoxy-D-glucose and when required, 2-chloro-2-deoxy-D-glucose respectively.Inject the test solution. The chromatogram obtained with the detector for carbohydrates shows a principal peak corresponding to D-glucose (test solutions from nucleophilic pathways) or 2-fuoro-2-deoxy-D-glucose (test solutions from electrophilic pathways). When the chromatograms are recorded in the prescribed conditions, 2-choloro-2-deoxy-D-glucose elutes after 2-fluoro-2-deoxy-D-glucose, but their corresponding peaks may not be completely resolved. In the chromatogram obtained with the test solution, the areas of the peaks corresponding to 2-fluoro-2-deoxy-D-glucose and 2-chloro-2-deoxy-D-glucose are not greater than the areas of the peaks in the chromatograms obtained with reference solution (b) and/or reference solution (c) (10 mg of 2-fluoro-2-deoxy-D-glucose per V and 0.5 mg of 2-chloro-2-deoxy-D-glucose per V respectively). (b) Aminopolyether. This test is performed only on the bulk solution before addition of sodium chloride by the producer and it is not intended for the final preparation to be injected. Examine by thin-layer chromatography, using a TLC silica gel plate R see Ph. Int. chapter. Test solution. The preparation to be examined. Reference solution. Dissolve 0.110 g of aminopolyether R in water R and dilute to 10.0 ml with the same solvent. Dilute 0.2ml of this solution to V with the same solvent, V being the maximum recommended dose in millilitres. Apply separately to the plate 2µl of the test solution and 2µl of the reference solution. Develop over a path of about 8 cm using a mixture of 1 volume of ammonia R and 9 volumes of methanol R. Allow the plate to dry in air for 15 minutes. Expose the plate to iodine vapour for at least 10 minutes. In the chromatogram obtained with the test solution the spot corresponding to aminopolyether is not more intense that the spot in the chromatogram obtained with the reference solution (2.2 mg per V). (c) Tetra-alkyl ammonium salts. Examine by liquid chromatography see Ph. Int. chapter.


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Test solution. The preparation to be examined. Reference solution. Dilute 2.1ml of 0.1M tetrabutylammonium hydroxide to 20ml with water R. Dilute 1ml of this solution to V with the same solvent, V being the maximum recommended dose in millilitres. The chromatographic procedure may be carried out using: – a column 0.125 m long and 4.0 mm in internal diameter packed with octadecylsilyl silica

gel for chromatography R (5 µm), – as mobile phase at a flow rate of 0.6ml/minutes a mixture of 25 volumes of a 0.95 g/l

solution of toluenesulphonic acid R and 75 volumes of acetonitrile R, – as detector a spectrophotometer set at 254 nm, – a loop injector maintaining the column at a constant temperature between 20C and 30C. Equilibrate the column with the mobile phase until a stable baseline is obtained. Inject the reference solution. Continue the chromatography for twice the retention time of tetrabutylammonium ions. Inject the test solution. In the chromatogram obtained with the test solution, the area of the peak corresponding to tetrabutylammonium ions is not greater than the area of the peak in the chromatogram obtained with the reference solution (2.75 mg per V). (d) Solid phase derivatisation agent 4-(4-methylpiperidiono)pyridine. Examine by ultraviolet spectrophotometry see Ph. Int. chapter. Test solution. The preparation to be examined. Reference solution. Dissolve 20 mg of 4-(4-methylpiperidio)pyridine R in water R and dilute to 100.0ml with the same solvent. Dilute 0.1ml of this solution to V with the same solvent, V being the maximum recommended dose in millilitres. Measure the absorbance of the test solution and the reference solution at the maximum of 263 nm. The absorbance of the test solution is not greater than that of the reference solution (0.02 mg per V). (e) Residual solvents. The concentration of acetonitrile does not exceed 4.1 mg per V, V being the maximum recommended dose in millilitres. The injection may be released for use before completion of the test. Assay Determine the radioactivity in suitable counting equipment by comparison with a standardized 18F solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 18F are available from national standardizing laboratories.


Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int.. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the maximum recommended dose in millilitres. The injection may be released for use before completion of the test.

***

Gallium Citrate (67

Ga) injection

Latin name. Gallii (67

Ga) citratis solutio iniectabilis Chemical name. 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, gallium-67Ga salt Chem. Structure. C6H5

67GaO7 Relative molecular mass. 256 Graphic formula

CH2−COO-

HO − C − COO- Ga+3

CH2 − COO- Description. Gallium citrate (

67Ga) injection is a clear and sterile solution.

Radionuclide production.

67Ga is a radioisotope of gallium and may be prepared by proton

irradiation of 68

Zn or alpha irradiation of 67

Zn and processed in such a manner that 67

Ga obtained is carrier free. Other nuclear reactions are also possible. The gallium

67Ga may be

separated from zinc by solvent extraction or column chromatography. The injection may be sterilized by Method 1 Heating in an Autoclave or Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with the general requirements for storage. See radiopharmaceutical preparation. Gallium citrate (

67Ga) injection should be stored in a refrigerator (2-8 oC) even if

it contains preservatives.


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Labelling. Complies with the general requirements for labelling. See radiopharmaceutical preparation. Additional Information. Complies with the general requirements for additional labelling. See radiopharmaceutical preparation. "Do not dilute" on the label of product containing preservative. Useful to have space on the label for writing "date and time of first dose withdrawal". Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Gallium Citrate (67Ga) injection is a sterile clear, colourless, isotonic, aqueous solution of

67Ga complexed with citrate which is present in excess. It may be made isotonic

by the addition of sodium chloride and sodium citrate and may contain a suitable antimicrobial preservative such as benzyl alcohol. The content of

67Ga is not less than 90.0 % and not more than 110.0 % of the content of

67Ga

stated on the label at the reference date and hour stated on the label. Not more than 0.2% of total activity as

66Ga. Not less than 95% of total

67Ga is present as Gallium Citrate.

Identification Either test A or B in addition to C. A. The gamma ray spectrum recorded measured in a suitable instrument with a sample of

67Ga citrate suitably diluted if needed, is identical to that of a specimen of

67Ga in that it

exhibits a major peak at 93, 185 and 300keV. 66

Ga which is an impurity has main peak 1039keV with half life of 9.4 hours. There should be no more than 0.2% of total radioactivity is due to

66Ga.

B. The half life determined using a suitable detector system is 3.26 days or between 75 and

80 hours. C. To 0.2ml of the injection to be examined add 0.2ml of a solution containing 1 g/l of

ferric chloride R and 0.1 per cent V/V of hydrochloric acid R and mix. Compare the colour with that of a solution containing 9g/l of benzyl alcohol R and 7 g/l of sodium chloride R treated in the same manner. A yellow colour develops in the test solution only.

Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between 5.0 to 8.0.


Radionuclidic purity. See radiopharmaceutical preparation. Complies with general assessment for radionuclide purity. Record the gamma-ray spectrum using suitable instrument and half life measured by methods described. Not less than 99% total radioactivity is present as

67Ga at the time of calibration and not more than 0.2% as 66Ga.

Radiochemical purity. Carry out Ascending Paper Chromatography as described. Apply ~5 µl of sample of Gallium citrate (

67Ga) injection, appropriately diluted to get optimum count

rate, to the paper (e.g. Whatman No.1, 3 X 30 cm) and develop with a solution of 1.36g of sodium acetate and 0.58ml of glacial acetic acid in 100ml water. Gallium citrate has an Rf value of about 0.9 in this system. Allow to dry and determine the radioactivity distribution by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to Gallium citrate. Chemical purity. See radiopharmaceutical preparation.

67Ga may be produced by different

nuclear reactions on different target elements and hence using different processing methods. The final product

67Ga may contain different impurities from the target and chemicals used

for processing. It is necessary to demonstrate the absence or lack of physiological effect of any of these impurities. Toxic substances or other metal impurities are to be controlled at appropriate limits. Conformance with these limits is to be demonstrated by the use of one or more limit tests using known separation chromatographic techniques. Zinc. To 0.1ml of the injection to be examined add 0.9ml of water R, 5ml of acetate buffer solution pH 4.7 R, 1ml of a 250g/l solution of sodium thiosulphate R and 5.0ml of a dithizone solution prepared as follows: dissolve 10mg of dithizone R in 100ml of methyl ethyl ketone R allow to stand for 5minutes, filter and immediately before use dilute the solution to ten times its volume with methyl ethyl ketone R. Shake vigorously for 2minutes and separate the organic layer. Measure the absorbance of the organic layer at 530nm, using the organic layer of a blank solution as the compensation liquid. The absorbance is not greater than that of the organic layer obtained with 0.1ml of zinc standard solution (5ppm Zn) R treated in the same manner. Assay. Measure the radioactivity as described in the general monograph using suitable counting equipment by comparison with standardized gallium-67 solution or by measurement in an instrument calibrated with the aid of such a solution. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Note: Quick end-user check alternative method: 6 cm ITLC strip, drop at 1 cm from lower end, develop in methanol-acetic acid (9:1) mixture, cut at 3 cm from origin. 67Ga citrate remains at the origin.

***


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Iobenguane (123I) injection Latin Name. Iobenguani 123I solution iniectabilis Chemical name. {[(3-Iodo-123I)-phenyl]methyl}guanidine sulfate (2:1) Other names. Metaiodobenzyl guanidine (I-123) injection,123I-MIBG Chemical structure. (C8H10

123IN3)2 · H2SO4 Relative molecular mass. 271 as free base; 640 as sulfate (2:1) salt Graphic formula Description. Iobenguane (123I ) injection (123I-MIBG) is a clear, generally colourless (occasionally slightly yellow), sterile aqueous solution. Radionuclide production. Complies with 123I production and general conditions in radiopharmaceutical preparation. Briefly, iodine-123 may be obtained by proton irradiation of xenon enriched in xenon-124 (not less than 98%) followed by decay of caesium-123 formed via xenon-123. Radiochemical synthesis. In brief, 123I- Iobenguane is generally prepared by exchange labelling and contains metaiodobenzylguanidine in the unlabelled form. The product may contain fillers, preservatives, buffers and stabilizing agents. Iobenguane injection may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Iobenguane (123I ) injection should be stored in a refrigerator (2-8 oC) and during transportation in freezer in appropriately labelled single dose or multi-dose vials in a container providing appropriate radiation shielding. Other conditions of storage include ‘protect from light’. Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. Iobenguane (123I ) injection should be labelled giving information on storage temperature and protect from light. Additional information. Iobenguane (123I ) injection may be provided in single patient dose vials containing volumes suitable for injection (e.g. 1 – 5ml). The preparation of this

N

NH

NH2

H

I1232

. H2SO4


radiopharmaceutical and its injection into a patient will generally occur within 24 hours. The label should specify radioactivity in MBq of iodine-123 gram of iobenguane base. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Iobenguane (123I ) injection (123I-MIBG) is a clear, generally colourless (occasionally slightly yellow), sterile aqueous solution containing metaiodobenzyl guanidine sulfate. A small percentage of the molecules of metaiodobenzyl guanidine will contain 123I in place of non-radioactive iodine. The content of 123I is not less than 90.0% and not more than 110.0% of the reported activity at the reference date and hour as stated on the label. Not less than 95% of total 123I activity is present as 123I-metaiodobenzyl guanidine. Not less than 10GBq of 123I per gram of iobenguane base. Not more than 0.35% of total radioactivity is due to radionuclides other than 123I. The product may contain fillers, preservatives, buffers and stabilizing agents. Where sterility is not adequately confirmed by product labelling, Iobenguane injection may be sterilized by Method 3 Filtration described under injections in Ph. Int. The radioactive half life of 123I is 13.2 hours. Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 123

I suitably diluted if needed, is identical to that of a specimen of 123

I in that it exhibits a major peak at 159keV.

124I has half life of 4.2 days and main peak 603keV.

125I with half life of 59.4 days and emits X-rays of 27keV and a photon of 35keV.

Tellurium-121 has a half life of 19.2 days and mains peaks at 507 and 573 keV.

Standardized iodine-123, iodine-125 and tellurium-121 solution are available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is 13 between 15 hours. C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between 3.5 to 8.0.


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Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 97% of the total radioactivity is present as 123I. Not more than 0.35% of total radioactivity is due to other radionuclides such as 125I and tellurium-121. No radionuclide with longer half lives than iodine-125 is detected. Retain the solution to be examined for a sufficient time to allow the 123I to decrease to a level which permits the detection of radionuclide impurities. Radiochemical purity. Carry out thin-layer chromatography using general procedures as described. Apply a small volume (e.g. 1 µL) of Iobenguane (123I ) injection to a silica gel thin-layer sheet ( 1.5 X 15 cm). Allow to dry and develop with a 1:1 mixture of ethyl acetate: ethanol. Determine the radioactivity distribution by a suitable method as described. Iobenguane (123I) injection and iodide have Rf values of about 0.6 and 0 in this system. Not less than 95 % of the total radioactivity is in the spot corresponding to MIBG. Reference solution A. Dissolve 0.1g of sodium iodide R in the mobile phase and dilute to 100ml. Reference solution B. dissolve 20.0mg of iobenguane sulfate CRS in 50ml of the mobile phase and dilute to 100ml Chemical identity. See radiopharmaceutical preparation. The thin-layer chromatography assay described above can serve to identify the radioactive substance as metaiodobenzyl guanidine. Authentic unlabelled compound can be analysed in conjunction with the radioactive sample. The authentic metaiodobenzylguanidine is located on the chromatogram by a suitable indicator technique and will have the same Rf value as the Iobenguane (123I) injection. Assay. Determine the radioactivity in suitable calibrated counting equipment. The assay will provide radioactive concentration in MBq/ml as well as total radioactivity. Measure the radioactivity as described in the general monograph using suitable counting equipment by comparison with standardized iodine-123 solution or by measurement in an instrument calibrated with the aid of such a solution. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The manufacturer will distribute or dispense iobenguane (123I) injection prior to completion of the test for sterility due to the short shelf-life of the product. Test for sterility will be initiated on the day of manufacture. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

***


Iobenguane (131I ) injection Latin Name. Iobenguani 131I solutio iniectabilis Chemical name. {[(3-Iodo-131I)-phenyl]methyl}guanidine sulfate (2:1) Other names. Iobenguane (131I) injection, 131I-MIBG Chemical structure. (C8H10

131IN3)2 · H2SO4 Relative molecular mass: 279 as free base; 656 as sulfate (2:1) salt Graphic formula Description. Iobenguane (131I ) injection (131I-MIBG) is a clear, generally colourless (occasionally slightly yellow), sterile aqueous solution. Radionuclide production. Complies with 131I production and general conditions in radiopharmaceutical preparation. Iodine-131 may be obtained by neutron irradiation of tellurium or by extraction from uranium fission products. Radiochemical synthesis. In brief, 131I- Iobenguane is generally prepared by exchange labelling and contains metaiodobenzylguanidine in the unlabelled form. The product may contain fillers, preservatives, buffers and stabilizing agents. Iobenguane injection may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic and therapeutic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Iobenguane (131I ) injection should be stored in a refrigerator (2-8 oC) and during transportation in freezer in appropriately labelled single dose or multidose vials in a container providing appropriate radiation shielding. Other conditions of storage include "protect from light". Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. Iobenguane (131I ) injection should be labelled giving information on storage temperature and protect from light. Additional information. Iobenguane (131I) injection may be provided in single patient dose vials containing volumes suitable for injection (e.g. 1–5ml) or larger vials for therapy. The

N

NH

NH2

H

I1312

. H2SO4


- 19 -

preparation of this radiopharmaceutical and its injection into a patient will generally occur within 24 hours. The label should specify radioactivity in MBq of iodine-131 gram of iobenguane base. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Iobenguane injection (131I-MIBG) is a clear, colourless, sterile aqueous solution containing metaiodobenzyl guanidine sulfate. A small percentage of the molecules of metaiodobenzyl guanidine will contain 131I in place of non-radioactive iodine. The content of 131I is not less than 90.0 % and not more than 110.0 % of the reported activity at the reference date and hour as stated on the label. Not less than 94% of total 131I activity is present as 131I- Iobenguane. The specific radioactivity is not less than 20GBq of iodine-131 per gram of iobenguane base. The product may contain fillers, preservatives, buffers and stabilizing agents. Iobenguane injection may be sterilized by Method 3 Filtration described under injections in Ph. Int. The radioactive half life of 131I is 8.06 days. Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 131



Standardized iodine-131 solutions are available from laboratories recognized by competent authority.

B. The half life determined using a suitable detector system is between 184 and 203 hours. C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between. 3.5 to 8.0. Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 99% of the total radioactivity is present as 131I. Determine the relative amounts of iodine-131, iodine-133, iodine-135 and other radionuclide impurities that may be present. Iodine-133 has a half-life of 20.8 hours and main peaks 530keV and 875keV. Iodine-135 has a half life of 6.55hours and is main peaks are 527keV, 1132keV and 1260keV. Not less than 99.9% of the total radioactivity is due to iodine-131.


Radiochemical purity. Carry out thin-layer chromatography using general procedures as described in Ph. Int. Apply a small volume (e.g. 1 µL) of Iobenguane (131I ) injection to a silica gel thin-layer sheet (1.5 X 15 cm). Allow to dry and develop with a 1:1 mixture of ethyl acetate: ethanol. Determine the radioactivity distribution by a suitable method as described. Iobenguane (131I ) injection and iodide have Rf values of about 0.6 and 0 in this system. Not less than 94 % of the total radioactivity is in the spot corresponding to Iobenguane (131I). Chemical identity. See radiopharmaceutical preparation. The thin-layer chromatography assay described above can serve to identify the radioactive substance as metaiodobenzyl guanidine. Authentic unlabelled compound can be analyzed in conjunction with the radioactive sample. The authentic metaiodobenzylguanidine is located on the chromatogram by a suitable indicator technique and will have the same Rf value as the Iobenguane (131I) injection. Assay: See radiopharmaceutical preparation. Determine the radioactivity in suitable calibrated counting equipment. Measure the radioactivity as described in the general monograph using suitable counting equipment by comparison with standardized iodine-131 solution or by measurement in an instrument calibrated with the aid of such a solution. The assay will provide radioactive concentration in MBq/ml as well as total radioactivity. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The manufacturer will distribute or dispense Iobenguane (131I) injection prior to completion of the test for sterility due to the short shelf-life of the product. Test for sterility will be initiated on the day of manufacture. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

*** Samarium (

153Sm) ethylene diamine tetramethylene phosphonate (EDTMP)

complex injection

Latin name. Samarium 153

Sm EDTMP solutio iniectabilis

Chemical name.

153Sm EDTMP, Samarium (153Sm) ethylene diamine tetramethylene

phosphonate.

Chem. Structure. A complex between

153Sm and the ligand EDTMP.


- 21 -

Description. Samarium ethylene diamine tetramethylene phosphonate injection (153

Sm-EDTMP) is a clear colourless, sterile solution. Radionuclide production. Complies with

153Sm production and general conditions in

radiopharmaceutical preparation. Samarium may be obtained by neutron irradiation of enriched samarium dioxide (

152Sm) Sm2O3 in quartz ampoule.

Radiochemical systhesis. In brief,

153Sm chloride is complexed by addition to solution of

EDTMP that is present in excess. EDTMP may be prepared previously synthesized from phosphorous acid, ethylenediamine and formaldehyde using the Mannich-type reaction. It should be purified by successive re-crystallizations and identification by IR spectroscopy. A stock solution of EDTMP is in sodium hydroxide therefore a pH adjustment to 7-7.5 is required for complexation with

153Sm. The final solution can be autoclaved by the method

described in Ph. Int. Category. Palliation radiopharmaceutical Storage. Complies with general requirements for storage. See radiopharmaceutical preparation.

153Sm EDTMP complex injection is heat sensitive and should therefore be

transported frozen at least to -10 oC . Prior to patient use it should be should be stored in a refrigerator. Labelling. See radiopharmaceutical preparation.

153Sm EDTMP injection should be labelled

giving information on storage temperature. Additional Information. See radiopharmaceutical preparation. (e.g. dilutions, concentration, etc.) Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Samarium ethylene diamine tetramethylene phosphonate complex (

153Sm )

injection (153

Sm-EDTMP) is a clear colourless, sterile solution of 153

Sm complexed with EDTMP that is present in excess. The content of

153Sm is not less than 90.0% and not more

than 110.0% of the content of 153

Sm stated on the label at the reference date and hour stated on the label. Not less than 95% of total

153Sm is present as

153Sm EDTMP complex. The

injection may be prepared from sterile starting materials and ideally sterilized by autoclaving described under injections in Ph. Int. The product may contain stabilizing agents as well as buffers. The radioactive half life of

153Sm is 46.3 hours.


Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 153

Sm EDTMP complex injection, suitably diluted if needed, is identical to that of a specimen of

153Sm in that it exhibits major peaks at 70 and 103 keV.

B. The half-life determined using a suitable detector system is between and 44 and 49

hours. Standardized samarium-153 solutions are available from laboratories recognized by competent authority.

C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. Methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between. 7.0 to 8.5. Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 99.8% total radioactivity is present as 153

Sm at the time of calibration. Using gamma spectrometry estimate the content of 154

Eu. It should be less than 0.01%. The sum of all gamma emitting impurities should be less than 0.2%. Radiochemical Purity. Carry out Ascending Paper Chromatography analysis as described, using paper chromatography 1 and a mixture of ammonia and water (0.2:40) as solvent. Apply approximately 5 µl of sample to the paper (1.5 X 25 cm) and develop till the solvent front reaches about 15 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method.

153Sm EDTMP complex has Rf of about 0.9 and ionic

153Sm Rf about 0 in this system. The percentage of 153Sm activity associated with the spot

corresponding to 153

Sm EDTMP complex is >95%. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized

153Sm solution or by measurement in an instrument calibrated with the aid of

such a solution. Standardized solutions of 153

Sm are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The manufacturer will distribute or dispense

153Sm EDTMP complex

injection prior to completion of the test for sterility due to the short shelf-life of the product. Test for sterility will be initiated on the day of manufacture.


- 23 -

Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

***

Sodium Iodide (131I ) capsules Latin Name. Natrii iodidi (131I) capsulae Chemical name. Sodium iodide capsules. Other names. Radio-iodide therapy capsules.

Description. White or coloured gelatine capsule contained in a sealed secondary container. It complies with the requirements for capsules as described in Ph. Int. Radionuclide production. Complies with 131I production and general conditions in radiopharmaceutical preparation. Iodine-131 may be obtained by neutron irradiation of tellurium or by extraction from uranium fission products. Radiopharmaceutical formulation. The content of 131I is not less than 90.0% and not more than 110.0% of the stated content on the label at the reference date and hour. The method of manufacture is such that the specific activity used is not less than 185MBq of iodine-131 per mg of iodine for diagnostic capsules and 185MBq of iodine-131 per microgram of iodine for therapeutic capsules. Category. Diagnostic and therapeutic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. See radiopharmaceutical preparation. Sodium Iodide (131I ) capsules should be stored at room temperature (below 30°C). Other conditions include storage of capsules in a fume hood or well ventilated room. Labelling. Complies with the requirements for "Labelling" of radiopharmaceuticals. See radiopharmaceutical preparation. Additional information. See radiopharmaceutical preparation. Measure the radioactivity in every capsule intended for therapeutic use and storage of capsules in a fume hood or well ventilated room. Requirements Complies with general requirements for capsule preparation of Ph. Int.


Definition. White or coloured gelatine capsule contained in a sealed secondary container. Each container has multiple capsules (for diagnosis) or a single capsule (for therapy). Sodium Iodide (131I) capsules, suitable for oral administration, contain radioactive 131I as sodium iodide adsorbed onto hard gelatine capsules or a solid matrix such as anhydrous sodium sulfate or anhydrous disodium hydrogen phosphate contained in the capsule. The capsule(s) shipped in sealed container has a single or multiple capsules for therapy. The content of 131I is not less than 90.0 % and not more than 110.0 % of the stated content on the label at the reference date and hour. The method of manufacture is such that the specific activity is not less than 185MBq of iodine-131 per mg of iodine. The radioactive half-life of 131I is 8.06 days. Identification Either test A or B. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 131



Standardized iodine-131 solution is available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is between 184 and 203 hours. Radionuclide purity. See radiopharmaceutical preparation. Using an appropriate volume of solution determined by the Disintegration test Ph. Int. A solution or suspension of Sodium Iodide (131I ) capsule complies with the requirements for radionuclide purity given under Sodium Iodide 131I solution. Determine the relative amounts of iodine-131, iodine-133, iodine-135 and other radionuclide impurities that may be present. Iodine-133 has a half-life of 20.8 hours and main peaks 530keV and 875keV. Iodine-135 has a half life of 6.55hours and is main peaks are 527keV, 1132keV and 1260keV. Not less than 99.9% of the total radioactivity is due to iodine-131. Radiochemical purity. Homogenize 1 capsule in 5ml of water, add 5ml methanol and centrifuge. The supernatant solution obtained meets the requirements of Radiochemical purity test given under Sodium Iodide (131I ) Solution. If necessary, dilute the solution to give an appropriate counting rate on the chromatogram. Add an equal volume of a solution containing 0.1% of potassium iodide, 0.2% of potassium iodate, and 1% potassium bicarbonate, mix, place 10µl of the mixture on a strip of chromatography paper and allow to dry. On the same paper place 10 µl of a 2% solution of potassium iodide and 10 µl of a 2% solution of potassium iodate and allow to dry. Develop the chromatogram by ascending chromatography using a mixture of 3 volumes of methanol and 1 volume of water. Allow to dry and determine the positions of the inactive potassium iodide and potassium iodate by the application on filter paper impregnated with acetic acid and potassium iodate and acetic acid and potassium iodide respectively. Determine the radioactivity distribution by scanning with a suitable instrument. The radioactivity of the iodide band is not less than 95%


- 25 -

of the total radioactivity. The Rf value for the iodide band falls within 5% of the value found for an iodine 131I sample of known purity when determined under parallel conditions. Disintegration. Warm 10ml of 0.20%w/v solution of potassium iodide in a small beaker on a water bath at 37C. Add one of the capsules to be examined and stir magnetically 20 revolutions per minute. The shell and its contents dissolve completely within 15minutes. Uniformity of the content. Using identical geometrical conditions and with no fewer than ten capsules determine the average radioactivity per capsule. The radioactivity of no capsules differs by more than 10% from average radioactivity. The relative standard deviation is not greater than 3.5%. Assay. Measure the radioactivity as described in the general monograph using suitable counting equipment by comparison with standardized iodine-131 solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 131I are available from national standardizing laboratories. Determine the radioactivity contained in 10 representative capsules or more individual results obtained from the uniformity of content test. Each capsule contains not less than 90% and not more than 110% of the declared iodine-131 radioactivity at the date and hour stated on the label.

***

Sodium Iodide (131I ) injection Latin Name. Natrii iodidi (131I) solutio iniectabilis Description. A clear, colourless sterile solution containing radioactive 131I as sodium iodide. Radionuclide production. Complies with 131I production and general conditions in radiopharmaceutical preparation. Iodine-131 may be obtained by neutron irradiation of tellurium or by extraction from uranium fission products. Radioformulation. The method of preparation is such that the specific radioactivity is not less than 185GBq of ioidine-131 per milligram of iodine at the date and hour on the label. Radio-iodine injection may be sterilized by Method 1 autoclaving described under injections in Ph. Int. Category. Diagnostic or therapeutic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium Iodide (131I ) injection should be stored at room temperature (below 30°C).


Labelling. See radiopharmaceutical preparation. Complies with the requirements under "Labelling". Additional information. See radiopharmaceutical preparation. The label should specify radioactivity in MBq of iodine-131 per ml. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Sodium Iodide (131I ) injection is a clear colourless solution which is sterile solution containing radioactive I-131 as sodium iodide. It is usually prepared by neutron irradiation of tellurium, as carrier free sodium iodide. Not less than 95% of total 131I is present as iodide. The content of 131I is not less than 90% and not more than 110% of the stated content on the label at the reference date and hour. The specific activity is not less than 185MBq (or 5mCi) or 185kBq (5µCi) per µg of iodine for therapeutic and diagnostic doses respectively, at the reference date and time stated on the label. Not less than 95% of total 131I is present as iodide. The injection may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int. The radioactive half-life of I-131 is 8.06 days. Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 131



Standardized iodine-131 solution is available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is between 184 and 203 hours. C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between but not less than pH 7.0 and not more than pH 8.0. Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 99% of the total radioactivity is present as


- 27 -

131I. Determine the relative amounts of iodine-131, iodine-133, iodine-135 and other radionuclide impurities that may be present. Iodine-133 has a half-life of 20.8 hours and main peaks 530keV and 875keV. Iodine-135 has a half life of 6.55hours and is main peaks are 527keV, 1132keV and 1260keV. Not less than 99.9% of the total radioactivity is due to iodine-131. Radiochemical purity. Complies with the general requirements for radiochemical purity, see radiopharmaceutical preparation. Carry out thin-layer chromatography using general procedures as described in Ph. Int. Sodium Iodide (131I ) capsules. If necessary, dilute the solution to give an appropriate counting rate on the chromatogram. Add an equal volume of a solution containing 0.1% of potassium iodide, 0.2% of potassium iodate, and 1% potassium bicarbonate, mix, place 10µl of the mixture on a strip of chromatography paper and allow to dry. On the same paper place 10 µl of a 2% solution of potassium iodide and 10 µl of a 2% solution of potassium iodate and allow to dry. Develop the chromatogram by ascending chromatography using a mixture of 3 volumes of methanol and 1 volume of water. Allow to dry and determine the positions of the inactive potassium iodide and potassium iodate by the application of filter paper impregnated with acetic acid and potassium iodate and acetic acid and potassium iodide respectively. Determine the radioactivity distribution by scanning with a suitable instrument. The radioactivity of the iodide band is not less than 95% of the total radioactivity. The Rf value for the iodide band falls within 5% of the value found for an iodine 131I sample of known purity when determined under parallel conditions. Assay. See radiopharmaceutical preparation. The radioactivity of the iodide band is not less than 95% of the total radioactivity when measured in suitable counting equipment compared with a standardized 131I solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 131I are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The manufacturer will distribute or dispense 131I

injection prior to

completion of the test for sterility due to the short shelf-life of the product. Test for sterility will be initiated on the day of manufacture. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

***


Sodium Iodide (131I) solution Latin Name: Natrii iodidi (131I) solutio Chemical name: Sodium iodide Other names: 131I Radio-iodine solution Description. Sodium Iodide 131I solution is a clear colourless solution containing radioactive 131I as sodium iodide and is suitable for oral administration. Radionuclide production. Complies with 131I production and general conditions in radiopharmaceutical preparation. Iodine-131 may be obtained by neutron irradiation of tellurium or by extraction from uranium fission products. Radioformulation. The method of preparation is such that the specific radioactivity is not less than 185GBq of ioidine-131 per milligram of iodine at the date and hour on the label. The oral solution may contain sodium thiosulfate or other suitable reducing agents and may contain a suitable buffer. Radioiodine injection may be sterilized to achieve required bio-burden for Ph. Int. oral solution by Method 1 autoclaving described under injections in Ph. Int. Category. Diagnostic or therapeutic radiopharmaceutical solution. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium Iodide (131I ) solution should be stored at room temperature (below 30°C). Labelling. See radiopharmaceutical preparation. Complies with the requirements under "Labelling". Additional information. See radiopharmaceutical preparation. The label should specify radioactivity in MBq of iodine-131 per ml. Requirement The radiopharmaceutical complies with the monograph in Ph. Int. for "Oral solution preparations". Definition. Sodium Iodide 131I solution is a clear colourless solution containing radioactive 131I as sodium iodide and is suitable for oral administration. The oral solution may contain sodium thiosulfate or other suitable reducing agents and may contain a suitable buffer. Not less than 95% of total 131I is present as iodide. The content of 131I is not less than 90% and not more than 110% of the stated content on the label at the reference date and hour. The specific activity is not less than 5 mCi (or 185MBq) per µg of iodine at the reference date and time stated on the label. The solution may also contain sodium thiosulfate, sodium hydrogen carbonate or other suitable reducing agent. The radioactive half-life of 131I is 8.06 days.


- 29 -

Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 131



Standardized iodine-131 solution are available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is between 184 and 203 hours. C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between but not less than pH 7.0 and not more than pH 8.0. Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 99% of the total radioactivity is present as 131I. Determine the relative amounts of iodine-131, iodine-133, iodine-135 and other radionuclide impurities that may be present. Iodine-133 has a half-life of 20.8 hours and main peaks 530keV and 875keV. Iodine-135 has a half life of 6.55hours and is main peaks are 527keV, 1132keV and 1260keV. Not less than 99.9% of the total radioactivity is due to iodine-131. Radiochemical purity. Complies with the general requirements for radiochemical purity See radiopharmaceutical preparation. Carry out thin-layer chromatography using general procedures as described in Ph. Int. Sodium Iodide (131I ) injection. If necessary, dilute the solution to give an appropriate counting rate on the chromatogram. Add an equal volume of a solution containing 0.1% of potassium iodide, 0.2% of potassium iodate, and 1% potassium bicarbonate, mix, place 10µl of the mixture on a strip of chromatography paper and allow to dry. On the same paper place 10 µl of a 2% solution of potassium iodide and 10 µl of a 2% solution of potassium iodate and allow to dry. Develop the chromatogram by ascending chromatography using a mixture of 3 volumes of methanol and 1 volume of water. Following development time of 2 hours allow the paper to dry in air and determine the positions of inactive potassium iodide and iodate. Determine the distribution of radioactivity using an appropriate detection and the Rf values of the spot should not be more than 5% of the spot corresponding to iodide. Further not less than 95% of total activity corresponds to iodide. Assay. See radiopharmaceutical preparation. Determine the radioactivity in suitable counting equipment by comparison with a standardized 131I solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 131I are available from national standardizing laboratories.


Bioburden test. Complies with general requirement of oral solution and microbiology for oral solution Ph. Int.

***

Sodium iothalamate 125I injection

Latin name. Natrii iothalamate iniectabilis Chemical name. Sodium iothalamate Graphic formula.

Description. A clear, colourless sterile solution containing iothalamate sodium 125I injection. Radionuclide production. Complies with 125I production and general conditions in radiopharmaceutical preparation. Iodine-125 may be obtained by neutron irradiation of xenon. Radiochemical synthesis. In brief, 125I- Iothalamate is generally prepared by exchange labelling and contains iodothalamate sodium in the unlabelled form. The product may contain fillers, preservatives, buffers and stabilizing agents. Iothalamate sodium injection may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Iothalamate sodium (125I ) injection should be stored in a refrigerator (2-8 oC) Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. The label should specify radioactivity in MBq per ml.


- 31 -

Additional Information. See radiopharmaceutical preparation. (e.g. dilutions, concentration, etc.). Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Iothalamate sodium 125I injection is a sterile solution of iothalamic acid in water for injection prepared with the aid of sodium bicarbonate. A portion of the molecules contain radioactive iodine (125I ) in the molecular structure. It may contain small amounts of suitable buffers or a stabilizer. Iodothalamate sodium 125I injection contains not less than 90.0 percent and not more than 110.0 percent of the concentration of iodothalamate sodium and of the labelled amount of 125I as iodothalamate Sodium expressed in kiloBecquerels (or in microcuries) per ml at the time indicated in the labelling. Other chemicals forms of radioactivity do not exceed 2.0 per cent of the total radioactivity. The solution may contain a preservative or stabilizer. Identification Either test A or B in addition to C. A. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a

sample of 125


I in that it exhibits a major peak at 27keV, corresponding to x-ray of tellurium. Iodine-126 has half-life of 13.0 days and peaks energies of 388keV and 666keV.

Standardized iodine-125 and caesium-137 solution are available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is 55 between 65days. C. Examine the distribution of radioactivity on a chromatogram obtained for radiochemical

purity. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between. 7.0 to 8.5. Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. The gamma ray and X-ray spectrum recorded measured in a suitable instrument with a sample of

125I suitably diluted if needed, is identical to that of

a specimen of 125

I in that it exhibits a major peak at 27keV, corresponding to X-ray of


tellurium. Iodine-126 has half life of 13.0 days and peaks energies of 388keV and 666keV. Determine the relative amounts of iodine-125 and iodine-126 present on the assumption that the 666keV gamma photon of iodine-126 is emitted in 33% of disintegrations, and that the 661keV gamma photon of caesium-137 is emitted in 85.4% of disintegrations. Not less than 95% of the total radioactivity is present as 125I. Standardized iodine-125 and caesium-137 solution are available from laboratories recognized by competent authority. Radiochemical purity. Carry out thin-layer chromatography using general procedures as described. Place a measured volume of injection, diluted with a suitable diluent so that it provides a count rate of about 20,000 counts per minute, about 25 mm from one end of a 25 x 300 mm strip of chromatographic paper, and allow to dray. Develop the chromatogram over a period of about 4 hours by ascending chromatography, using methanol and ammonium hydroxide (100:1.5) adjusted with 2N sulphuric acid to a pH of 3 to 6, and air-dry. Determine the radioactivity distribution with a suitable collimated radiation detector. The radioactivity under the free radio iodide peak is not more than 2% of the total area of all peaks: not less than 98% of the total activity is found at the point of application (as iothalamate sodium). Chemical identity. See radiopharmaceutical preparation. The thin-layer chromatography assay described above can serve to identify the radioactive substance as iothalamate sodium. Authentic unlabelled compound can be analysed in conjunction with the radioactive sample. The authentic iothalamate sodium is located on the chromatogram by a suitable indicator technique and will have the same Rf value as the iothalamate (125I) injection. Assay. See radiopharmaceutical preparation. Determine the radioactivity in suitable counting equipment, in kiloBecquerels (or µCi) per ml, of the injection by use of a calibrated system. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

***


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Sodium Pertechnetate (99mTc) injection (fission)

This monograph applies to sodium pertechnetate (99mTc) injection obtained from generators containing molybdenum-99 extracted from fission products of uranium. Latin name. Natrii pertechnetatis (99mTc) fissione formati solutio iniectabilis Chemical name. Sodium pertechnetate Other names.

99mTc sodium pertechnetate

Description. Sodium Pertechnetate (99mTc) injection is a clear colourless sterile solution containing technetium-99m in the form of pertechnetate ion and sufficient Sodium Chloride to make the solution isotonic with blood. Radionuclide production. Technetium-99m is a radioactive nuclide formed by the radioactive decay of molybdenum-99 (99Mo). Molybdenum-99 is a radioactive isotope of molybdenum and may be produced by neutron irradiation of natural molybdenum or of molybdenum enriched in molybdenum-98 or it may be produced by uranium fission. The label must show whether or not the molybdenum-99 was produced by uranium fission. Generator. In brief, the molybdenum-99 is normally loaded onto an exchange column which allows separation of 99mTc from parent 99Mo using a suitable generator system. Sterile solution is used to elute under aseptic conditions. The generator must state on the label that it contains molybdenum-99 (fission). Category. Diagnostic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium pertechnetate (99mTc) injection should be stored at room temperature (below 30 oC). Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. The label should specify radioactivity in MBq per ml. If the injection has been prepared from molybdenum-99 produced from uranium fission this shall be stated on the label. Some national rules require the level of 99Mo per vial to be stated on the label. Additional Information. See radiopharmaceutical preparation. (e.g. colloid, reduced hydrolysis (Reduced hydrolysed [RH-Tc]), dilutions, concentration, etc.). Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations".


Definition. Sodium pertechnetate (99mTc) injection is a clear colourless sterile solution containing technetium-99m in the form of pertechnetate ion and sufficient sodium chloride to make the solution isotonic with blood. Technetium-99m is a radioactive nuclide formed by the radioactive decay of molybdenum-99. Molybdenum-99 is a radioactive isotope of molybdenum and may be produced by neutron irradiation of natural molybdenum or of molybdenum enriched in molybdenum-98 or it may be produced by uranium fission. The generator label must show the molybdenum-99 was produced by uranium fission. The content of technetium-99m is not less than 90.0% and not more than 110.0% of the content of technetium-99m stated on the label at the reference date and hour stated on the label. The radioactivity due to other radionuclides should not be greater than amount expressed as percentage of total radioactivity and calculated with reference to the date and hour of administration: molybdenum-99 (0.1%),iodine-131(5x10-3%),ruthenium-103 (5x10-3%), strontium-89 (6x10-5%), strontium-90(6x10-6%), alpha-emitting impurities (1x10-7%) and other gamma impurities (0.01%). When the molybdenum-99 has been produced by uranium fission there is an additional requirement that not more than 10-7 % of the total radioactivity shall be due to alpha emitting radionuclides and as a further exception to the requirement that not more than 0.01% of the total activity shall be due to radionuclides other than technetium-99m, iodine-131 may be present to the extent of 0.005% of the total radioactivity all calculated to the time of administration. The injection may be prepared from the use columns of molybdenum-99 sterilized by Method 1 heating in an autoclave and the actual separation to sodium pertechnetate under validated aseptic conditions in addition to Method 3- Filtration described under injections in Ph. Int. The radioactive half-life of technetium 99m is 6.02 hours. Identification A. The gamma ray spectrum measured in a suitable instrument is identical with that of a

standardized technetium 99m solution; the most prominent gamma photon has energy of 140 keV.

Standardized solutions of molybdenum-99, iodine-131, ruthenium-103, strontium-89, strontium-90, alpha-emitting impurities and other gamma impurities from available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours. C. The test for radiochemical purity described below also serves to identify the chemical

nature of the product Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter.


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pH. Complies with general description for pH. See radiopharmaceutical preparation. Between. 4.5 to 7.5 Radionuclidic purity. Complies with the requirements of radionuclidic purity described under “Sodium Pertechnetate 99mTc injection” See radiopharmaceutical preparation. Molybdenum-99. The presence of molybdenum-99 is revealed by its characteristic gamma ray spectrum; the most important photons have energies of 181, 740 and 778keV. The instrument should be calibrated using a standardized solution of Molybdenum-99. The radioactive half life of molybdenum-99 is 66.2 hours. Not more than 0.1% of the total radioactivity shall be due to molybdenum-99. Take 37MBq (1 mCi) of the injection and determine the gamma ray spectrum using a sodium iodide detector with a shield of lead of thickness 6mm interposed between the sample and the detector. The response in the region corresponding to the 740 keV photon of molybdenum-99 does not exceed that obtained using 37kBq (1 uCi) of a standardized solution of molybdenum-99 measured under the same conditions, when all measurements are calculated to the time of administration. It should be noted that, when the molybdenum-99 has been produced by uranium fission, iodine-132 may be present. Iodine-132 has a high abundance of gamma photons in the 700 to 800 keV regions and its presence may cause the failure, in this test, of a product that meets the formal requirements for radionuclide purity. Iodine-132 may be distinguished from molybdenum-99 by its short half life (2.29 hours). Standardized solutions of molybdenum-99 are available from national laboratories. Iodine-131. The presence of iodine-131 is revealed by its characteristic gamma ray spectrum; the most prominent photons have energies of 284, 364 and 637 keV. The instrument should be calibrated using a standardized solution of iodine-131. The radioactive half life of iodine-131 is 8.06 days. Not more than 0.005% of the total radioactivity shall be due to iodine-131. When the injection has been prepared from molybdenum-99 produced by uranium fission, the above test should be suitably modified to measure also the iodine-131 content. This should not exceed 18.5kBq in 37MBq (0.5uci per 1mCi) of technetium 99m at the time of administration. Standardized solutions of iodine-131 are available from national laboratories. Retain a sample of the injection for a sufficient length of time to allow technetium-99m to decay to a sufficiently low level to permit the detection of radionuclide impurities. All measurements of radioactivity are to be expressed at the time of administration of the injection. Ruthenium-103. The presence of ruthenium-103 is revealed by its characteristic gamma ray spectrum; the most prominent photons have energies of 497 keV. The instrument should be calibrated using a standardized solution of ruthenium-103. The radioactive half life of ruthenium-103 is 39.3 days. Not more than 0.005% of the total radioactivity shall be due to ruthenium-103.


Stronium-89. The presence of Stronium-89 is revealed by its characteristic beta ray spectrum and may require initial chemical separation. The most prominent peak has beta-emission of maximum energy of 1.492MeV. The instrument should be calibrated using a standardized solution of Stronium-89. The radioactive half-life of Stronium-89 is 50.6 days. Not more than 6x10-5% of the total radioactivity shall be due to Stronium-89. Strontium-90. The presence of Stronium-90 is revealed by its characteristic gamma ray spectrum. To distinguish strontium-89 from strontium-90 compare with yttrium-90 the daughter nuclide of strontium-90 with respective beta-missions of maximum energy 546keV and 2.284MeV, radioactive half lives 29.1years and 64.0hours. The instrument should be calibrated using a standardized solution of yttrium-90. Not more than 6x10-6% of the total radioactivity shall be due to Stronium-90. Other radionuclide impurities. The gamma ray spectrum of the retained sample of injection should be examined for the presence of other radionuclide impurities which should, where possible, be identified and quantified. The total radioactivity due to these other impurities shall not exceed 0.01% of the total radioactivity of the sample. Alpha-emitting impurities. When the injection has been prepared from molybdenum-99 produced by uranium fission it may also be appropriate to examine the sample of the injection for the presence of beta emitting and alpha emitting impurities. The total radioactivity due to alpha-emitting impurities shall not exceed 1x10-7% of the total radioactivity of the sample. Radiochemical purity. Complies with general requirements see radiopharmaceutical preparation. Dilute the injection with water to a suitable radioactive concentration. Carry out ascending paper chromatography as described. Apply ~ 5 µl of the sample to the paper. Allow to dry and develop the chromatogram for 2hours using a mixture of 80 volumes of methanol and 20 volumes of water. Allow the chromatogram to dry and determine the areas of radioactivity by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to pertechnetate ion and having an Rf value of about 0.6. Chemical purity. Complies with general requirements, see radiopharmaceuticals preparation. Aluminium. In a test tube of about 12mm internal diameter add 2ml of 10%v/v solution of the injection, to which mix 1ml of acetate buffer pH 4.6 and then add 0.05ml of 1% w/v solution of chrome azurol S. Allow to stand for 3minutes for the colour to develop, which should not be more intense than a solution of aluminium standard solution (2ppm Al) in place of injection( 20ppm). Sterility. It meets the requirements under injections (reference Ph. Int.) See radiopharmaceutical preparation. Aseptic validation and any filter integrity testing are essential part of the assessment. The radiopharmaceutical injection may be released for use before completion of the sterility test.


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Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Elution volumes of greater than 15ml require individual bacterial endotoxins testing. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Standardized solution of technetium-99m, molybdenum-99, iodine-131, ruthenium-103, strontium-89, yittrium-90 and strontium-90 are available from competent authorities.. Biological distribution. See radiopharmaceutical preparation. Carry out biodistribution to assess normal distribution for sodium pertechnetate with significant uptake in salivary glands, thyroid, stomach and renal uptake.

***

Sodium Pertechnetate (99mTc) injection (non-fission)

This monograph applies to sodium pertechnetate (99mTc) injection obtained from generators containing molybdenum-99 produced by neutron irradiation of molybdenum and extracted for generator columns. Latin name. Natrii pertechnetatis (99mTc) sine fissione formati solutio iniectabilis Chemical name. Sodium pertechnetate Other names.

99mTc sodium pertechnetate

Description. Sodium Pertechnetate (99mTc) injection is a clear colourless solution sterile solution containing technetium-99m in the form of pertechnetate ion and sufficient Sodium Chloride to make the solution isotonic with blood. Radionuclide production. Technetium-99m is a radioactive nuclide formed by the radioactive decay of molybdenum-99 (99Mo). Molybdenum-99 is a radioactive isotope of molybdenum and may be produced by neutron irradiation of natural molybdenum or of molybdenum enriched in molybdenum-98. The label must show the molybdenum-99 was produced by non-fission. Generator. In brief, the molybdenum-99 is normally loaded into an ion exchange column which allows separation of 99mTc from parent 99Mo using a suitable generator system. Sterile


solution is used to elute under aseptic conditions. The generator must state on the label that it contains molybdenum-99 (non-fission). Category. Diagnostic radiopharmaceutical Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium pertechnetate (99mTc) injection should be stored at room temperature (below 30 oC). Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. The label should specify radioactivity in MBq per ml. If the injection has been prepared from molybdenum-99 produced from uranium fission this shall be stated on the label. Additional Information. See radiopharmaceutical preparation. (e.g. colloid, reduced hydrolysis (Reduced hydrolysed [RH-Tc], dilutions, concentration, etc). If the injection has been prepared from molybdenum-99 produced from non-fission this shall be stated on the label. Some national rules require the level of 99Mo per vial. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Sodium Pertechnetate (99mTc) injection is a clear colourless solution sterile solution containing technetium-99m in the form of pertechnetate ion and sufficient Sodium Chloride to make the solution isotonic with blood. Technetium-99m is a radioactive nuclide formed by the radioactive decay of molybdenum-99. Molybdenum-99 is a radioactive isotope of molybdenum and may be produced by neutron irradiation of natural molybdenum or of molybdenum enriched in molybdenum-98. The label must show the molybdenum-99 was produced by non-fission. The content of technetium-99m is not less than 90.0% and not more than 110.0% of the content of technetium-99m stated on the label at the reference date and hour stated on the label. The radioactivity due to other radionuclides should not be greater than amount expressed as percentage of total radioactivity and calculated with reference to the date and hour of administration: molybdenum-99 (0.1%) and other radionuclidic impurities (0.01%). The injection may be prepared from the use columns of molybdenum-99 sterilized by Method 1 heating in an autoclave and the actual separation to sodium pertechnetate under validated aseptic conditions in addition to Method 3- Filtration described under injections in Ph. Int.. The radioactive half-life of technetium-99m is 6.02 hours.


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Identification A. The gamma ray spectrum measured in a suitable instrument is identical with that of a

standardized technetium 99m solution; the most prominent gamma photon has energy of 140 keV.

Standardized solution of molybdenum-99 is from available from laboratories recognized by competent authority.

B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours C. The test for radiochemical purity described below also serves to identify the chemical

nature of the product Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general description for pH. See radiopharmaceutical preparation. Between. 4.5 to 7.5 Radionuclidic purity. Complies with the requirements of radionuclidic purity described under “Sodium Pertechnetate 99mTc injection (fission)” See radiopharmaceutical preparation. Not more than 0.1% molybdenum-99 and 0.01% of other radionuclides in the total radioactivity other than technetium-99m, except that technetium-99 resulting from the decay of technetium-99m may be present and except that molybdenum 99 may be present to the extent of 0.1% of the total radioactivity, all calculated to the time of administration. Standardized solutions of molybdenum-99 are available from national laboratories. Molybdenum-99. The presence of molybdenum-99 is revealed by its characteristic gamma ray spectrum; the most important photons have energies of 181, 740 and 778keV. The instrument should be calibrated using a standardized solution of Molybdenum99. The radioactive half life of molybdenum-99 is 66.2 hours. Not more than 0.1% of the total radioactivity shall be due to molybdenum-99. Take 37MBq (1 mCi) of the injection and determine the gamma ray spectrum using a sodium iodide detector with a shield of lead of thickness 6mm interposed between the sample and the detector. The response in the region corresponding to the 740 keV photon of molybdenum-99 does not exceed that obtained using 37kBq (1 uCi) of a standardized solution of molybdenum-99 measured under the same conditions, when all measurements are calculated to the time of administration. Radiochemical Purity. See radiopharmaceutical preparation. Dilute the injection with water to a suitable radioactive concentration. Carry out ascending paper chromatography as described. Apply ~5 µl of the sample to the paper. Allow to dry and develop the chromatogram for 2 hours using a mixture of 80 volumes of methanol and 20 volumes of water. Allow the chromatogram to dry and determine the areas of radioactivity by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to pertechnetate ion and having an Rf value of about 0.6.


Chemical purity. Complies with general requirements see radiopharmaceuticals preparation. Aluminium. In a test tube of about 12mm internal diameter add 2ml of 10%v/v solution of the injection, to which mix 1ml of acetate buffer pH 4.6 and then add 0.05ml of 1% w/v solution of chrome azurol S. Allow to stand for 3miniutes for the colour to develop, which should not be more intense than a solution of aluminium standard solution (2ppm Al) in place of injection( 20ppm). Sterility. It meets the requirements under injections (reference Ph. Int.) See radiopharmaceutical preparation. Aseptic validation and any filter integrity testing are essential part of the assessment. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Eluation volumes of greater than 15ml require individual bacterial endotoxins testing. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Standardized solution of technetium-99m, molybdenum-99, iodine-131, ruthenium-103, strontium-89, yittrium-90 and strontium-90 are available from competent authorities.. Biological distribution. See radiopharmaceutical preparation. Carry out biodistribution to assess normal distribution for sodium pertechnetate with significant uptake in salivary glands, thyroid, stomach and renal uptake.

***

Sodium Phosphate (32P ) injection Latin name. Natrii phosphatis (32P) solutio iniectabilis Chemical name. Disodium and monosodium (32P) orthophosphate. Description. A clear, colourless sterile solution containing radioactive disodium and monosodium (32P) orthophosphate made isotonic to blood with sodium chloride. Radionuclide production. 32P is radioactive isotope of phosphorous and may be produced by neutron irradiation of sulfur.


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Radio-formulation. A clear, colourless sterile solution containing radioactive disodium and monosodium (32P) orthophosphate made isotonic to blood with sodium chloride. The solution may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int.. The radioactive half-life of 32P is 14.3 days Category. Therapeutic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium phosphate (32P) injection should be stored at room temperature (about 27oC). Labelling. Complies with general requirements of labelling. See radiopharmaceutical preparation. Sodium phosphate (32P) injection should be labelled as specified activity MBq per ml. Additional information. Advice to use Perspex for radiation protection and not lead. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution. Sodium Phosphate (32P) injection is a sterile solution of 32P as sodium phosphate. The solution contains added phosphate. 32P is a radioisotope of phosphorus and may be prepared by neutron irradiation of sulfur. It is produced in the form of sodium phosphate. The content of 32P is not less than 90.0% and not more than 110.0% of the content of 32P stated on the label at the reference date and hour stated on the label. The specific activity is not less than 37MBq per mg (1mCi per mg) of phosphate ion at the reference date and hour stated on the label. The solution may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int.. The radioactive half-life of 32P is 14.3 days. Identification Either test A or B in addition to C. A. The beta emission spectrum measured in a suitable instrument is identical with that of a

standardized phosphorus-32 solution available from laboratories recognized by competent authority. The maximum energy of the beta radiation is 1.71MeV.

B. The half-life determined using a suitable detector system is 13.5 between 15 days. C. The test for radiochemical purity described below also serves to identify the chemical

nature of the product


Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements see radiopharmaceutical preparation. Between 6.0 to 8.0. Radionuclide purity. The beta ray absorption coefficient calculated from the absorption curve obtained by measurement in a suitable instrument is identical with that obtained using a standardized phosphorous-32 solution. For the determination evaporate the sample on the aluminium plate, mount rigidly under a GM counter with a thin end window, interpose a series of aluminium foils between the source and the counting tube, and determine the counting rate for each foil. Use at least six foils, ranging in thickness from 10 to 200 mg/cm2 and a single absorber of not less than 800 mg/cm2. Radiochemical purity. Complies with general requirements see radiopharmaceutical preparation. Dilute the injection with water until its activity is about 20000 counts per minute, add an equal volume of a 10% v/v solution of phosphoric acid, mix and place 10µl of the mixture on a strip of chromatographic paper. Develop the chromatogram by descending chromatography using a mixture of 40 volumes of tertiary butanol, 20 volumes of water, and 5 volumes of formic acid. Allow to dry and determine the position of the inactive phosphoric acid by spraying the paper with a solution prepared in the following way: Dissolve 5 g. of ammonium molybdate in 100ml water and pour, with constant stirring, into a mixture of 12ml of nitric acid and 24ml of water. Determine the position of the radioactive distribution by scanning with a collimated GM counter; the radioactivity appears in one band only corresponding in value to the phosphoric acid. Chemical purity Total phosphate. Dilute the injection with water to produce a solution containing 10 uCi of phosphorous (32P ) per ml. To 1ml add 0.5ml of a 0.25% solution of ammonium vanadate, 0.5ml of ammonium molybdate, 1ml perchloric acid (70%w/w) and 2ml of water, mixing after each addition, and allow to stand for 30 minutes. The colour produced is not deeper than that produced by treating in the same manner 1 ml of a solution containing 47.3mg of sodium phosphate, anhydrous per litre. Assay. Determine the radioactivity in suitable calibrated for beta counting equipment. Determine the radioactivity in a suitable beta counting equipment by comparison with a standardized 32P solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 32P are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int.


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Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres.

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Strontium Chloride (89Sr) injection

Latin name Strontium chloridum (89Sr) solution iniectabilis. Description. A clear, colourless sterile solution containing radioactive strontium Chloride (89Sr) injection as strontium chloride in presence of excess chloride ions. Radionuclide production. Strontium (89Sr) is produced by neutron irradiation of strontium enriched in strontium-88. Radioformulation. The specific radioactivity is not less than 1.8MBq of strontium-89 per mg of strontium. The injection contains 6.0mg/ml to 12.5mg/ml of strontium. The solution may be sterilized by Method 1 Heating in an Autoclave or Method 3 Filtration described under injections in Ph. Int.. Category. Palliative radiopharmaceutical. Storage. Complies with general requirements for storage see radiopharmaceutical preparation. Strontium Chloride (89Sr) injection should be stored at room temperature (about 30 oC). Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. Strontium Chloride (89Sr) injection should be labelled as specified activity MBq per ml. Additional information. Advice to use Perspex for radiation protection and not lead. Requirement The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution. Strontium Chloride (89Sr) injection is a sterile solution of 89Sr as strontium chloride in presence of excess chloride ions. 89Sr is a radioisotope of strontium and may be prepared by neutron irradiation of 89Sr the specific activity of 89Sr is > 2 MBq per mg of strontium at the date and time of calibration. The content of 89Sr is not less than 90.0% and not more than 110.0% of the content of 89Sr stated on the label at the reference date and hour stated on the label. Not more than 0.6% of total radioactivity is due to radionuclides other than strontium-89. The specific radioactivity is


not less than 1.8MBq of strontium-89 per mg of strontium. The injection contains 6.0mg/ml to 12.5mg/ml of strontium. The solution may be sterilized by Method 1 Heating in an Autoclave or Method 3 Filtration described under injections in Ph. Int.. The radioactive half life of 89Sr is 50.53 days. Identification Either test A or B in addition to C. A. The beta ray spectrum recorded with a sample of Strontium Chloride (89Sr) injection,

suitably diluted if needed, is identical to that of a specimen of 89Sr in that it exhibits maximum beta energy of 1495 keV. The photon detection has an energy of 909keV and is due to the short-lived daughter products, yttrium-89m (formed in 0.01% of the disintegrations), in equilibrium with the strontium-89. Compare with standardized solution of strontium-89 from competent national authority.


days. C. A reddish-brown precipitate is formed when 0.1ml of injection is added with freshly

prepared 1g/l solution of sodium rhodizonate. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 4.0 to 7.5 Radionuclide purity. Complies with the general requirements for radionuclide purity, see radiopharmaceutical preparation. Gamma emitters. Record and examine the injection gamma-ray and X-ray spectrum using suitable instrument. Not more than 0.4% of total activity should be due gamma emitting radionuclide other than yttrium-89m. Beta emitters. Using suitable cationic exchange resin and chemical separation determine the radioactivity due to sulphur-35 and phosphorus-32 in the injection sample. Not more than 0.2% of total beta emitting impurities. Not less than 99% total radioactivity is present as 89Sr at the time of calibration and the total beta emitting impurities will be < 0.2% at the time of administration. . Not more than 0.6% of total radioactivity is due to radionuclides other than strontium-89. Radiochemical purity. Complies with general requirements for radiochemical purities see radiopharmaceutical preparation. A sample (~50 µl) of strontium Chloride (89Sr) injection is examined for strontium content together with other metallic impurities using AES (Atomic Emission Spectrometry, see Ph. Int.) suitably housed to handle radioactive solutions.


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Chemical purity. Complies with general requirements of chemical impurity Ph. Int. A sample (~50 µl) of strontium Chloride (89Sr) injection is examined for strontium content together with other metallic impurities using AES (Atomic Emission Spectrometry, see Ph. Int.) suitably housed to handle radioactive solutions. The contents of Aluminium(Al), iron(Fe), lead(Pb) measured against respective standards will be less than 2, 5 and 5 microgram per ml. respectively. Assay. Determine the radioactivity in a suitable beta counting equipment by comparison with a standardized 89Sr solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 89Sr are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins.

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Technetium (99mTc) Bicisate complex injection (99mTc -ECD) Latin name Technetii (99mTc) Bicisati solutio iniectabilis Chemical name. 99mTc Ethylene dicysteine Diester Other names.

99mTc bicisate dihidrocloride (ECD), 99mTc-L,L-ECD


99mTc and the ligand ethylene dicysteine diester.

Graphic formula of the ligand.

Description. A clear, colourless sterile solution containing radioactive 99mTc -ECD. Radionuclide production. Described under sodium pertechnetate

99mTc injection.


Radioformulation.

99mTc ECD is prepared aseptically from pre-sterile kit containing ll-

ethylene dicysteine diester and with sodium pertechnetate injection. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc ECD injection should be stored at in a refrigerator (2-8 oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of

99mTc is 6.02 hours.

Requirement The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Technetium (99mTc) Bicisate dihidrocloride (ECD) injection is a sterile, clear colourless, aqueous solution suitable for intravenous administration of dihidrocloride complexed to radioactive technetium (99mTc with bicisate . It contains not less than 90.0 percent and not more than 110.0 of the labelled amount of 99mTc as Bicisate complex expressed in mega Becquerels (or microcuries) per ml. at the time indicated in the labelling. Other chemicals forms of radioactivity do not exceed 10.0 per cent of the total radioactivity. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. II. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents as well as buffers. The radioactive half life of 99mTc is 6.02 hours. Identification A. Complies with tests for identification described under Sodium pertechnetate

99mTc

injection. Standardized solutions of technetium-99m with main peak 140keV are available from competent authorities.

B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours.


- 47 -

C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests solution should have retention time as the peak in the chromatography system compared with reference solution.

Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 4.0 to 8.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Establish the radiochemical purity of the final solution by thin-layer chromatography (TLC) using silica gel IB-F plates and a solvent system of ethyl acetate (HPLC grade). Procedure-Using fresh ethyl acetate pour enough solvent into the developing tank to a depth of 3 to 4 mm. Seal the tank with Para film and allow 15 – 40 minutes for solvent equilibration. It is important to pre-equilibrate and preserve the integrity of the headspace in the chromatography tank; otherwise irreproducible TLC results are obtained. With a pencil, draw a faint line across the TLC plate heights of 2 cm, 4.5 cm and 7 cm from the bottom of the TLC. Place approximately 5 µl of the final solution at the centre of the 2 cm mark. The diameter of the spot should not be grater than 10 mm. Allow the spot to dry for 5 to 10 minutes, no longer. Place the plate in the pre-equilibrated TLC tank and develop to the 7.0 cm line (about 15 minutes). Remove the plate and dry in a ventilated area. This procedure must be realized in 4 vials of the injection. Quantification-Cut the TLC plate at the 4.5 cm mark with scissors. Count the activity on each piece using a dose calibrator or a gamma counter. The top portion contains the 99mTc Bicisate and the bottom portion contains all radio impurities. Calculate the radiochemical purity using the following equation: 100P / (P + C) In which: P = activity of the top piece and C= activity of the bottom piece. Not less than 90% of the total radioactivity is found as 99mTc Bicisate. The average % of the radiochemical purity must be calculated. Other impurities. This test is done within the same sample used to conduct the Radiochemical purity test, after 30 minutes of incubation period and with a minimum delay in the seeding of chromatography mediums execute the test in parallel form. Place approximately 2 µl of the injection at heights of 1 cm from one end of the thin layer the radiochemical or chromatography plates in reversed phase of 2.5 x7.5 ( or equivalent ), and allow to dry. To place the plate in the pre-equilibrate TLC tank using acetone and


ammonium acetate 0.5 M (60:40), develop 7cm, Remove the plate and dry. Determine the present compounds by calculating the retention factors (Rf) of all present peaks. The compounds and approximate Rf values are: 99mTc Bicisate 0.15 – 0.44 99mTc (1V) Bicisate 0.3 - 0.4 99mTc Bicisate y 99mTc Bicisate 0.15 -0.44 Bicisate Reduced hydrolysed Technetium 0.00 -0.14 Free pertechnetate and 99mTc cysteinate Monomer of etilene 0.70 – 0.84 99mTc EDTA 0.95 – 1.0 Determine the quantity of 99mTc (IV) in the injection subtracting the % of 99mTc Bicisate obtained from the Radiochemical Purity test from the % of the 99mTc 99m Bicisate and 99mTc V combined, obtained from the radionuclide impurities . The sum of the impurities should not be more than 10%. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three mice as described. At 5-10 minutes post injection not less than 1.5 % and 20% of the radioactivity should be found in the brain and in the intestine respectively. Not more than 15% of the radioactivity should be found in the liver.

***


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Technetium (99m

Tc ) Exametazime (99m

Tc -HMPAO) injection

Latin name. Technetii (99m

Tc) exametazimi solutio iniectabilis Chemical name. [(RR,SS)-4.8-diaza-3,6,6,9-tetramethylundecane-2,10-dione bisoxime] (this is the chemical name of exametazime without the

99mTc.

Other names:

99mTc d,l-Hexamethylpropyleneamine oxime complex.

Chem. Structure. Exametazime C13H28N4O2. A complex between

99mTc and the ligand of d,l-

hexamethylpropyleneamine oxime complex which the structure is not known. Graphic formula of complex.

Description. A clear, colourless sterile solution containing radioactive

99mTc- exametazime

injection. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radioformulation.

99mTc exametazime is prepared aseptically from pre-sterile kit containing

[(RR,SS)-4.8-diaza-3,6,6,9-tetramethylundecan-2,10-dione bisoxime] and stannous salt (minimum 0.6 microgram stannous) with sodium pertechnetate injection. The kit may have pH adjusted and may contain stabilizers and inert additives. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc exametazime injection is for immediate use or should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. Technetium

99mTc exametazime injection should be used within 30 minutes of


reconstitution of the unlabelled kit with 99m

Tc, unless the preparation has been stabilized with either cobalt chloride solution or methylene blue solution. If not stabilized, the exametazime is converted to a less lipophilic (secondary) form that does not cross the blood-brain barrier. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Technetium

99mTc exametazime injection is a sterile clear, colourless aqueous

solution of exametazime complexed with 99m

Tc. It is prepared by dissolving a racemic mixture of (3RS,9RS)-4.8-diaza-3,6,6,9-tetramethylundecan-2,10-dione bisoxime in the presence of a stannous salt in sodium pertechnetate

99mTc injection. It is suitable for

intravenous administration. The preparation may contain stabilizers and inert additives. It contains 90% to 110% of the declared

99mTc radioactivity at the time and date stated on the

label and not less than 80% of the labelled amount of 99m

Tc as the primary exametazime complex at the time indicated on the label. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. The radioactive half-life of


Identification A. Complies with tests for identification described under Sodium pertechnetate

99mTc

injection. Standardized solution of technetium-99m main peak 140keV is available from competent authorities.

B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests

solution should have retention time as the peak in the chromatography system compared with reference solution.


99mTc injection.


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Radiochemical purity. Place a drop of 99m

Tc exametazime 2.5 cm from the bottom of each of two ITLC-SG (20cm length) and one Whatman 1 or Whatman 3MM strip and immediately develop in butan-2-one (methyl-ethyl-ketone, MEK), 0.9% NaCl solution and 50% aqueous acetonitrile respectively. After a 15cm elution, remove strips, mark solvent fronts and determine distribution of activity with suitable equipment. On strip 1 (ITLC, MEK) secondary exametazime complex and reduced-hydrolysed Tc remain at the origin, while lipophilic exametazime complex and free pertechnetate migrate to Rf 0.8-1.0. On strip 2 (ITLC, saline) only pertechnetate migrates to Rf 0.8-1.0, while lipophilic exametazime complex, secondary exametazime complex and reduced-hydrolysed Tc remain at the origin. On strip 3 (Whatman, 50% acetonitrile) reduced-hydrolysed Tc remains at the origin, lipophilic exametazime complex, secondary exametazime complex and pertechnetate migrate to Rf 0.8-1.0. The radiochemical purity of

99mTc exametazime (lipophilic) can be determined from the

combined values of strip 1 and 2. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should contain minimum of 0.6microgram as stannous. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three mice as described. At 5-10 minutes post injection not less than 1.5% and 20% of the radioactivity should be found in the brain and in the intestine respectively. Not more than 15% of the radioactivity should be found in the liver.

***


Technetium (99mTc) labelled Macrosalb (MAA) injection Latin name. Technetii (99mTc) Marcosalb iniectabilis Chemical name. Denatured human serum albumin. Other names.

99mTc-macroaggegated albumin; 99mTc -MAA.

Chem. Structure. Particles of aggregated human serum albumin of undefined structure. Description. Technetium (99mTc) MAA, 99mTc albumin aggregated injection is a sterile, pyrogen-free suspension of human serum albumin suitable for injection. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radio-formulation. Technetium (99mTc) MAA, 99mTc albumin aggregated injection is prepared from kits containing a sterile, pyrogen-free suspension of human serum albumin suitable for injection. The majority of particles will be in the range of 10 to 100 µm and no particles will exceed 150 µm. Product must be prepared sterile as terminal sterilization procedures are not possible. The product may contain antimicrobial agents, reducing agents, chelating agents, stabilizers, buffers, fillers and antioxidizing agents as well as non-denatured human albumin. An inert gas may replace air in the head space of the vial. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc MAA injection should be stored at in a refrigerator (2-8 oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation: "Shake the vial". Additional information. National requirements and may be a label that indicates that in making dosage and particle counts calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Technetium (99mTc) MAA, 99mTc albumin aggregated injection is a sterile, pyrogen-free suspension of human serum albumin suitable for injection. It has been denatured in such a manner as to form insoluble aggregates with a controlled size range and has been labelled with 99mTc. The majority of particles will be in the range of 10 to 100 µm and no


- 53 -

particles will exceed 150 µm. The human serum employed shall contain not more than 5% globulin and shall complies with the national regulations of the country in which the 99mTc albumin aggregated injection is used. On observation the suspension will appear white or faintly yellow and may settle on standing. The content of 99mTc is not less than 90.0 % and not more than 110.0 % of the reported activity at the reference hour and minute as stated on the label. Not less than 95% of total 99mTc is present as labelled aggregated albumin. Product must be prepared sterile as terminal sterilization procedures are not possible. The product may contain antimicrobial agents, reducing agents, chelating agents, stabilizers, buffers, fillers and antioxidizing agents as well as non-denatured human albumin. An inert gas may replace air in the head space of the vial. It should have been suitably treated to prevent transmission of serum hepatitis and HIV. The specific activity of the preparation is not less than 1.0 mCi of 99mTc per mg of macroaggregated human serum albumin at the time of administration. The radioactive half life of 99mTc is 6.02 hours. Identification Either test A or B in addition to C. A. Complies with tests for identification described under Sodium pertechnetate

99mTc


B. The tests for non-filterable radioactivity and particle size.

Non-filterable radioactivity Using a polycarbonated membrane filter with circular pores 3um in diameter, place 0.2ml of injection and filter with 20ml of sodium chloride solution 9g/l (normal saline). Count the radioactivity remaining on the membrane, not less than 90% of the total radioactivity of the injection.

C. Place 1ml of injection to a centrifuge tube and centrifuge at 2500g for 5minutes.

Remove the supernatant liquid. Add 5ml of cupritartaric solution to the residue and mix. Heat to dissolve the particles and allow to cool. Add 0.5ml of dilute phosphomolybdotungstic reagent and a blue colour should develop.


99mTc injection.

Radiochemical purity Test I: Chromatography: Carry out thin-layer chromatography by applying a small volume (e.g. 1 µL) of 99mTc albumin aggregated injection to a silica gel ITLC strip. Immediately develop with sodium chloride solution 9g/l (normal saline). Determine the radioactivity distribution by a suitable method.99mTc macro aggregated albumin will have an Rf value of 0


in this system while free pertechnetate will be at the solvent front. Not less than 95 % of the total radioactivity is in the spot corresponding to 99mTc macro aggregated albumin. Test II. Soluble radioactivity: Place measured volumes of 99mTc albumin aggregated injection, which may be diluted with sterile normal saline, in a centrifuge tube and determine the net radioactivity in a suitable counting assembly. Centrifuge at an appropriate 1000g force and time to ensure complete separation of the particles from the supernatant. Remove the supernatant liquid by aspiration and determine its net radioactivity in a suitable counting assembly as above. Not more than 5% of the radioactivity in the original sample is found in the supernatant liquid after centrifugation. Particle size. Gently agitate the 99mTc albumin aggregated injection vial and visually observe the absence of large particle aggregations. Withdraw a sample using a needle of 23 gauge (0.32 mm internal diameter) or greater. Place a small drop of sample on a haemocytometer having an appropriate grid to determine sizes in the 10 to 150 µm range. Place a cover slide over the sample. Apply an appropriate microscopic technique to clearly observe the particles against the haemocytometer grid. A minimum of 90% of the particles must be from 10 to 90 µm in diameter. No particles will be greater than 150 µm. Chemical purity Aggregated albumin test. Take a volume of solution equal to 1mg of aggregated albumin in a centrifuge tube and centrifuge at 2500g for 5minutes. Remove supernatant and resuspend the sediment in 2.0ml of normal saline solution. Centrifuge again for 5minutes at 2500g. Decant the supernatant and re-suspend in 5ml sodium carbonate solution. Heat in water bath to 80C to dissolve. Allow to cool and transfer to volumetric flask before diluting to 10ml. Take 3ml of this solution into 25ml flask. Add 15.0ml of cupritartaric acid solution and mix for 10minutes. Add 1.5ml diluted phosphomolybdotungstic reagent. Allow to stand and measure absorbance (Ph. Int.) at 750nm. Prepare a reference solutions containing 0.05mg to 0.2mg of human albumin per ml and measure absorbance using the same process. Using the absorbance obtained from reference solution draw a calibration curve and calculate the content of aggregated albumin in the injection. The specific radioactivity is not less than 37MBq per mg of aggregated albumin at the date and hour of administration. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 3mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int.. The radiopharmaceutical injection may be released for use before completion of the sterility test.


- 55 -

Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. Mice or rats may be used as locally appropriate do determine the biological distribution of the 99mTc albumin aggregated injection. Tail vein or other intravenous sites for injection may be used as permitted by local regulations concerning animal use. Inject about 40 MBq of activity using a needle of 23 gauge (0.32 mm internal diameter) or greater into each of three animals. After 5 minutes sacrifice the animals and remove the lungs and liver by dissection. Determine the activity in the dissected organs and the residual carcass using an appropriate calibrated detector system. Apply the formulas: Lung activity = lung activity / (lung activity + liver activity + carcass activity) x 100% Liver activity = liver activity / (lung activity + liver activity + carcass activity) x 100% Not less than 80% of the activity must be in the lungs and not more than 5% of the activity in the liver in a suitable preparation of 99mTc albumin aggregated injection.

***

Technetium (99mTc)- Mebrofenin injection Latin name. Technetii (99mTc) Mebrofenin solutio iniectabilis Chemical name.

99mTc Mebrofenin.


99mTc and the ligand N-(3 bromo-2,4,6-trimethyl

acetanilido)-iminodiacetate complex. Graphic formula of the ligand.

X=CH3 Y=CH3 Z=Br Description. A clear, colourless sterile solution containing radioactive

99mTc Mebrofenin.

Radionuclide production. Described under sodium pertechnetate

99mTc injection.


Radioformulation. 99m

Tc mebrofenin is prepared aseptically from pre-sterile kit containing N-(3 bromo-2,4,6-trimethyl acetanilido)-iminodiacetate and stannous salt (not greater than 0.5mg/ml with sodium pertechnetate injection. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc mebrofenin injection should be stored at in a refrigerator (2-8 oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition A clear colourless solution. Technetium (99mTc)- N-(3 bromo-2,4,6-trimethyl acetanilido)-iminodiacetate complex (99mTc bromo HIDA or 99mTc Mebrofenin) injection is a sterile solution of 99mTc complexed with Mebrofenin that is present in excess. The structure and formula of the complex formed is not known with certainty at this time. The content of 99mTc is not less than 90.0% and not more than 110.0% of the content of 99mTc stated on the label at the reference date and hour stated on the label. Not less than 95% of total 99mTc is present as 99mTc Mebrofenin complex. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. II. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents as well as buffers. The radioactive half-life of 99mTc is 6.02 hours.


- 57 -


99mTc


B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests


Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter pH. Complies with general requirements for pH, see radiopharmaceutical preparation. Between 4.0 to 6.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out two separate paper/thin layer chromatography (TLC) analyses using two systems one (A) using methyl ethyl ketone (MEK) and 3M paper (soaked in 0.3 M carbonate buffer pH 9 and dried) and another (B) using 50% acetonitrile and Silica gel impregnated glass fibre paper, (ITLC SG). Apply approximately 5 µl of sample each to the strips (ex. 1.5 X 15cm) and develop till the solvent front reaches about 10 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method. 99mTc Mebrofenin complex and hydrolysed 99mTc have Rf of 0 and 99mTc pertechnetate has Rf of 1 in system ‘A’. In system ‘B’ 99mTc Mebrofenin complex and 99mTc pertechnetate have Rf of 1 and hydrolysed 99mTc has Rf of 0. The sum of % radioactivity of 99mTc pertechnetate from “A” and that of hydrolysed 99mTc from system “B” should be less than 5%. Chemical purity. Complies with general requirements for chemical purity see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 0.5mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test.


Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in rats as described. At 30 minutes post injection not less than 70 % of the injected activity should be found in intestine, not more than 15% in the bladder and urine, not more than 2.5% per gram of kidney and not more than 1% per gram of liver.

***

Technetium (99mTc) Mertiatide injection (99mTc-MAG3)

Latin name. Technetii (

99mTc ) mertiatidi solutio iniectabilis

Chemical name: [N-[N-[N-(mercaptoacetyl)-glycil] glycine benzoate(ester)] Other names:

99mTc mercaptoacetyltriglycine complex injection.

Chem. Structure:

99mTc -C8H8N3Na2O6S. A complex between

99mTc and the ligand

Technetate(2) 99m

Tc -[N-[N--[N-(mercaptoacetyl)-glycil]glycil]glycinato (5)-N,N’,N’’,S]-oxo-,disodium, [N-[N-[N-(mercaptoacetyl)-glycil]glycil]glycinato(5)-N,N’,N’’,S]-oxo[99mTc]tecnetato(V)disodico of which the structure is known. Graphic formula


99mTc mertiatide


99mTc injection.


- 59 -

Radioformulation. In brief

99mTc mertiatide is prepared aseptically by the addition of

sodium pertechnetate 99m

Tc injection to a pre-sterilized kit containing chelating agent such as tartrate, stannous salt and S-benzoylmercaptoacetyltriglycine (betiatide) heated to at least 60C to pre-determined optimal time. It may have pH adjusted and with a buffer. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc MAG3 injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation.

99mTc MAG3 injection should be labelled as specified the time and date of

calibration; the amount of 99m

Tc as labelled mertiatide expressed as total mega Becquerels per ml. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution.

99mTc mertiatide injection is a sterile, aqueous

solution suitable for intravenous administration. It contains 99m

Tc in the form of mertiatide chelate. It contains not less than 90.0% and not more than 110.0% of the labelled amount of 99m

Tc as mertiatide complex expressed in megaBecquerels (or microcuries) per ml. at the time indicated in the labelling. It contains uncomplexed Betiatide, a transfer ligand and stabilizers. Not less than 95% of total

99mTc is present as

99mTc MAG3 complex. The injection may be

prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents as well as buffers. The radioactive half-life of



Identification Either test A, B and C.

A. Complies with tests for identification described under Sodium pertechnetate 99m

Tc injection. Standardized solutions of technetium-99m with main peak 140keV are available from competent authorities.

B. The half-life determined using a suitable detector system is between 5.72 to 6.32 hours. C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests


Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements for pH, see radiopharmaceutical preparation. Between 5.0 to 6.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out thin-layer chromatography (TLC) as described. Apply ~5 µl of sample to the plate (silica gel plates 1.5 X 20 cms) and develop for 1.5 hr with a mixture of 45ml methanol, 55ml of 0.9%NaCl and 1ml acetic acid.

99mTc MAG3 complex,

99mTc

pertechnetate and hydrolysed 99m

Tc have Rf values of about 0.45-0.55, 0.9-1 and 0.0-0.1 respectively. Allow to dry and determine the areas of radioactivity by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to

99mTc MAG3 complex.

Detection of free

99mTc , hydrolyzed reduced

99mTc

Method 1: Apply approximately 5-10 µl (100-250 µl CIE), 15 mm from the bottom of a 25 mm x 20 cm strip of chromatographic paper. Develop immediately by ascending chromatography, using a mobile phase of a mixture of methanol and ammonium hydroxide (60:40), until their front has moved 13 cm of the length of the strip. Determine the distribution of the radioactivity by the use of a strip scanner or other suitable method .Calculate the percentage of Hydrolysed and reduced

99mTc using the formula:

100(Aht /Bs ) In which: A ht = is the sum of all peaks at or near the origin, where Rf is less than 0.25, and Bs I s the sum of all the peaks: no more than 2.0% of hydrolyzed reduced technetium is found. Method 2: (Simultaneous determination of free pertechnetate and

99mTc Mertiatide)

Solution A: Prepare a filtered and degassed solution of monobasic potassium phosphate, in water to obtain a solution of 1.36 mg per ml. To each litre of this solution, add 1.0ml of triethylamine and adjust with 1.0 N hydrochloride acid a pH 4.9 -5.1.Make adjustment s if necessary.


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Solution B: Prepare a filtered and degassed solution of monobasic potassium phosphate, in 900ml of water and add 100ml of tetrahydrofuran to obtain a solution containing 1.36 mg per ml. To each litre of this solution add 1.0ml of Triethylamine and adjust with 1N hydrochloride acid to a pH 4.9 -5.1. Make adjustment s if necessary. Mobile phase: Mix specified portions of freshly prepared and degassed Solution A and solution B. Test Solution: Immediately before testing, dilute a portion of injection with Water for injection to obtain a concentration between 400 to 600 µCi. The liquid chromatograph is equipped with a 3.9-mm × 15-cm column that contains packing L1 and a flow-through gamma-ray detector and is programmed to provide a Mobile phase consisting of variable mixtures of solution A and solution B. The system is equilibrated for 15 minutes with a Mobile phase consisting of a mixture of 90% Solution A and 10% Solution B. After injecting the Test solution, change the composition of the mobile phase linearly over the next 30 minutes so that the final mobile phase composition consists of 20% Solution A and 80% Solution B. Hold with this composition for 5 minutes and then change in reverse to a composition of 90% Solution A and 10% Solution B over a 5-minute period. The flow rate is about 1ml per minute. Procedure: Inject about 20 µL of the Test solution into the chromatograph, record the chromatograms by gradient elution. The retention time is between 1.8 and 2.2 minutes for 99m

Tc pertechnetate and between 10 and 14 minutes for 99m

Tc mertiatide. Calculate the percentage of

99mTc pertechnetate by the formula:

100(rpt / rs), in which rpt is the peak response of

99mTc pertechnetate and rs is the sum of all peak

responses: not more than 6.0% of 99m

Tc pertechnetate is found. Calculate the percentage of

99mTc mertiatide by the formula:

100(rmt / rs), in which rmt is the peak response of

99mTc mertiatide, and rs is the sum of all peak responses:

not less than 95.0% of 99m

Tc mertiatide is found. Chemical purity. Complies with general requirements for chemical purity see radiopharmaceutical preparation. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories.


Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins: See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V IU of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three mice as described. At 1 hour post injection not less than 80% in urine and not more than 5% in kidney should be found.

***

Technetium(

99mTc ) Methylene Diphosphonate complex injection (

99mTc -

MDP) Latin name. Technetii (

99mTc ) medronati solutio iniectabilis

Chemical name.

99mTc Methylene Diphosphonate

Other names. 99m

Tc -Dihydrogen methylene diphosphonate, 99m

Tc -MDP


99mTc and the ligand methylene diphosphonate, of

which the structure is mixture. Graphic formula of the ligand

Description. A clear, colourless sterile solution containing Technetium (

99mTc) Medronate

(MDP) injection.


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Radionuclide production. Described under sodium pertechnetate 99m

Tc injection. Radioformulation.

99mTc Methylene Diphosphonate is prepared aseptically from pre-sterile

kit containing sodium methylenediphosphonate and stannous salt with sodium pertechnetate injection. The injection contains variable quantity of tin (Sn) not greater than 3mg/ml. It may have pH adjusted and with a buffer, stabilizer and anti-oxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc MDP injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Technetium (

99mTc ) Medronate (MDP) injection is a clear colourless sterile

aqueous solution suitable for intravenous administration, of sodium medronate and a stannous salt or other reducing agent suitable for pertechnetate that is complexed with 99mTc. The content of

99mTc activity is not less than 90.0% and not more than 110.0% of the content of

99mTc stated on the label at the reference date and hour stated on the label. The product may

contain filling agents, antioxidants and buffers. Not less than 95% of total 99m

Tc is present as 99m

Tc MDP complex. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph.Int.. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidising agents as well as buffers. The radioactive half-life of



99mTc




C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests


Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 3.5 and 7.5. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Complies with the minimum required standards stipulated for “radiochemical purity of

99mTc labelled compound in definition. At least 95% of

99mTc is

present as 99m

Tc MDP complex and not more than 5% each of free pertechnetate (99m

TcO 4-)

and colloid (99m

TcO2) should be present as impurities, when tested as described under 99m

Tc medronate injection. Either Method A or method B may be used. Carry out two separate thin-layer chromatography (TLC) analyses as described using two systems one (A) using methyl ethyl ketone (MEK) and another (B) using 1M sodium acetate as solvents and silica gel impregnated glass fibre plates. Apply approximately 5 µl of sample to the plates (ex. thin silica gel plate 1.5 X 15 cm) and develop till the solvent front reaches about 10 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method.

99mTc MDP complex and hydrolysed

99mTc have Rf of 0 and

99mTc

pertechnetate has Rf of 1 in system ‘A’. In system ‘B’ 99m

Tc MDP complex and 99m

Tc pertechnetate have Rf of 1 and hydrolysed

99mTc has Rf of 0. The sum of % radioactivity of

99mTc pertechnetate from “A” and that of hydrolysed

99mTc from system “B” should be less

than 5%. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 3mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories.


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Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three rats as described. Inject a volume less than 0.2ml containing not more than 0.05 mg MDP. In not fewer than two of the three rats not less than 2.5% of the radioactivity is present in the femurs, not more than 1% is present in the liver, the ratio A1/A2 is not less than 100 and the ratio A1/A3 is not less than 40. The radioactivity per gram weight is represented in the femora (A1), muscle (A2) and blood (A3).

***

Technetium (99mTc ) Nanocolloid (albumin) injection

Latin name. Technetii (99mTc) nanocolloid iniectabilis Description. A clear, colourless or faintly yellow, slightly opalescent solution. Technetium (99mTc) Albumin Nanocolloid injection is a sterile, pyrogen-free, aqueous colloidal suspension. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radio-formulation. Technetium (99mTc) Albumin Nanocolloid injection is prepared from a kit containing a sterile, pyrogen-free, aqueous colloidal suspension of human albumin that has been denatured to produce colloids of controlled particle size of < 100nm and > 50 nm that are labelled with technetium-99m which is suitable for intravenous administration. The human serum employed shall contain not >5% globulin. The product may contain antimicrobial agents, reducing agents, chelating agents, stabilizers, buffers, fillers and antioxidizing agents as well as non-denatured human albumin. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc nanacolloid injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation: "Shake the vial".


Additional information. National requirements and may be a label that indicates that in making dosage and particle counts calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear, colourless or faintly yellow, slightly opalescent solution. Technetium (99mTc) Albumin Nanocolloid injection is a sterile, pyrogen-free, aqueous colloidal suspension of Human Albumin that has been denatured to produce colloids of controlled particle size of <100nm and >50 nm that are labelled with technetium-99m which is suitable for intravenous administration. The human serum employed shall contain not >5% globulin and shall complies with national regulations of the country in which the 99mTc albumin nanocolloid is used. It should have been suitably treated to prevent transmission of serum hepatitis and HIV. The content of 99mTc is not less than 90.0% and not more than 110.0% of the content of 99mTc stated on the label at the reference date and hour stated on the label. Not less than 95% of total 99mTc is present as 99mTc albumin nanocolloid. The injection is prepared under strict aseptic conditions because terminal sterilization is not practicable. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents, buffers as well as non-denatured human albumin. The radioactive half-life of 99mTc is 6.02 hours. Identification Either test A or B in addition to C.

A. Complies with tests for identification described under Sodium pertechnetate 99m

Tc injection. Standardized solutions of technetium-99m with main peak 140keV are available from competent authorities.

B. The tests for non-filterable radioactivity and particle size.

Non-filterable radioactivity Using a polycarbonated membrane filter with circular pores 3um in diameter, place 0.2ml of injection and filter with 20ml of sodium chloride solution 9g/l (normal saline). Count the radioactivity remaining on the membrane, not less than 90% of the total radioactivity of the injection.

C. Place 1ml of injection to a centrifuge tube and centrifuge at 2500g for 5minutes.

Remove the supernatant liquid. Add 5ml of cupritartaric solution to the residue and mix. Heat to dissolve the particles and allow to cool. Add 0.5ml of dilute phosphomolybdotungstic reagent and a blue colour should develop.


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Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 4.0 to 8.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out Thin Layer Chromatography (TLC) analyses using MEK (Methyl Ethyl ketone) and Silica gel impregnated glass fibre paper, (ex. ITLC SG Gelman). Apply approximately 5 µl of sample to the strip ( ex. 1.5 X 15 cm) and develop till the solvent front reaches about 10 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method. 99mTc albumin nanocolloid has Rf of 0 and 99mTc pertechnetate has Rf of 1 in this system. . The % radioactivity of 99mTc pertechnetate should be less than 5%. Particle size. It is controlled by filtration method using membrane filters of 100 and 50 nm pore size. Dilute 0.1ml of 99mTc albumin nanocolloid injection with 0.9ml of 0.9% saline in a glass vial. Measure the radioactivity of this sample in a suitable instrument such as dose calibrator. Using a syringe and needle, pass the diluted sample through a 100 nm filter pre-washed with 1ml of 0.9% saline. Pass 2ml of 0.9% saline to wash the filter. The total volume of sample and washing is 3ml whose radioactivity is measured using the same measuring instrument. This is expressed as a % of the initial sample activity corrected for what remained in the vial and syringe plus filter. This gives the % Radioactivity due to particles of <100 nm size. Similarly the % Radioactivity due to particles of >50 nm size is calculated using 50 nm size membrane filter. More than 90% of labelled colloid particles shall be in the 100 to 50 nm range. Chemical purity Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 3mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph.Int.. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins.


Biodistribution. Mice or rats may be used as locally appropriate do determine the biological distribution of the 99mTc albumin aggregated injection. Tail vein or other intravenous sites for injection may be used as permitted by local regulations concerning animal use. Inject about 40 MBq of activity using a needle of 23 gauge (0.32 mm internal diameter) or greater into each of three animals. After 5 minutes sacrifice the animals and remove the lungs and liver by dissection. Determine the activity in the dissected organs and the residual carcass using an appropriate calibrated detector system. Apply the formulas: Lung activity = lung activity / (lung activity + liver activity + carcass activity) x 100% Liver activity = liver activity / (lung activity + liver activity + carcass activity) x 100% Not less than 80% of the activity must be in the liver and not more than 5% of the activity in the lung in a suitable preparation.

***

Technetium(

99mTc ) Pentetate complex injection (

99mTc -DTPA)

Latin name. Technetii (99mTc) pentetatis solutio iniectabilis Chemical name.

99mTc –DTPA, Technetium diethylenetriaminepentaacetic acid

Graphic formula


99mTc –DTPA


99mTc injection.

Radioformulation.

99mTc DTPA is prepared aseptically from pre-sterile kit containing

sodium or calcium diethylenetriaminepenta-acetate and stannous salt with sodium pertechnetate injection. The injection contains a variable quantity of tin (Sn) not greater than 1mg/ml. It may have pH adjusted and with a buffer, stabilizer and anti-oxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int.


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Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements, see radiopharmaceutical preparation. 99m

Tc DTPA injection should be stored at in a refrigerator (2-8 oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution. Technetium (

99mTc) Pentetate (DTPA) complex

injection is a sterile solution of 99m

Tc complexed with pentetic acid [N,N-bis[2-[biscarboxymethyl)-amino]ethyl]-glycine or Diethylene triamine pentaacetic acid, DTPA] that is present in excess. The structure and formula of the complex formed is not known with certainty at this time. The content of

99mTc is not less than 90.0% and not more than 110.0%

of the content of 99m

Tc -99m stated on the label at the reference date and hour stated on the label. Not less than 95% of total

99mTc is present as

99mTc pentetate complex. The injection

may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents as well as buffers. The radioactive half-life of



99mTc




Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter


pH. Complies with general requirements for pH, see radiopharmaceutical preparation. Between 4.0 and 7.5. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out two separate thin-layer chromatography (TLC) analyses using two systems one (A) using methyl ethyl ketone (MEK) and another (B) using 0.9% NaCl. Apply approximately 5 µl of sample to the plates (silica gel impregnated glass fibre plates 1.5 X 15 cm and develop till the solvent front reaches about 10 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method.

99mTc

pentetate complex and hydrolysed 99m

Tc have Rf of 0 and 99m

Tc pertechnetate has Rf of 1 in system ‘A’. In system ‘B’

99mTc pentetate complex and

99mTc pertechnetate have Rf of 1 and

hydrolysed 99m

Tc has Rf of 0. The sum of % radioactivity of 99m

Tc pertechnetate from “A” and that of hydrolysed

99mTc from system “B” should be less than 5%.

Chemical purity. Complies with general requirements for chemical purity see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 1mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three rats as described. Inject a volume less than 0.2ml. At 2 hours post injection the sum of the percentages of radioactivity found in urine and bladder should be more than 85% of injected radioactivity. Less than 1% of injected activity should be found in liver.

***


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Technetium(99m

Tc ) Pyrophoshate tin complex injection (99m

Tc -PYP) Latin name. Technetii (

99mTc ) pyrophosphati solution iniectabilis

Chemical name.

99mTc pyrophosphate


99mTc and the ligand tin pyrophosphate.

Graphic formula of the ligand

Description. A clear, colourless sterile solution containing Technetium

99mTc PYP injection.


99mTc injection.

Radio-formulation.

99mTc PYP is prepared aseptically from pre-sterile kit containing sodium

pyrophosphate and stannous salt (not greater than 3mg/ml with sodium pertechnetate injection. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc PYP injection should be stored at in a refrigerator (2-8 oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation.


Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Technetium (

99mTc) PYP injection is a clear colourless sterile aqueous solution

suitable for intravenous administration, of sodium pyrophosphate and a stannous salt or other reducing agent suitable for pertechnetate that is complexed with 99mTc. The content of

99mTc

activity is not less than 90.0% and not more than 110.0% of the content of 99m

Tc stated on the label at the reference date and hour stated on the label. The product may contain filling agents, antioxidants and buffers. Not less than 95% of total

99mTc is present as

99mTc PYP

complex. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int.. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidising agents as well as buffers. The radioactive half-life of



99mTc





99mTc injection.

Radiochemical purity. Complies with the minimum required standards stipulated for “radiochemical purity of

99mTc labelled compound in definition. At least 95% of

99mTc is

present as 99m

Tc PYP complex and not more than 5% each of free pertechnetate (99m

TcO 4-)

and colloid (99m

TcO2) should be present as impurities, when tested as described under 99m

Tc PYP injection. Either Method A or method B may be used.


- 73 -

Carry out two separate thin layer chromatography (TLC) analyses as described using two systems one (A) using methyl ethyl ketone (MEK) and another (B) using 1M sodium acetate as solvents and silica gel impregnated glass fibre plates. Apply approximately 5 µl of sample to the plates (ex. thin silica gel plate 1.5 X 15 cm) and develop till the solvent front reaches about 10 cm from point of application. Allow to dry and determine the areas of radioactivity by a suitable method.

99mTc PYP complex and hydrolysed

99mTc have Rf of 0 and

99mTc

pertechnetate has Rf of 1 in system ‘A’. In system ‘B’ 99m

Tc PYP complex and 99m

Tc pertechnetate have Rf of 1 and hydrolysed

99mTc has Rf of 0. The sum of % radioactivity of

99mTc pertechnetate from “A” and that of hydrolysed

99mTc from system “B” should be less

than 5%. Chemical purity. Complies with general requirements for chemical purity see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 3mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in a set of three rats as described. Inject a volume less than 0.2ml containing not more than 0.05 mg PYP. In not fewer than two of the three rats not less than 2.5% of the radioactivity is present in the femurs, not more than 1% is present in the liver, the ratio A1/A2 is not less than 100 and the ratio A1/A3 is not less than 40. The radioactivity per gram weight is represented in the femora (A1), muscle (A2) and blood (A3).

***


Technetium (99mTc ) labelled Red Blood Cells (autologous) injection (99mTc -RBC)

Description. A dark red suspension. Technetium (99mTc) labelled Red Blood Cells injection is a preparation of anti-coagulated whole blood in which the RBCs are predominantly labelled with 99mTc. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radioformulation. Caution – Strict aseptic technique together with safe blood handling practices is essential. The blood sample must be labelled with patient name and key identification systems to prevent processing and administration errors. The cells are prepared for labelling by collection of an autologous sample of whole blood which is anticoagulated with Heparin Sodium or ACD solution. The labelling kit may contain anticoagulants, chelating agents (e.g. pyrophosphate) stannous chloride and sodium hypochlorite. It may have pH adjusted and with a buffer, stabilizer and antioxidants. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements, see radiopharmaceutical preparation. 99m

Tc RBC injection should be stored at room temperature for optimal radiochemical purity and kept in a cool place 2-8 oC following radiolabelling. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Patient name with unique identification code is mandatory. Gently mix contents of vial before withdrawing patient dose. "Shake the vial" label. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A dark red suspension. Technetium (99mTc) labelled Red Blood Cells injection is a preparation of anticoagulated whole blood in which the RBCs are predominantly labelled with 99mTc. The cells are prepared for labelling by collection of an autologous sample of whole blood which is anticoagulated with Heparin Sodium or ACD solution. The content of 99mTc is not less than 90.0% and not more than 110.0% of the content of 99mTc stated on the label at the reference date and hour stated on the label.


- 75 -

Not less than 90% of total 99mTc is present as 99mTc RBCs. The injection is prepared under strict aseptic conditions because terminal sterilization is not practicable. The product may contain anticoagulants, chelating agents, stannous salts and sodium hypochlorite. The radioactive half life of 99mTc is 6.02. Identification A. Complies with tests for identification described under Sodium pertechnetate

99mTc





99mTc injection.

Radiochemical purity. Transfer 0.2ml of 99mTc RBC injection to 2ml of 0.9% NaCl solution taken in a centrifuge tube. Centrifuge for five minutes and carefully withdraw the supernatant solution. Measure the radioactivity of the two samples in a suitable instrument. The radioactivity in the supernatant is less than 10% of the total. The supernatant should also be clear and have a colourless to a slight pink or yellow appearance. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test.


Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Positive confirmation of patient identity.

***

Technetium (99mTc) Sestamibi complex injection (99mTc -MIBI) Latin name. Technetii (99mTc) sestamibi solutio iniectabilis Chemical name. Technetium (1+)-99mTc,hexakis(1-isocyano-2methoxy-2methylpropane)-(OC-6-11)- Hexakis(isocianuro de 2 metoxi-2metilpropilo)[99mTc]tecnecio (1+) Other names.

99mTc -MIBI

Chem. Structure: A complex between

99mTc and the ligand sestamibi of which the structure

is known. Graphic formula of the ligand: 99mTc -C36H66N606


99mTc -MIBI

.


99mTc injection.

Radioformulation.

99mTc MIBI is prepared aseptically from pre-sterile kit containing

tetrakis(2–methoxy-isobutyl isonitrile) copper (I) tetrafluoroborate and with sodium pertechnetate injection. The mixture is boiled for optimal radiolabelling. It may have pH


- 77 -

adjusted and with a buffer, stabilizer and anti-oxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc MIBI injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution. Technetium 99mTc Sestamibi injection is a sterile, aqueous solution of tetrakis(2–methoxy-isobutyl isonitrile) copper (I) tetrafluoroborate that is labelled with 99mTc suitable for intravenous administration. It contains not less than 90% and not more than 110% of the labelled amount of 99mTc as a complex with sestamibi, expressed in mega Becquerels (or in milicuries) per ml at the time indicated in the labelling. It contains reducing agents, a buffer, and inert filler. Other chemical forms of radioactivity do not exceed 10 percent of the total radioactivity. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidizing agents as well as buffers. The radioactive half- life of 99mTc is 6.02 hours. Identification A. Complies with tests for identification described under Sodium pertechnetate

99mTc






99mTc injection.

Radiochemical Purity. Preparation of the test vials – Constitute each of 4 vials of pre-sterilized kits with 1 ml (1875 ± 187.5 MBq, or 50 ± 5 mCi) of Sodium Pertechnetate 99mTc injection. Heat the vials in boiling water for 10 minutes. After heating, allow the vials to cool to room temperature for 15 minutes. Method 1 (Thin-layer chromatography) – Apply 1 to 2 µL of injection about 1 cm from the bottom of a 25-mm × 7.75-cm reverse-phase chromatographic plate, and allow to dry. Position the plate in a chromatographic chamber and develop the chromatograms in a freshly prepared (not more than 4 hours) solvent system consisting of a mixture of acetonitrile, methanol, 3.85% ammonium acetate, and tetrahydrofuran (4:3:2:1) until the solvent front has moved about 6 cm from the origin. Remove the plate and allow it to air-dry. Determine the radioactivity distribution by scanning the chromatogram with a suitable radiation detector. A mean of not less than 90% (area %) of the radioactivity is found at an RF value between 0.3 and 0.6. Free pertechnetate is located at about the RF 0.8 to 1.0, and radio colloid is located at about RF 0 to 0.1. The sum of the mean percentages of free pertechnetate and colloid does not exceed 10%. Method 2 (High-performance liquid chromatography -HPLC) Mobile phase – Prepare a filtered and degassed mixture of methanol, 0.05 M ammonium sulfate solution, and acetonitrile (45:35:20). Make adjustments if necessary. Chromatographic system – The liquid chromatograph is equipped with a 3.9-mm × 30-cm column that contains 10-µm packing L1. It is also equipped with a flow-through gamma-ray detector. The flow rate is about 2 ml per minute. If 99mTc pentamibi dimethylvinyl isonitrile is present, the relative retention between the 99mTc sestamibi peak and the 99mTc pentamibi dimethylvinyl isonitrile peak is 1.3 to 1.5. Procedure – Inject about 5 µL (9.375 MBq or 250 µCi) of Sodium Pertechnetate 99mTc injection into the chromatograph, and adjust the integrator/recording device so that the peak is 25% to 100% of full scale. Separately inject equal volumes (about 5 µL, 9.375 MBq, or 250 µCi) of the injection under test into the chromatograph, record the chromatograms, and measure the area percentage for all of the peaks present. The retention time for 99mTc sestamibi is about 5 to 10 minutes. The retention time for 99mTc pentamibi dimethylvinyl isonitrile is about 6 to 13 minutes. Correct for the presence of colloid, which is not measured by this method, taken by the equation: Cf = [(100%) (Ac)] / 100, in which Cf is the correction factor, and Ac is the mean area percentage for the colloid obtained from Method 1. Obtain corrected area percentage by multiplying the correction


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factor (Cf) by the area percentage of the peaks present in the chromatogram. A mean of not less than 90% (corrected area percentage) of the total radioactivity is represented by 99mTc sestamibi, and a mean of not more than 5% (corrected area percentage) of the total radioactivity is present as 99mTc pentamibi dimethylvinyl isonitrile. Carry out solvent extraction procedure as follows: Add 0.1ml of 99mTc MIBI complex injection to a vial containing 3ml chloroform and 2.9ml of 0.9% saline. Vortexes the mixtures for about 10 seconds and separate the phases for about 1 minute. Transfer the top saline layer to another vial. Measure the radioactivity in both vials using a suitable measuring device such as dose calibrator. The radioactivity in the chloroform layer should be >90% of total. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. See radiopharmaceutical preparation. At 1 hour post-injection not less than 1.5 % of injected activity should be found in the heart of guinea pig.

***

Technetium (99m

Tc ) Succimer complex (99m

Tc -DMSA) injection Latin name. Technetii (

99mTc ) Succimeri solutio iniectabilis

Chemical name.

99mTc DMSA, meso-2,3-dimercaptosuccinic acid

Chem. Structure: A complex between

99mTc and the ligand dimercaptosuccinate.


Graphic formula of the ligand:


99mTc DMSA injection.


99mTc injection.

Radio-formulation.

99mTc DMSA is prepared aseptically from pre-sterile kit containing

meso-2,3-dimercatosuccinic acid and stannous salt with sodium pertechnetate injection. (he injection contains variable amounts of Tin (Sn) but not greater than 1mg/ml. It may have pH adjusted and it may also contain a buffer, stabilizer and anti-oxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc DMSA injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations".


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Definition. A clear colourless solution. Technetium (99m

Tc) Dimercaptosuccinate (DMSA) complex injection is a sterile solution of

99mTc complexed with DMSA that is present in

excess. The structure and formula of the complex formed is not known with certainty at this time. The content of

99mTc is not less than 90.0% and not more than 110.0% of the content of

99mTc stated on the label at the reference date and hour stated on the label. Not less than 85%

of total 99m

Tc is present as 99m

Tc DMSA complex. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. The product may contain antimicrobial, reducing, chelating, stabilizing, filling and antioxidising agents as well as buffers. The radioactive half-life of



99mTc





99mTc injection.

Radiochemical purity. Examine by thin-layer chromatography using silica gel as the coating substance on a glass-fibre sheet. Heat the plate at 110oC for 10 min. Use plate such that during development the mobile phase migrates over a distance of 10-15 cm in approximately 10 minutes.

Apply to the plate 5 to 10µl of the injection. Develop immediately using methyl ethyl ketone. Allow the plate to dry. Determine the distribution of radioactivity using a suitable detector. Technetium succimer complex remains at the starting point. Pertechnetate ion migrates near to the solvent front. Not less than 95% of the total radioactivity is found in the spot corresponding to technetium succimer complex. The radioactivity corresponding to pertechnetate ion represents not more than 2.0% of the total radioactivity


Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 1mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in rats as described. At 1 hour post injection the % of radioactivity found in both kidneys should be more than 40% of injected activity. The ratio of % uptake in kidneys to the combined uptake in liver and spleen taken together should be more than 6.

***

Technetium (99mTc ) Sulphur colloidal injection

Latin name. Sulfuris colloidalis et technetii (99mTc) solutio iniectabilis Chemical name.

99mTc Sulfur Colloid

Description. A colourless to yellowish sterile solution containing radioactive 99mTc Colloidal sulfur. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radio-formulation.

99mTc colloidal sulfur is prepared aseptically from pre-sterile kit

containing apyrogenic colloidal dispersion of sulfur, the micelles of which are labelled with technetium-99m. It may have pH adjusted, gelatine and with a buffer (acetate, citrate or phosphate) stabilizer and antioxidants. The injection may be prepared from sterile starting


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materials under aseptic conditions since it can not be terminally sterilized. The product may contain antimicrobial. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99mTc Sulfur Colloid injection should be stored at room temperature (below 30 oC). Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. "Shake the vial" label is essential. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition A white or pale yellow or brownish colloidal suspension; may settle down on standing and re suspended on shaking. Technetium (99mTc ) Sulfur Colloid injection is a sterile, pyrogen-free colloidal dispersion of sulfur labelled with radioactive 99mTc. It may be formed in situ by decomposition of thiosulfate in presence of 99mTc pertechnetate and a suitable stabilizer in acid medium. When using stabilizer such as gelatin care should be exercised to ensure apyrogenicity. The precise chemical composition of Technetium- 99m Sulfur Colloid injection is uncertain. The content of 99mTc is not less than 90.0% and not more than 110.0% of the content of 99mTc stated on the label at the reference date and hour stated on the label. Not less than 95% of total 99mTc is present bound to the colloidal particles. The injection may be prepared from sterile starting materials under aseptic conditions since it can not be terminally sterilized. The product may contain antimicrobial, reducing, chelating, stabilizing, agents as well as buffers. The radioactive half life of 99mTc is 6.02 hours. Identification A. Complies with tests for identification described under Sodium pertechnetate

99mTc




C. Perform and examine chromatogram obtained in test for radiochemical purity. The tests solution should have retention time as the peak in the chromatography system compared with reference solution.

Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter. pH. Complies with general requirements for pH, see radiopharmaceutical preparation. Between 4.0 to 7.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out Paper Chromatography as described using chromatography 1 paper and 85% v/v methanol as solvent. Apply ~5 µl of sample to the paper and develop for 10 cm. Technetium- 99m Sulfur Colloid and 99mTc pertechnetate have Rf values of about 0 and 0.6 respectively. Allow to dry and determine the areas of radioactivity by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to 99mTc Sulfur Colloid. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Must be checked before release. Biodistribution. Carry out biodistribution in a set of three mice as described. At 30 minutes post injection not less than 80% of the injected radioactivity should be found in liver and spleen taken together. Less than 5% of the injected activity should be found in lungs.

***


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Technetium (99m

Tc ) Tetrofosmin complex injection Latin name. Technetii (

99mTc) Tetrofosmin solutio iniectabilis

Chemical name.

99mTc Tetrofosmin


99mTc and the tetrofosmin.

Graphic formula.


99mTc Tetrofosmin

complex injection. Radionuclide production. Described under sodium pertechnetate

99mTc injection.

Radio-formulation.

99mTc Tetroformin is prepared aseptically from pre-sterile kit containing

tetroformin and stannous salt with sodium pertechnetate injection. The injection contains variable amounts of tin (Sn) but not greater than 1mg/ml. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 99m

Tc tetrofosmin injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity.


Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Protect from light. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A clear colourless solution. Technetium (

99mTc ) Tetrofosmin (1,2 bis[bis(2-

ethoxy ethyl)phosphino]ethane) complex injection is a sterile solution of 99m

Tc complexed with Tetrofosmin that is present in excess. The structure and formula of the complex formed is not known with certainty at this time. The content of

99mTc is not less than 90.0% and not more than 110.0% of the content of

99mTc

stated on the label at the reference date and hour stated on the label. Not less than 90% of total

99mTc is present as

99mTc Tetrofosmin complex.

The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. It contains no antimicrobial agents. Other chemical forms of radioactivity do not exceed 10.0 percent of the total. The radioactive half-life of



99mTc





99mTc injection.


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Radiochemical purity. To determine the amount of free technetium, apply a 10- to 20-µL volume of injection about 3.0 cm from the bottom of a 2 × 20-cm instant thin-layer chromatographic silica gel strip. Immediately develop the chromatogram by ascending chromatography to a height of 15 cm using a solvent system consisting of a mixture of acetone and dichloromethane (35:65). Allow the chromatogram to air-dry. Determine the radioactivity distribution of the chromatogram by scanning with a suitable radiation detector. The RF value of the technetium

99mTc tetrofosmin spot is approximately 0.5: the sum of

radioactivity at the solvent front (unbound pertechnetate) and the origin (reduced hydrolysed technetium and hydrophilic impurities) is not more than 10%. Carry out thin-layer chromatography (TLC) as described; apply ~5 µl of sample to the sheet (silica gel impregnated glass fibre sheets ex. ITLC-SG, 1.5 X 10 cm) and develop with a mixture of 35ml acetone and 65ml dichloromethane solvent.

99mTc tetrofosmin complex,

99mTc pertechnetate and hydrolysed

99mTc have Rf values of about 0.45-0.55, 0.9-1 and 0.0-

0.1 respectively. Allow to dry and determine the areas of radioactivity by a suitable method. Not less than 90% of the total radioactivity is in the spot corresponding to

99mTc tetrofosmin

complex. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Tin. See radiopharmaceutical preparation section to note the different methods. The test solution should not exceed 1mg of Sn per ml. Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Not more than 175/V I.U. of endotoxins per millilitre, V being the recommended dose in millilitres. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in rats as described. At 1 hour post injection not less than 1.5 % of injected activity should be found in the heart of guinea pig.

***


Technetium [99mTc] Tin colloidal injection Latin name. Technetii (99mTc) stannous colloid iniectabilis Description. Technetium (99mTc) colloidal tin injection is a sterile, colloidal dispersion of tin labelled with technetium-99m. Radionuclide production. Described under sodium pertechnetate

99mTc injection

Radio-formulation.

99mTc Tin colloid is prepared aseptically from pre-sterile kit containing

stannous fluoride and with sodium pertechnetate injection. The amount of tin should not exceed 1mg of Sn per ml. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The injection may be prepared from sterile starting materials under aseptic conditions or may be sterilized by Method 3 Filtration described under injections in Ph. Int. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements, see radiopharmaceutical preparation. 99m

Tc tin colloid injection should be stored at in a refrigerator (2-8oC) to retain optimal radiochemical purity. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. National requirements and may be a label that indicates that in making dosage calculations, correction is to be made for radioactive decay, and also indicates the radioactive half-life of


Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition Technetium (99mTc) colloidal tin injection is a sterile, colloidal dispersion of tin labelled with technetium-99m. The amount of tin should not exceed 1mg of Sn per ml exceeding 1 mg of Sn per ml. It contains fluoride ions, and may be stabilised with a suitable, apyrogenic colloid-protecting substance and a suitable buffer. It is prepared from sodium pertechnetate (99mTc) injection using suitable sterile ingredients and calculating the ratio of radionuclide impurities with reference to the date and hour of administration. Syringes for handling the elute intended for labelling of the final product, or the final product, should not contain rubber parts. It contains not less than 90.0% and not more than 110.0% of the labelled amount of 99mTc as tin colloid expressed in mega Becquerels (or microcuries) per ml at the time indicated in the labelling. Not less than 95% of the 99mTc radioactivity is due 99mTc in colloidal form.


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99mTc


B. Perform and examine chromatogram obtained in test for radiochemical purity. The tests


C. Mix 0.05ml of zirconyl nitrate solution R with 0.05ml of alizarin S solution R. Add

0.05ml of the injection to be examined. A yellow colour is produced. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 4.0 to 7.0. Radionuclide purity. Described under Sodium pertechnetate

99mTc injection.

Radiochemical purity. Carry out Paper Chromatography as described using chromatography 1 paper and sodium chloride 9g/l (normal saline (0.9%)) as solvent. . Apply ~5 µl of sample to the paper and develop for 10 cm. Technetium- 99m tin Colloid and 99mTc pertechnetate have Rf values of about 0 and 0.6 respectively. Allow to dry and determine the areas of radioactivity by a suitable method. Not less than 95% of the total radioactivity is in the spot corresponding to 99mTc tin colloid. Chemical purity Tin. Test solution-Dilute 3.0ml of the injection to be examined to 50.0ml with 1 M hydrochloric acid. Reference solution – Dissolve 0.115 g of stannous chloride R in 1 M hydrochloric acid and dilute to 1000.0ml with the same acid. To 1.0ml of each solution add 0.4ml of a 20g/l solution of sodium laurilsulfate R, 0.05 ml of thioglycollic acid R, 0.1ml of dithiol reagent R and 3.0ml of 0.2M hydrochloric acid. Mix. Measure the absorbance (2.2.25) of each solution at 540 nm, using 0.2 M hydrochloric acid as the compensation liquid. The absorbance of the test solution is not greater than that of the reference solution (1 mg of Sn per ml). Assay. Determine the radioactivity in suitable counting equipment by comparison with a standardized 99mTc solution or by measurement in an instrument calibrated with the aid of such a solution. A good approximation may be obtained using an ionization chamber and employing a standardized solution of Cobalt-57 provided that correction for the differences in


the radiations emitted are made. Standardized solutions of 99mTc and Cobalt-57 are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. Carry out biodistribution in a set of three mice as described. At 30 minutes post injection not less than 80 % of the injected radioactivity should be found in liver and spleen taken together. Less than 5% of the injected activity should be found in lungs.

***

Thallous Chloride (201Tl) injection Latin name. Thallosi (201Tl) chloridi solutio iniectabilis Chemical name.

201Tl choride

Chem. Structure:

201TlCl.

Description. A clear colourless solution. Thallous chloride

201Tl injection is a sterile, isotonic,

aqueous solution. Radionuclide production. Thallium-201 is a radioactive isotope of thallium formed by decay of lead-201. Lead-201 is a radioactive isotope of lead from irradiation with protons of suitable energy, of thallium which may be enriched in thallium-203. Separation of Thallium-201 may be by ion-exchange resin. Radioformulation. Thallium chloride injection is made isotonic by addition of sodium chloride and final injection may have suitable antimicrobial preservatives such as benzyl alcohol. Category. Diagnostic radiopharmaceutical. Storage. Complies with general storage requirements see radiopharmaceutical preparation. 201

Tl injection should be stored at room temperature below 30oC. Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation.


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Additional information. Complies with the general requirements for additional labelling, see radiopharmaceutical preparation. "Do not dilute" on the label of product containing preservative. Useful to have space on the label for writing "date and time of first dose withdrawal". Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition A clear colourless solution. Thallous chloride

201Tl injection is a sterile, isotonic, aqueous

solution of radioactive thallium (201

Tl) in the form of thallous chloride suitable for intravenous administration. It contains not less than 90.0% and not more than 110.0% of the labelled amount of

201Tl as chloride, expressed in mega Becquerels per ml, at the time indicated in the

labelling. Other chemical forms of radioactivity do not exceed 5.0% of the total radioactivity. It may contain a preservative or stabilizer. The injection may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int. The radioactive half-life of 201

Tl is 73.1 hours. Identification A. The gamma ray spectrum recorded with a sample of Thallous Chloride (

201Tl ) injection,

suitably diluted if needed, is identical to that of a specimen of Tl201 in that it exhibits major peak at 135, 166, and 167 keV and X-rays have energies of 69 and 83keV.


hours. Clarity and colour of solution. Assessed using apparatus for visible particles as described in Ph. Int. methods of analysis chapter pH. Complies with general requirements for pH see radiopharmaceutical preparation. Between 4.0 and 7.0. Radionuclide purity. Record and examine gamma-ray and X-ray spectrum using a suitable instrument calibrated with aid of standardized Thallous-201 and Thallous-202 solutions from competent authority. Determine relative amounts of thallium-201 and thallium-202. The latter has half-life of 12.2 days and main peak at 440keV. Thallium-200 has half-life of 1.09 days and main peaks at 368, 579, 828 and 1206 keV. Lead-201 has half-life of 9.4 hours and main peak at 331keV. Lead-203 has half-life of 2.17 days and main peak at 270keV. Not more than 2% of total activity is due to thallium-202 and not less than 95.0% is due to thallium-201. Radiochemical purity. Soak a 2.5 × 15.0-cm cellulose polyacetate strip in 0.05 M edetate disodium for 45 to 60 minutes. Remove the strip with forceps, taking care to handle the outer edges only. Place the strip between two absorbent pads, and blot to remove excess solution.


Apply not less than 5 µL of a previously mixed solution consisting of equal volumes of injection and 0.05 M edetate disodium to the centre of the blotted strip, and mark the point of application. Attach the strip to the support bridge of an electrophoresis chamber containing equal portions of 0.05 M edetate disodium in each side of the chamber. Ensure that each end of the strip is in contact with the 0.05 M edetate disodium. Attach the chamber cover, and perform the electrophoresis at 250 volts for 30 minutes. Remove the strip from the chamber, and allow to air-dry without blotting. Using a suitable scanner and counting assembly, determine the radioactivity. Not less than 95.0% of the radioactivity on the strip migrates toward the cathode as a single peak. Alternative method Carry out paper electrophoresis as described using cellulose polyacetate strip as support and 0.05M disodium ethylenediaminetetraacetate as electrolyte. Apply ~5 µl of sample of thallous chloride (

201Tl) injection, appropriately diluted to get optimum count rate, to the strip and

perform electrophoresis at 250 V for 30 minutes. Thallous ion migrates towards the cathode as a single peak. Allow to dry and determine the radioactivity distribution by a suitable method. Not less than 95 % of the total radioactivity is in the spot corresponding to thallous ion. Chemical purity Content of thallium. Standard thallium solution – Transfer 235 mg of thallous chloride, accurately weighed, to a 1000ml volumetric flask, dilute with water to volume, and mix. Transfer 1.0ml of the resulting solution to a 100ml volumetric flask, dilute with saline TS containing 0.9% benzyl alcohol to volume, and mix. This standard solution contains 2 µg of thallium per ml. Procedure – Transfer 1.0ml portions of the Standard thallium solution and the injection to separate screw-cap test tubes. To each tube add 2 drops of a solution, prepared by carefully mixing 18ml of nitric acid and 82ml of hydrochloric acid, and mix. Then add to each tube 1.0ml of sulphosalicylic acid solution (1 in 10), and mix. Add 2 drops of 12 N hydrochloric acid to each tube, and mix. To each tube add 4 drops of rhodamine B solution (50 mg of rhodamine B diluted with hydrochloric acid to 100.0ml), and mix. Add 1.0ml of diisopropyl ether. Screw the caps on tightly, shake the tubes by hand for 1 minute, accurately timed, releasing any pressure build-up by loosening the caps slightly. Recap the tubes and allow the phases to separate. Transfer 0.5ml of the di-isopropyl ether layer from each tube to clean tubes. Visually compare the ether layers: the colour of the ether layer from the injection is not darker than that from the Standard thallium solution. Iron. Into separate cavities of a spot plate, place 0.1ml of the injection and 0.1ml of Standard Iron Solution diluted with water to a concentration of 5 µg per ml. Add to each cavity 0.1ml of hydroxylamine hydrochloride solution (1 in 10), 1ml of sodium acetate solution (1 in 4), and 0.1ml of 0.5% dipyridyl solution (0.5 g of 2,2�-dipyridyl dissolved in 100ml of water containing 0.15ml of hydrochloric acid), and mix. After 5 minutes, the colour of the specimen of injection is not darker than that of the Standard Iron Solution.


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Copper. Standard copper solution – Dissolve 0.982 g of CuSO4•5H2O in 1000ml of 0.1 N hydrochloric acid. Transfer 2.0ml of this solution to a 100ml volumetric flask, dilute with 0.1 N hydrochloric acid to volume, and mix to obtain a Standard solution containing 5 µg of copper per ml. Procedure – Into separate cavities of a spot plate, place 0.2ml of the injection and 0.2ml of Standard copper solution. Add to each cavity 0.2ml of water and 0.1ml of iron thiocyanate solution (1.5g ferric chloride and 2g potassium thiocyanate dissolved in water and diluted with water to 100.0ml). Mix, then add 0.1ml of sodium thiosulphate solution (1 in 100), and again mix. The time required for the specimen of thallous chloride Tl-201 injection to decolorize is equal to or longer than that observed for the standard copper solution. Assay. Determine the radioactivity in suitable calibrated counting equipment. Determine the radioactivity in suitable counting equipment by comparison with a standardized

201Tl solution

or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of

201Tl are available from national standardizing laboratories.

Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. See radiopharmaceutical preparation. Carry out biodistribution in rats as described. At 1 hour post injection not less than 1.5 % of injected activity should be found in the heart of guinea pig.

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Yttrium silicate (90Y ) colloid injection Latin name. Yttrium 90Y silicate solution iniectabilis Chemical name: Yttrium 90Y silicate Description. A white to pale white sterile suspension containing radioactive Yttrium 90Y silicate. Radionuclide production. 90Y is a radioisotope of yttrium and may be obtained by neutron irradiation of 89Y or from 90Sr, a product of uranium fission. Radio-formulation. Yttrium 90Y is bound to silicate to form a fine colloid. It may have pH adjusted and with a buffer, stabilizer and antioxidants. The Yttrium silicate (90Y) colloid


injection may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int. Category. Therapeutic radiopharmaceutical – Radiosynovectomy. Storage. Complies with general storage requirements see radiopharmaceutical preparation. Yttrium 90Y silicate injection should be stored at room temperature below 30oC. Labelling. Complies with general requirements for labelling, see radiopharmaceutical preparation. Additional information. It should have a statement "Shake well before use; for intra-articular administration". Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. A white to pale white suspension. Yttrium silicate (90Y) colloid injection is a sterile aqueous suspension of 90Y in the form of yttrium silicate suitable for intra-articular administration. 90Y is a radioisotope of yttrium and may be obtained by neutron irradiation of 89Y or from 90Sr, a product of uranium fission. The content of 90Y is not less than 90.0% and not more than 110.0% of the content of 90Y stated on the label at the reference date and hour stated on the label. Not less than 95% of 90Y activity is present bound to the particles. The Yttrium silicate (90Y ) colloid injection may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int. The radioactive half-life of 90Y is 64 hours. Identification A. Complies with test for identification given under Yttrium (90Y ) solution. The beta ray

spectrum recorded with a sample of Yttrium Chloride (90Y ) solution, suitably diluted if needed, is identical to that of a specimen of 90Y in that it exhibits maximum beta energy of 2280 keV.

B. The half-life determined using a suitable detector system is between 62 to 66 hours. Clarity and colour of solution pH. Complies with general requirements for pH, see radiopharmaceutical preparation. Between 9.0 to 11.0. Radionuclide purity. Complies with the general requirements for radionuclide purity, see radiopharmaceutical preparation.


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Strontium-90. The presence of Stronium-90 is revealed by its characteristic beta ray spectrum. To distinguish strontium-90 from strontium-89 compare with yttrium-90 the daughter nuclide of strontium-90 with respective beta-missions of maximum energy 546keV and 2.284MeV, radioactive half-lives 29.1years and 64.0hours. The instrument should be calibrated using a standardized solution of yttrium-90. The content of 90Sr is not more than 0.001%. Not less than 99% total radioactivity is present as 90Y at the time of calibration. The content of 90Sr is determined after co precipitating 90Y with Ferric hydroxide: To 1ml of a 1:1000 diluted solution of Yttrium Chloride (90Y) solution 10ml of distilled water, 10 mg of Fe3+, and 25 mg of standardized natural strontium carrier are added. The solution is made alkaline by addition of dilute NaOH. The filtrate is analysed for 90Sr using a suitable beta counter. The content of 90Sr is not more than 0.001%. Radiochemical purity. Add 0.2ml of Yttrium silicate (90Y) colloid injection to 2ml water and centrifuge for 10n minutes. Carefully separate the supernatant and measure the 90Y activity in the sedimented particles and the supernatant using a suitable measuring instrument. More than 95% of the total 90Y activity is associated with the particles. Particle size. Observe the size distribution of a representative sample contained in a suitable chamber by optical microscopy using a micrometer attachment or by reference to a haemocytometer grid. The particles should be in the range of 5 to 10 um with no particle less than 2um or more than 15 um. Chemical purity. Complies with general requirements for chemical purity, see radiopharmaceutical preparation. Assay. Determine the radioactivity in a suitable beta-counting equipment by comparison with a standardized 90Y solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 90Y are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int. The radiopharmaceutical injection may be released for use before completion of the sterility test. Bacterial endotoxins. See radiopharmaceutical preparation. It complies with the requirements for bacterial endotoxins. Biodistribution. Mainly to assess leakage from the knee joint. No more than 5% in 24 hours or more than 15% after 4days.

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monographs for individual radiopharmaceutical preparations … · working document qas/07.243 page...

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