Monographs for individual radiopharmaceutical preparations (September 2007)

Transcription

1 September 2007 RESTRICTED Monographs for individual radiopharmaceutical preparations (September 2007) DRAFT FOR COMMENT 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) or kopps@who.int and rabouhansm@who.int by 10 November 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) ; kopps@who.int. 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.

2 page 2 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/ Monographs for individual radiopharmaceutical preparations 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

3 RADIOPHARMACEUTICALS Working document QAS/ page 3 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 3 rd 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 4 th 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, High performance liquid chromatography, 3.4 Test for bacterial endotoxins)

4 page 4 RADIOPHARMACEUTICALS Monographs for individual radiopharmaceutical preparations 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 ( 131 I) injection Samarium ethylene diamine tetramethylene phosphonate complex ( 153 Sm) injection Sodium Iodide ( 131 I) capsules Sodium Iodide ( 131 I) injection Sodium Iodide ( 131 I) solution Sodium iothalamate ( 125 I) injection Sodium Pertechnetate ( 99m Tc) injection Sodium Phosphate ( 32 P) injection Strontium Chloride (89Sr) injection Technetium (99mTc) Bicisate complex injection Technetium 99mTc Exametazime complex injection. Technetium ( 99m Tc) labelled Macrosalb ( 99m Tc MAA) injection Technetium ( 99m Tc)- Mebrofenin complex injection Technetium ( 99m Tc) Mertiatide injection Technetium(99mTc) Methylene Diphosphonate (MDP) complex injection Technetium ( 99m Tc) Nanocolloid injection

5 page 5 Technetium ( 99m Tc) Pentetate complex injection Technetium(99mTc ) Pyrophoshate tin complex injection Technetium (99mTc) labelled Red Blood Cells injection Technetium(99mTc) Sestamibi complex injection Technetium ( 99m Tc) Succimer complex injection Technetium ( 99m Tc) Sulphur Colloid injection Technetium ( 99m Tc) Tetrofosmin complex injection Technetium [ 99m Tc] Tin colloidal injection Thallous Chloride ( 201 Tl) injection Yttrium silicate ( 90 Y) colloid injection List 2: Draft monographs in preparation (Will form addendum to this document) - 5 -

6 page 6 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/ 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 ( 18 F) injection Latin name. Fludeoxyglucosi solution iniectabilis Chemical name. 2-[ 18 F] fluoro-2-deoxy-d-glucopyranose (2-[ 18 F] fluoro-2- deoxy -Dglucose) Other names. 18 F-FDG Graphic formula. Description. Fludeoxyglucose ( 18 F) injection ( 18 F-FDG) is a colourless or slightly yellow and sterile solution. Radionuclide production. 18 F 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 18 F 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.

7 page 7 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-[ 18 F]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 [ 18 F]fluoride. Generally [ 18 F]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 [ 18 F]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-[ 18 F]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-[ 18 F]fluoro-2-deoxy-D-glucose proceed by the reaction of molecular [ 18 F]fluorine or [ 18 F]acetylhypofluorite with 3,4,6-tri-O-acetyl-D-glucal. [ 18 F]Acetylhypofluorite is obtained by conversion of molecular [ 18 F]fluorine on a solid complex of acetic acid and potassium acetate. The production of molecular [ 18 F]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 [ 18 F]fluorinated sugar yields 2-[ 18 F]fluoro-2-deoxy-Dglucose and usually small amounts of 2-[ 18 F]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

8 page 8 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 ( 18 F) injection ( 18 F-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 18 F in the molecular structure. The content of 18 F is not less than 90.0 % and not more than % 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 18 F is present as 18 F-fluoro 2-deoxy D glucose and 18 F-fluoro 2-deoxy D mannose. The later should not exceed 10% limit. The specific activity of 18 F 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 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 18 F FDG, suitably diluted if needed, is identical to that of a specimen of 18 F 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.

9 page 9 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 18 F 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). 18 F 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 18 F FDG. Chemical purity. 18 F-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

10 page 10 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 anionexchange 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 20 o C and 30 o C. 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-Dglucose 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-Dglucose, 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-Dglucose 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 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.

11 page 11 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 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 18 F solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 18 F are available from national standardizing laboratories

12 page 12 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- 67 Ga salt Chem. Structure. C 6 H 5 67 GaO 7 Relative molecular mass. 256 Graphic formula CH 2 COO - HO C COO - Ga +3 CH 2 COO - Description. Gallium citrate ( 67 Ga) injection is a clear and sterile solution. Radionuclide production. 67 Ga 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 67 Ga 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 ( 67 Ga) injection should be stored in a refrigerator (2-8 o C) even if it contains preservatives.

13 page 13 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 ( 67 Ga) injection is a sterile clear, colourless, isotonic, aqueous solution of 67 Ga 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 67 Ga is not less than 90.0 % and not more than % of the content of 67 Ga stated on the label at the reference date and hour stated on the label. Not more than 0.2% of total activity as 66 Ga. Not less than 95% of total 67 Ga 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 67 Ga citrate suitably diluted if needed, is identical to that of a specimen of 67 Ga 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 66 Ga. 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

14 page 14 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 67 Ga at the time of calibration and not more than 0.2% as 66 Ga. Radiochemical purity. Carry out Ascending Paper Chromatography as described. Apply ~5 µl of sample of Gallium citrate ( 67 Ga) 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. 67 Ga may be produced by different nuclear reactions on different target elements and hence using different processing methods. The final product 67 Ga 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. 67 Ga citrate remains at the origin. ***

15 Iobenguane ( 123 I) injection Latin Name. Iobenguani 123 I solution iniectabilis Chemical name. {[(3-Iodo- 123 I)-phenyl]methyl}guanidine sulfate (2:1) Other names. Metaiodobenzyl guanidine (I-123) injection, 123 I-MIBG Working document QAS/ page 15 Chemical structure. (C 8 H IN 3 ) 2 H 2 SO 4 Relative molecular mass. 271 as free base; 640 as sulfate (2:1) salt Graphic formula N H NH NH 2. H2 SO I 2 Description. Iobenguane ( 123 I ) injection ( 123 I-MIBG) is a clear, generally colourless (occasionally slightly yellow), sterile aqueous solution. Radionuclide production. Complies with 123 I 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, 123 I- 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 ( 123 I ) injection should be stored in a refrigerator (2-8 o C) 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 ( 123 I ) injection should be labelled giving information on storage temperature and protect from light. Additional information. Iobenguane ( 123 I ) injection may be provided in single patient dose vials containing volumes suitable for injection (e.g. 1 5ml). The preparation of this

16 page 16 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 ( 123 I ) injection ( 123 I-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 123 I in place of non-radioactive iodine. The content of 123 I 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 123 I activity is present as 123 I-metaiodobenzyl guanidine. Not less than 10GBq of 123 I per gram of iobenguane base. Not more than 0.35% of total radioactivity is due to radionuclides other than 123 I. 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 123 I 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. 124 I has half life of 4.2 days and main peak 603keV. 125 I 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.

17 page 17 Radionuclide purity. See radiopharmaceutical preparation. Complies with the general requirements for radionuclide purity. Not less than 97% of the total radioactivity is present as 123 I. Not more than 0.35% of total radioactivity is due to other radionuclides such as 125 I 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 123 I 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 ( 123 I ) 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 ( 123 I) 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 ( 123 I) 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 ( 123 I) 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. ***

18 page 18 Iobenguane ( 131 I ) injection Latin Name. Iobenguani 131 I solutio iniectabilis Chemical name. {[(3-Iodo- 131 I)-phenyl]methyl}guanidine sulfate (2:1) Other names. Iobenguane ( 131 I) injection, 131 I-MIBG Chemical structure. (C 8 H IN 3 ) 2 H 2 SO 4 Relative molecular mass: 279 as free base; 656 as sulfate (2:1) salt Graphic formula N H NH NH 2. H2 SO I 2 Description. Iobenguane ( 131 I ) injection ( 131 I-MIBG) is a clear, generally colourless (occasionally slightly yellow), sterile aqueous solution. Radionuclide production. Complies with 131 I 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, 131 I- 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 ( 131 I ) injection should be stored in a refrigerator (2-8 o C) 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 ( 131 I ) injection should be labelled giving information on storage temperature and protect from light. Additional information. Iobenguane ( 131 I) injection may be provided in single patient dose vials containing volumes suitable for injection (e.g. 1 5ml) or larger vials for therapy. The

19 page 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 ( 131 I-MIBG) is a clear, colourless, sterile aqueous solution containing metaiodobenzyl guanidine sulfate. A small percentage of the molecules of metaiodobenzyl guanidine will contain 131 I in place of non-radioactive iodine. The content of 131 I is not less than 90.0 % and not more than % of the reported activity at the reference date and hour as stated on the label. Not less than 94% of total 131 I activity is present as 131 I- 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 131 I 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 I suitably diluted if needed, is identical to that of a specimen of 131 I in that it exhibits a major peak at 364keV. 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 131 I. 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

20 page 20 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 ( 131 I ) 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 ( 131 I ) 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 ( 131 I). 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 ( 131 I) 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 ( 131 I) 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 ( 153 Sm) ethylene diamine tetramethylene phosphonate (EDTMP) complex injection Latin name. Samarium 153 Sm EDTMP solutio iniectabilis Chemical name. phosphonate. 153 Sm EDTMP, Samarium ( 153 Sm) ethylene diamine tetramethylene Chem. Structure. A complex between 153 Sm and the ligand EDTMP.

21 page 21 Description. Samarium ethylene diamine tetramethylene phosphonate injection ( 153 Sm- EDTMP) is a clear colourless, sterile solution. Radionuclide production. Complies with 153 Sm production and general conditions in radiopharmaceutical preparation. Samarium may be obtained by neutron irradiation of enriched samarium dioxide ( 152 Sm) Sm 2 O 3 in quartz ampoule. Radiochemical systhesis. In brief, 153 Sm 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 is required for complexation with 153 Sm. 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. 153 Sm EDTMP complex injection is heat sensitive and should therefore be transported frozen at least to -10 o C. Prior to patient use it should be should be stored in a refrigerator. Labelling. See radiopharmaceutical preparation. 153 Sm 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 ( 153 Sm ) injection ( 153 Sm-EDTMP) is a clear colourless, sterile solution of 153 Sm complexed with EDTMP that is present in excess. The content of 153 Sm 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 153 Sm is present as 153 Sm 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 153 Sm is 46.3 hours

22 page 22 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 153 Sm 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. 153 Sm EDTMP complex has Rf of about 0.9 and ionic 153 Sm Rf about 0 in this system. The percentage of 153 Sm 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 153 Sm 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 153 Sm 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 page 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. *** Latin Name. Natrii iodidi ( 131 I) capsulae Chemical name. Sodium iodide capsules. Other names. Radio-iodide therapy capsules. Sodium Iodide ( 131 I ) 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 131 I 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 131 I 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 ( 131 I ) 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

24 page 24 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 ( 131 I) capsules, suitable for oral administration, contain radioactive 131 I 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 131 I is not less than 90.0 % and not more than % 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 131 I 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 I suitably diluted if needed, is identical to that of a specimen of 131 I in that it exhibits a major peak at 364keV. 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 ( 131 I ) capsule complies with the requirements for radionuclide purity given under Sodium Iodide 131 I 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 ( 131 I ) 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 page 25 of the total radioactivity. The Rf value for the iodide band falls within 5% of the value found for an iodine 131 I 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 131 I 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 ( 131 I ) injection Latin Name. Natrii iodidi ( 131 I) solutio iniectabilis Description. A clear, colourless sterile solution containing radioactive 131 I as sodium iodide. Radionuclide production. Complies with 131 I 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 ( 131 I ) injection should be stored at room temperature (below 30 C)

26 page 26 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 ( 131 I ) 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 131 I is present as iodide. The content of 131 I 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 131 I is present as iodide. The injection may be sterilized by Method 1 Heating in an Autoclave described under injections in Ph. Int. The radioactive halflife 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 I suitably diluted if needed, is identical to that of a specimen of 131 I in that it exhibits a major peak at 364keV. 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 page I. 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 ( 131 I ) 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 131 I 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 131 I solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 131 I 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 131 I 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. ***

28 page 28 Latin Name: Natrii iodidi ( 131 I) solutio Chemical name: Sodium iodide Other names: 131 I Radio-iodine solution Sodium Iodide ( 131 I) solution Description. Sodium Iodide 131 I solution is a clear colourless solution containing radioactive 131 I as sodium iodide and is suitable for oral administration. Radionuclide production. Complies with 131 I 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 bioburden 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 ( 131 I ) 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 131 I solution is a clear colourless solution containing radioactive 131 I 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 131 I is present as iodide. The content of 131 I 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 131 I is 8.06 days.

29 page 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 I suitably diluted if needed, is identical to that of a specimen of 131 I in that it exhibits a major peak at 364keV. 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 131 I. 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 ( 131 I ) 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 131 I solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 131 I are available from national standardizing laboratories

30 page 30 Bioburden test. Complies with general requirement of oral solution and microbiology for oral solution Ph. Int. *** Latin name. Natrii iothalamate iniectabilis Chemical name. Sodium iothalamate Graphic formula. Sodium iothalamate 125 I injection Description. A clear, colourless sterile solution containing iothalamate sodium 125 I injection. Radionuclide production. Complies with 125 I production and general conditions in radiopharmaceutical preparation. Iodine-125 may be obtained by neutron irradiation of xenon. Radiochemical synthesis. In brief, 125 I- 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 ( 125 I ) injection should be stored in a refrigerator (2-8 o C) Labelling. Complies with general requirements for labelling. See radiopharmaceutical preparation. The label should specify radioactivity in MBq per ml.

31 page 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 125 I 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 ( 125 I ) in the molecular structure. It may contain small amounts of suitable buffers or a stabilizer. Iodothalamate sodium 125 I injection contains not less than 90.0 percent and not more than percent of the concentration of iodothalamate sodium and of the labelled amount of 125 I 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 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. 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 125 I 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

32 page 32 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 125 I. 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 ( 125 I) 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. ***

33 page 33 Sodium Pertechnetate ( 99m Tc) injection (fission) This monograph applies to sodium pertechnetate ( 99m Tc) injection obtained from generators containing molybdenum-99 extracted from fission products of uranium. Latin name. Natrii pertechnetatis ( 99m Tc) fissione formati solutio iniectabilis Chemical name. Sodium pertechnetate Other names. 99m Tc sodium pertechnetate Description. Sodium Pertechnetate ( 99m Tc) 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 ( 99 Mo). 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 99m Tc from parent 99 Mo 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 ( 99m Tc) injection should be stored at room temperature (below 30 o C). 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 99 Mo 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"

34 page 34 Definition. Sodium pertechnetate ( 99m Tc) 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.

35 page 35 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 99m Tc 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

36 page 36 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.

37 page 37 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 99m Tc 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 99m Tc 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 ( 99m Tc) injection (non-fission) This monograph applies to sodium pertechnetate ( 99m Tc) injection obtained from generators containing molybdenum-99 produced by neutron irradiation of molybdenum and extracted for generator columns. Latin name. Natrii pertechnetatis ( 99m Tc) sine fissione formati solutio iniectabilis Chemical name. Sodium pertechnetate Other names. 99m Tc sodium pertechnetate Description. Sodium Pertechnetate ( 99m Tc) 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 ( 99 Mo). 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 99m Tc from parent 99 Mo using a suitable generator system. Sterile

38 page 38 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 ( 99m Tc) injection should be stored at room temperature (below 30 o C). 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 99 Mo per vial. Requirements The radiopharmaceutical complies with the monograph in Ph. Int. for "Parenteral preparations". Definition. Sodium Pertechnetate ( 99m Tc) 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.

39 page 39 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 99m Tc 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

40 page 40 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 99m Tc 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 99m Tc 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 ( 32 P ) injection Latin name. Natrii phosphatis ( 32 P) solutio iniectabilis Chemical name. Disodium and monosodium ( 32 P) orthophosphate. Description. A clear, colourless sterile solution containing radioactive disodium and monosodium ( 32 P) orthophosphate made isotonic to blood with sodium chloride. Radionuclide production. 32 P is radioactive isotope of phosphorous and may be produced by neutron irradiation of sulfur.

41 page 41 Radio-formulation. A clear, colourless sterile solution containing radioactive disodium and monosodium ( 32 P) 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 32 P is 14.3 days Category. Therapeutic radiopharmaceutical. Storage. Complies with general requirements for storage. See radiopharmaceutical preparation. Sodium phosphate ( 32 P) injection should be stored at room temperature (about 27 o C). Labelling. Complies with general requirements of labelling. See radiopharmaceutical preparation. Sodium phosphate ( 32 P) 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 ( 32 P) injection is a sterile solution of 32 P as sodium phosphate. The solution contains added phosphate. 32 P 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 32 P is not less than 90.0% and not more than 110.0% of the content of 32 P 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 32 P 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

42 page 42 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 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 ( 32 P ) 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 32 P solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 32 P are available from national standardizing laboratories. Sterility. See radiopharmaceutical preparation. It complies with the requirements for sterility as described in Ph. Int.

43 page 43 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. *** Strontium Chloride ( 89 Sr) injection Latin name Strontium chloridum ( 89 Sr) solution iniectabilis. Description. A clear, colourless sterile solution containing radioactive strontium Chloride ( 89 Sr) injection as strontium chloride in presence of excess chloride ions. Radionuclide production. Strontium ( 89 Sr) 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 ( 89 Sr) injection should be stored at room temperature (about 30 o C). Labelling. Complies with general requirements for labelling see radiopharmaceutical preparation. Strontium Chloride ( 89 Sr) 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 ( 89 Sr) injection is a sterile solution of 89 Sr as strontium chloride in presence of excess chloride ions. 89 Sr is a radioisotope of strontium and may be prepared by neutron irradiation of 89 Sr the specific activity of 89 Sr is > 2 MBq per mg of strontium at the date and time of calibration. The content of 89 Sr is not less than 90.0% and not more than 110.0% of the content of 89 Sr 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

44 page 44 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 89 Sr is days. Identification Either test A or B in addition to C. A. The beta ray spectrum recorded with a sample of Strontium Chloride ( 89 Sr) injection, suitably diluted if needed, is identical to that of a specimen of 89 Sr 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. B. The half-life determined using a suitable detector system is between and 48 and 53 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 89 Sr 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 ( 89 Sr) 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.

45 page 45 Chemical purity. Complies with general requirements of chemical impurity Ph. Int. A sample (~50 µl) of strontium Chloride ( 89 Sr) 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 89 Sr solution or by measurement in an instrument calibrated with the aid of such a solution. Standardized solutions of 89 Sr 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. *** Technetium ( 99m Tc) Bicisate complex injection ( 99m Tc -ECD) Latin name Technetii ( 99m Tc) Bicisati solutio iniectabilis Chemical name. 99m Tc Ethylene dicysteine Diester Other names. 99m Tc bicisate dihidrocloride (ECD), 99m Tc-L,L-ECD Chem. Structure. A complex between 99m Tc and the ligand ethylene dicysteine diester. Graphic formula of the ligand. Description. A clear, colourless sterile solution containing radioactive 99m Tc -ECD. Radionuclide production. Described under sodium pertechnetate 99m Tc injection