(Technetii (99mTc) succimeri multiplex injectio) (September 2017)

[Pages:7]Working document QAS/17.735 September 2017

Draft document for comment

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3 Monograph for Technetium (99mTc) succimer complex injection

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(Technetii (99mTc) succimeri multiplex injectio)

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(September 2017)

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DRAFT FOR COMMENT

Please send any comments on the revision of this draft document to Dr Sabine Kopp Group Lead, Medicines Quality Assurance, Technologies Standards and Norms (kopps@who.int) with a copy to Ms Xenia Finnerty (finnertyk@who.int ) by 1 November 2017.

Our working documents will be sent out electronically only and will also be placed on the Medicines website for comment under "Current projects". If you do not already receive our draft working documents please let us have your email address (to bonnyw@who.int) and we will add it to our electronic mailing list.

10 11 12 13 ? World Health Organization 2017

14 All rights reserved.

15 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 16 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any 17 form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 18 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website.

19 Please send any request for permission to:

20 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential 21 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: 22 kopps@who.int.

23 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 24 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its 25 authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines 26 for which there may not yet be full agreement.

27 The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended 28 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 29 excepted, the names of proprietary products are distinguished by initial capital letters.

30 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 31 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility 32 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for 33 damages arising from its use.

34 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 35

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SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/17.735

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Monograph for Technetium (99mTc) succimer complex injection

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(Technetii (99mTc) succimeri multiplex injectio)

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IAEA consultation

Date 3?7 December 2012

IAEA consultation

6?10 May 2013

Draft monograph received from IAEA in track-change mode according to format/template described in QAS/13.544

June 2013

Discussion at informal consultation on new medicines, quality control and laboratory

12?14 June 2013

standards

Feedback to IAEA by WHO Secretariat

June 2013

Circulation for comments to IAEA and WHO Panel of Experts

Feedback to IAEA, as appropriate

June 2013 August?September 2013

Discussion during WHO Expert Committee

on Specifications for Pharmaceutical

October 2013

Preparations

Follow up by IAEA, including review of comments received

October 2013?February 2014

Discussion of revised version at IAEA consultation, Vienna, Austria

February 2014

Finalization by IAEA

February 2014

Circulation of revision to WHO and IAEA mailing list of experts for comments

Compilation of feedback

March 2014 April 2014

Discussion at informal consultation on Specifications for The International Pharmacopoeia and laboratory standards in Geneva

3?4 April 2014

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Compilation of feedback to IAEA

Presentation to forty-ninth WHO Expert Committee on Specifications for Pharmaceutical Preparations

Update during the fiftieth WHO Expert Committee on Specifications for Pharmaceutical Preparations Review and discussion of situation regarding monograph development for radiopharmaceuticals at informal consultation on quality control laboratory tools and specifications for medicines

IAEA update during the fifty-first WHO Expert Committee on Specifications for Pharmaceutical Preparations

Review and discussion during informal consultation on quality control laboratory tools and specifications for medicines

IAEA delegated final review and modifications to Professor Alain Nicolas, France

Mailing of revised monograph for public consultation

Presentation to the fifty-second WHO Expert Committee on Specifications for Pharmaceutical Preparations

Any further action as necessary

Working document QAS/17.735 page 3

May 2014 13?17 October 2014 12?16 October 2015 9?11 May 2016

17?21 October 2016 2?4 May 2017 May?September 2017 September 2017 16?20 October 2017

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46

Monograph for Technetium (99mTc) succimer complex injection

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(Technetii (99mTc) succimeri multiplex injectio)

48 49 Latin.Technetii (99mTc) succimeri multiplex injectio.

50 51 English. Technetium (99mTc) succimer complex injection.

52 53 Chemical name. (2R,3S)-2,3-disulfanylbutanedioic acid complexed with [99mTc] technetium 54 (III).

55 56 Other names. (99mTc)-meso-2,3-dimercaptosuccinic acid complex injection; (99mTc)-DMSA 57 injection, 99mTc-Succimer, Technetium-99m-DMSA, Technetium- [99mTc] succimer, 99mTc(III)58 DMSA

59 60 Description. Technetium (99mTc) succimer complex injection is a clear, colourless aqueous 61 solution. 62 63 Technetium-99m has a half-life of 6.02 hours.

64 65 Category. Diagnostic.

66 67 Storage. Technetium (99mTc) succimer complex injection is kept in single-dose containers, at a 68 temperature between 15 ?C and 30 ?C and should be protected from light.

69 70 Labelling. The label complies with the General monograph Radiopharmaceuticals. (Note: A 71 beyond-use time of 30 minutes shall be stated on the label upon constitution with Sodium 72 Pertechnetate (99mTc) injection).

73 74 Manufacture 75 76 Technetium (99mTc) succimer complex injection is prepared aseptically from sterile starting

77 materials such as a sterile kit containing meso-2,3-dimercaptosuccinic acid (DMSA) and a 78 stannous salt with Sodium pertechnetate (99mTc) injection (Fission) or Sodium Pertechnetate 79 (99mTc) injection (Non-fission). It may have the pH adjusted and may contain chelating, 80 stabilizing, filling, antioxidants such as ascorbic acid, and inert additives as well as antimicrobial 81 preservatives and buffers. (99mTc) DMSA is prepared in acidic pH and the oxidation state of 82 99mTc is 3+ in this complex, otherwise its biological behavior will be different. The injection may 83 also be prepared under aseptic processing combined with sterilization by filtration (see 5.8 84 Methods of sterilization). The Technetium (99mTc) DMSA injection should be used within 4 85 hours from the stated date and time of preparation. 86

87 Additional information 88 89 Wherever V is used within the tests of this monograph, V is the maximum recommended dose, in 90 millilitres.

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91 Requirements

92

93 Complies with the monograph for Parenteral Preparations and with that for

94 Radiopharmaceuticals.

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96 Definition

97 98 Technetium (99mTc) succimer complex injection, is a sterile solution of Sodium pertechnetate 99 (99mTc) injection (Fission) or Sodium Pertechnetate (99mTc) injection (Non-fission) complexed

100 with meso-2,3-dimercaptosuccinic acid (DMSA) that is present in excess. The injection is

101 suitable for intravenous administration and contains sufficient sodium chloride to make the

102 solution isotonic. The content of technetium-99m is not less than 90% and not more than 110%

103 of the content of technetium-99m stated on the label at the reference date and time.

104 105 Not less than 95.0% of the total technetium-99m radioactivity is present as technetium (99mTc)

106 succimer complex. The injection contains a variable quantity of tin (Sn) not greater than 1

107 mg/mL.

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109 Identity tests

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111 ? Either tests A and C or tests B and C may be applied.

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113 A. Record the gamma-ray spectrum using a suitable instrument with a sample of technetium-

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99m, suitably diluted if needed. The spectrum is concordant with the reference spectrum of

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a specimen of technetium-99m in that it exhibits a major peak of 141 keV.

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Standardized technetium-99m solutions are available from laboratories recognized by the

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relevant national or regional authority.

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

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122 C. In the test for Radiochemical purity, the chromatogram obtained contributes to the

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identification of the Technetium (99mTc) DMSA.

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125 pH. Carry out the test as described under 1.13 or R1.5 Determination of pH under the

126 monograph for Radiopharmaceuticals, the pH of the injection should be between 2.3 and 3.5.

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128 Tin. Carry out the test as described under R2.1.4 Tin estimation by UV absorption, using 1.0 mL

129 of a test solution prepared by diluting 1.5 mL of the injection to be examined to 25.0 mL with

130 hydrochloric acid (103 g/L) VS and mixing thoroughly. Prepare the reference solution by

131 dissolving 0.115 g of stannous chloride R using a solution in hydrochloric acid R (103 g/L HCl)

132 and dilute to 1000.0 mL using the same acid. To the test solution and to 1.0 mL of the reference

133 solution add 0.05 mL of thioglycollic acid R, 0.1 mL of dithiol reagent R, 0.4 mL of a 20 g/L

134 solution of sodium laurilsulfate R, 3.0 mL of 21 g/L solution of hydrochloric acid R. Mix and

135 measure the absorbance of each solution at 540 nm using 21 g/L solution of hydrochloric acid as

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136 a compensation liquid. The absorbance of the test solution is not greater than that of the 137 reference solution; not more than 1 mg of Sn per mL. 138 139 Biodistribution 140 141 Perform the test as described under R3.1 Biological distribution using three rats each weighing 142 150?250 g. Inject each of the three rats with a volume not greater than 0.2 mL and containing not 143 more than 0.1 mg of dimercaptosuccinic acid intravenously in a caudal vein or a saphenous vein. 144 Euthanize the rats 1 hour after the injection. Remove the kidneys, the liver, the spleen, the 145 stomach, the lungs and, if a caudal vein has been used for the injection, the tail. Using a suitable 146 instrument determine the radioactivity in these organs. 147 148 In not fewer than two of the three rats used, the radioactivity in the kidneys is not less than 40%, 149 and that in the liver is not more than 10.0%, that in the lungs is not more than 5.0% and that in 150 the stomach is not more than 2.0%. 151 152 Sterility. Test for sterility will be initiated on the day of manufacture. The injection may be 153 released for use before completion of the test. 154 155 The injection complies with 3.2 Test for sterility, modified as described in the monograph for 156 Radiopharmaceuticals. 157 158 Bacterial endotoxins. The test must be completed prior the preparation release. 159 160 Perform the test as described under 3.4 Test for bacterial endotoxins, modified as described in 161 the monograph for Radiopharmaceuticals. The injection contains not more than 175/V I.U. of 162 endotoxins per millilitre. 163 164 Radiochemical purity 165 166 Either test 1 or test 2 to be applied 167 168 Test 1. Perform the test as described under 1.14.2 Paper chromatography and ascending 169 conditions using paper for chromatography R. Two strips of Whatman No 1 (size 1 x 8 cm) are 170 used. The solvent to be used is acetone. Spot about 2?5 ?L of 99mTc(III)-DMSA injection at 1 cm 171 from one end of the strip in duplicate. 172 173 Develop the chromatogram until the solvent front reaches 6 cm from the point of spotting. Cut 174 the strip into 2 sections; the lower half (0?3 cm) and the upper half (3?6 cm) and count in a well175 type scintillation counter. Free pertechnetate impurity (impurity A) has a Rf of 0.9?1.0 in the 176 upper half. 177 178 The percentage of activity in the 99mTc-pertechnetate zone should not be more than 2.0% of the 179 total activity. The radiochemical purity of 99mTc(III)-DMSA (Rf = 0.0 - 0.1) should not be less 180 than 95.0%. 181

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182 Test 2. Perform the test as described under 1.14.1 Thin-layer chromatography, using silica gel

183 for chromatography R as the coating substance. Heat the plate at 110 ?C for 10 minutes. Apply to

184 the plate about 5 L of the injection to be examined, suitably diluted to give an optimum count

185 rate. Develop immediately for a distance of about 10 cm with methyl ethyl ketone R. Allow the

186 plate to dry in air and determine the radioactivity distribution by a suitable method. In this 187 system, the technetium 99mTc(III)-DMSA complex has a Rf value of 0.0?0.1 and the 188 (99mTc)pertechnetate ion has a Rf value of 0.9?1.0. Not less than 95.0% of the total technetium189 99m radioactivity is present as 99mTc(III)-DMSA. Not more than 2.0% of the total technetium190 99m radioactivity is present as (99mTc)pertechnetate ion (impurity A).

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192 Radioactivity

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194 Measure the radioactivity using a suitable counting instrument as described under R.1.1

195 Detection and measurement of radioactivity.

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197 Impurities

198 199 A.

[99mTc] pertechnetate ion.

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