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Technetium-99M Radiopharmaceuticals: Manufacture of Kits of Manufacture Radiopharmaceuticals: Technetium-99M Technetium-99M Radiopharmaceuticals: Manufacture of Kits

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Technetium-99M Radiopharmaceuticals: Manufacture of Kits of Manufacture Radiopharmaceuticals: Technetium-99M Technetium-99M Radiopharmaceuticals: Manufacture of Kits 200 pages 12 mm technical reportS series no. This report describes the procedures for preparing kits for the formulation of 23 selected 99mTc radiopharmaceuticals. Details of the preparation of ten of the active ingredients are also included. The procedures described here can be used to develop manuals, monographs and standard operating procedures. This 466 report is expected to serve as a guide to radiopharmaceutical manufacturing centres and Technical Reports SeriEs No. 466 centralized pharmacies involved in the production of kits. It will be a useful resource for the many hospital radiopharmacies that routinely use the kits to compound 99mTc radiopharmaceuticals, and a source of information for regulators of radiopharmaceuticals. Technetium-99m Radiopharmaceuticals: Manufacture of Kits Technetium-99m Radiopharmaceuticals: Manufacture of Kits INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA ISBN 978–92–0–100408–6 ISSN 0074–1914 D466_covI-IV.indd 1 2008-08-19 10:20:00 TECHNETIUM-99m RADIOPHARMACEUTICALS: MANUFACTURE OF KITS The following States are Members of the International Atomic Energy Agency: AFGHANISTAN GREECE NORWAY ALBANIA GUATEMALA PAKISTAN ALGERIA HAITI PALAU ANGOLA HOLY SEE PANAMA ARGENTINA HONDURAS PARAGUAY ARMENIA HUNGARY PERU AUSTRALIA ICELAND PHILIPPINES AUSTRIA INDIA POLAND AZERBAIJAN INDONESIA PORTUGAL BANGLADESH IRAN, ISLAMIC REPUBLIC OF QATAR BELARUS IRAQ REPUBLIC OF MOLDOVA BELGIUM IRELAND ROMANIA BELIZE ISRAEL RUSSIAN FEDERATION BENIN ITALY SAUDI ARABIA BOLIVIA JAMAICA SENEGAL BOSNIA AND HERZEGOVINA JAPAN SERBIA BOTSWANA JORDAN SEYCHELLES BRAZIL KAZAKHSTAN SIERRA LEONE BULGARIA KENYA SINGAPORE BURKINA FASO KOREA, REPUBLIC OF SLOVAKIA CAMEROON KUWAIT SLOVENIA CANADA KYRGYZSTAN SOUTH AFRICA CENTRAL AFRICAN LATVIA SPAIN REPUBLIC LEBANON SRI LANKA CHAD LIBERIA SUDAN CHILE LIBYAN ARAB JAMAHIRIYA SWEDEN CHINA LIECHTENSTEIN SWITZERLAND COLOMBIA LITHUANIA SYRIAN ARAB REPUBLIC COSTA RICA LUXEMBOURG TAJIKISTAN CÔTE D’IVOIRE MADAGASCAR THAILAND CROATIA MALAWI THE FORMER YUGOSLAV CUBA MALAYSIA REPUBLIC OF MACEDONIA CYPRUS MALI TUNISIA CZECH REPUBLIC MALTA TURKEY DEMOCRATIC REPUBLIC MARSHALL ISLANDS UGANDA OF THE CONGO MAURITANIA UKRAINE DENMARK MAURITIUS UNITED ARAB EMIRATES DOMINICAN REPUBLIC MEXICO UNITED KINGDOM OF ECUADOR MONACO GREAT BRITAIN AND EGYPT MONGOLIA NORTHERN IRELAND EL SALVADOR MONTENEGRO UNITED REPUBLIC ERITREA MOROCCO OF TANZANIA ESTONIA MOZAMBIQUE UNITED STATES OF AMERICA ETHIOPIA MYANMAR URUGUAY FINLAND NAMIBIA UZBEKISTAN FRANCE NETHERLANDS VENEZUELA GABON NEW ZEALAND VIETNAM GEORGIA NICARAGUA YEMEN GERMANY NIGER ZAMBIA GHANA NIGERIA ZIMBABWE The Agency’s Statute was approved on 23 October 1956 by the Conference on the Statute of the IAEA held at United Nations Headquarters, New York; it entered into force on 29 July 1957. The Headquarters of the Agency are situated in Vienna. Its principal objective is “to accelerate and enlarge the contribution of atomic energy to peace, health and prosperity throughout the world’’. TECHNICAL REPORTS SERIES No. 466 TECHNETIUM-99m RADIOPHARMACEUTICALS: MANUFACTURE OF KITS INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2008 COPYRIGHT NOTICE All IAEA scientific and technical publications are protected by the terms of the Universal Copyright Convention as adopted in 1952 (Berne) and as revised in 1972 (Paris). The copyright has since been extended by the World Intellectual Property Organization (Geneva) to include electronic and virtual intellectual property. Permission to use whole or parts of texts contained in IAEA publications in printed or electronic form must be obtained and is usually subject to royalty agreements. Proposals for non-commercial reproductions and translations are welcomed and considered on a case-by-case basis. Enquiries should be addressed to the IAEA Publishing Section at: Sales and Promotion, Publishing Section International Atomic Energy Agency Wagramer Strasse 5 P.O. Box 100 1400 Vienna, Austria fax: +43 1 2600 29302 tel.: +43 1 2600 22417 email: [email protected] http://www.iaea.org/books © IAEA, 2008 Printed by the IAEA in Austria August 2008 STI/DOC/010/466 IAEA Library Cataloguing in Publication Data Technetium-99m radiopharmaceuticals : manufacture of kits. — Vienna : International Atomic Energy Agency, 2008. p. ; 24 cm. — (Technical reports series, ISSN 0074–1914 ; no. 466) STI/DOC/010/466 ISBN 978–92–0–100408–6 Includes bibliographical references. 1. Technetium — Therapeutic use. 2. Radiopharmaceuticals — Quality control. 3. Radiopharmaceutical industry. — I. International Atomic Energy Agency. II. Series: Technical reports series (International Atomic Energy Agency); 466. IAEAL 08–00527 FOREWORD Technetium-99m radiopharmaceuticals are in widespread use owing to the availability and affordability of 99Mo/99mTc generators and the variety of kits for formulating the desired products. Together, they provide an array of specific tools for diagnosing a large number of diseases affecting the bones and major organs of the body such as the heart, brain, liver, kidney and thyroid. Nuclear medicine requires high quality radiopharmaceuticals and kits that are safe for administration and efficacious for a given application. The IAEA supports Member States in building capacity in the area of 99mTc generators and ‘cold kits’ through coordinated research projects (CRPs), technical cooperation activities and the publication of relevant reports that help disseminate useful information. These efforts have contributed greatly to reducing costs and increasing the efficiency of resource utilization, thereby helping to make nuclear medicine cost effective in Member States. This publication presents the theoretical basis of and describes the procedures for preparing 23 selected kits. Details of the preparation of ten of the active ingredients are also included. The procedures described here can be used to develop manuals, monographs and standard operating procedures. This report is expected to serve as a guide to radiopharmaceutical manufacturing centres and centralized pharmacies involved in the production of such kits. It will be a useful resource for the many hospital radiopharmacies that routinely use the kits to compound 99mTc radiopharmaceuticals, and a useful source of information for regulators of radiopharmaceuticals. The IAEA thanks J. Környei and K. Ozker for compiling and reviewing the manuscript, the experts who provided input for the report, and the reviewers for their valuable suggestions and comments. The IAEA officer responsible for this publication was M.R.A. Pillai of the Division of Physical and Chemical Sciences. EDITORIAL NOTE Although great care has been taken to maintain the accuracy of information contained in this publication, neither the IAEA nor its Member States assume any responsibility for consequences which may arise from its use. The use of particular designations of countries or territories does not imply any judgement by the publisher, the IAEA, as to the legal status of such countries or territories, of their authorities and institutions or of the delimitation of their boundaries. The mention of names of specific companies or products (whether or not indicated as registered) does not imply any intention to infringe proprietary rights, nor should it be construed as an endorsement or recommendation on the part of the IAEA. CONTENTS 1. INTRODUCTION . 1 1.1. Background . 1 1.2. Objective . 5 1.3. Scope . 5 REFERENCES TO SECTION 1 . 6 2. TECHNETIUM CHEMISTRY: THE STATE OF THE ART . 7 2.1. Basic chemical properties of technetium . 7 2.2. First generation technetium radiopharmaceuticals . 7 2.3. Second generation technetium radiopharmaceuticals . 11 2.4. Novel technetium chemistry . 14 2.5. Designed molecules and bioconjugates . 19 2.6. Precursors and chelating agents needed for the labelling of biomolecules . 21 REFERENCES TO SECTION 2 . 22 3. GOOD MANUFACTURING PRACTICE . 26 3.1. Main components of GMP . 26 3.2. Quality management . 27 3.3. Personnel . 27 3.4. Premises and equipment . 28 3.5. Documentation . 36 3.6. Production . 37 3.7. Quality control . 39 3.8. Stability testing . 40 3.9. Contract manufacture and analysis . 42 3.10. Complaints and product recalls . 42 3.11. Self-inspections . 42 3.12. Relationship between GMP and ISO regulation . 43 BIBLIOGRAPHY . 43 4. GENERAL PROCEDURES FOR PRODUCTION OF KITS . 44 4.1. Batch planning . 45 4.2. Washing and sterilization of glassware and stoppers . 45 4.3. Starting materials . 46 4.4. Preparation of bulk solutions . 46 4.5. Sterile filtration . 47 4.6. Dispensing . 47 4.7. Crimping . 48 4.8. Summary of in-process controls . 48 4.9. Quarantine . 49 4.10. Packaging . 49 4.11. Leaving the production premises . 49 BIBLIOGRAPHY . 50 5. GENERAL PROCEDURES IN QUALITY CONTROL . 50 5.1. Quality control of starting materials . 50 5.2. Quality control of active substances used in the kit . 51 5.3. Quality control of finished kits . 54 BIBLIOGRAPHY . 57 6. QUALITY SPECIFICATIONS . 58 6.1. Clean rooms . 59 6.2. Freeze-drying . 59 6.3. Packing materials: Vials, stoppers and caps . 60 6.4. Water for injection . 60 6.5. Nitrogen gas . 61 6.6. Commonly used chemicals . 62 6.7. Other excipients . 62 REFERENCES TO SECTION 6 . 63 BIBLIOGRAPHY . 63 7. PRODUCTION METHODS AND SPECIFICATIONS FOR KITS . 64 7.1. Preparation of kit for 99mTc-MDP . 66 7.2. Preparation of kit for 99mTc-HMDP . 69 7.3. Preparation of kit for 99mTc-pyrophosphate . 72 7.4. Preparation of kit for 99mTc-DTPA . 74 7.5. Preparation of kit for 99mTc-glucoheptonate . 77 99m 7.6. Preparation of kit for Tc-MAG3 . 79 7.7. Preparation of kit for 99mTc-EC . 83 7.8. Preparation of kit for 99mTc-DMSA(III) . 86 7.9. Preparation of kit for 99mTc-DMSA(V) . 89 7.10. Preparation of kit for 99mTc-mebrofenin (bromo-HIDA) . 91 7.11. Preparation of kit for 99mTc-EHIDA . 93 7.12. Preparation of kit for 99mTc-phytate . 96 7.13. Preparation of kit for 99mTc-sulphur colloid . 98 7.14. Preparation of kit for 99mTc-tin colloid . 102 7.15. Preparation of kit for 99mTc-rhenium-sulphide colloid . 104 7.16. Preparation of kit for 99mTc–human serum albumin (HSA) nanocolloid . 108 7.17. Preparation of kit for 99mTc–human serum albumin (HSA) colloid . ..
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