Inclusion of Radiopharmaceuticals in the Indian Pharmacopeia: A Step Forward

Introduction

The term “pharmacopeia” is derived from the ancient Greek word pharmakopiia, which means “to make drug.” Pharmacopeia is an official compilation of drug quality standards intended to serve as source material for reference or adaptation for individuals and organizations involved in pharmaceutical research, development, manufacture, quality control, and analysis.[1] Monograph of a pharmacopeia contains detail description of a specific pharmaceutical, regarding nomenclature, classification, physical characteristics, dosage, purity, limits for impurities, identification, assay, and conditions for storage.[2] The objective of publishing pharmacopeia is to ensure quality, safety, and efficacy of drugs by preventing the marketing of inconsistent drugs.[3] Many countries across the world have their own national pharmacopeias such as US Pharmacopeia for the United States of America and British Pharmacopeia for Britain.[4] The World Health Organization also regularly publishes Pharmacopeia, International Pharmacopeia for the use of its member states.[4] India has its own pharmacopeia, which is known as Indian Pharmacopeia (IP). It is published periodically by the IP Commission on behalf of the Ministry of Health and Family Welfare, Government of India, in compliance with the requirements of the Drugs and Cosmetics Act, 1940 and Rules 1945.[5]

The role of nuclear medicine in the medical sciences is increasing with each passing day. The advent of Positron emission tomography–computed tomography(PET-CT) PT-computed tomography and positron emission tomography-magnetic resonance has increased its role in many folds. Radiopharmaceuticals (RPs) are an integral component of nuclear medicine practice and are employed for the diagnosis and treatment of many malignant and nonmalignant diseases.[67] Like its western counterpart, nuclear medicine in India has also expanded extensively in recent years. Many private and public establishments including teaching institute have now well-equipped nuclear medicine facility engaged in the diagnosis and treatment of various diseases.[8]

RPs are distinct and different from conventional pharmaceutical products as it contains both pharmaceutical and radionucleotide components.[9] Unlike conventional pharmaceutical products, the licensing for the production, use, and storage of RPs needs to be in agreement with the rules and regulation set up by the regulatory authority governing pharmaceutical preparations as well as the regulatory authority governing radioactive materials. It may also need additional regulation for transportation or dispensing.[10] Therapeutic RPs do not enjoy any special privilege and are treated in the same way as any other conventional drug products during the clinical trial. However, the diagnostic RP is treated differently due to its distinctive characteristics such as single use or infrequent use and microdosing. Regulatory agencies across the world have realized the importance of a systematic approach for the preclinical development of RPs which will reduce the time and resources spent on microdose RP diagnostic drug development while protecting safety of patients. In 2018, the US Food and Drug Administration has published a new guidance, Microdose RP Diagnostic Drugs: Nonclinical study recommendations, which recommends reduction or elimination of any additional toxicology and nonclinical studies for Phase 1–3 studies for diagnostic RPs.[1112] The new regulations on clinical trial brought out by the European Parliament and the Council of European Union also exempted good manufacturing practice for diagnostic RPs.[1113]

In India, RPs use is regulated under the provision of the Drugs and Cosmetics Act, 1940 and Rules 1945 though some exemption is granted from the provisions of rules of its Chapter IV.[7] Bhabha Atomic Research Centre, Mumbai, is responsible for the regulation and safety monitoring of RPs used in India, whereas the Board of Radiation and Isotopic Studies produced RPs in India.[1415]

In view of the increasing role of RPs in healthcare delivery, it has become imperative to maintain its quality and ensure its safety and effectiveness. However, sometimes, alteration in preparation procedure has unfavorable consequences such as unwanted adverse effects and decrease in effectiveness and this menace can be decreased by complying with provisions of the pharmacopeia. The IP Commission recognized this and initiated the effort to include RPs in IP for the first time in 2014 in the Seventh Edition of IP. The number has increased to 37 in 2019.[16]

Radiopharmaceuticals in Indian Pharmacopeia -2014

In 2014, 19 drug monographs and one general chapter were devoted to RPs. The RPs used for diagnosis as well as therapy were included in the pharmacopeia.[17]

Nineteen RPs found place in IP-2014 were fluorodeoxyglucose (¹⁸F) injection, technetium (^99mTc) medronate complex injection, and technetium (^99mTc) MIBI technetium methoxyisobutyl isonitrile injection, (¹³¹I) meta-iodobenzyl guanidine injection, (¹³¹I) meta-iodobenzyl guanidine injection, technetium (^99mTc) EC injection, technetium (^99mTc) ethyl cysteinate dimer injection, technetium (^99mTc) glucoheptonate injection, technetium (^99mTc) mebrofenin injection, samarium (¹⁵³Sm) ethylene diamine tetramethylene phosphonate injection, sodium fluoride (¹⁸F) injection, sodium iodide (¹³¹I) capsules, sodium iodide (¹³¹I) capsules, sodium iodide (¹³¹I) solution, sodium pertechnetate (^99mTc) injection [fission], sodium pertechnetate (^99mTc) injection (nonfission), sodium phosphate (³²P) injection, technetium (^99mTc) dimercaptosuccinic acid injection, and technetium (^99mTc) DTPA technetium diethylene-triamine-pentaacetate injection.[17]

Subsequently, ten more RPs were added in the addendum 2015. Those RPs were gallium citrate (⁶⁷Ga) injection, strontium (⁸⁹Sr) chloride injection, technetium (^99mTc) colloidal rhenium sulfide injection, technetium (^99mTc) exametazime injection, technetium (^99mTc) HYNIC-TOC injection, technetium (^99mTc) macrosalb injection, technetium (^99mTc) mertiatide injection, technetium (^99mTc) tetrofosmin complex injection, technetium (^99mTc) trodat injection, and urea (¹⁴C) capsules.[18]

In the addendum 2016, three more RPs included were samarium phosphate (³²P) colloid injection, technetium (^99mTc) labeled human serum albumin nanocolloid injection, and thallous (²⁰¹Tl) chloride injection.[19]

Radiopharmaceuticals in Indian Pharmacopeia -2018

In 2018, the IP Commission brought out the Eighth Edition of IP. Three new RP monographs were included in IP-2108 and those were gallium (⁶⁸Ga) chloride and sodium iodide (¹²³I) solution and sodium iodide (¹²³I) injection.[20] Subsequent to that two more RPs, gallium (⁶⁸Ga) edotreotide injection and sodium chromate (⁵¹Cr) injection were added in the addendum 2019.[21]

Conclusion

RPs are important for the diagnosis and management of many medical conditions. The quality of RP products is very vital as it may have a direct bearing on the safety of the patient and on the outcome of diagnosis and therapy. The inclusion of RPs in IP will help in improving the quality which in turn will promote the safety in public health as it can be used as reference sources for the quality specification of RPs.