All healthcare professionals that have interactions with PET/MRI imaging will benefit from the information in this presentation.This presentation will review the radiopharmaceutical practices in different countries and educate the audience on regulatory framework for the use of radiopharmaceuticals throughout the world. Radiopharmaceuticals are drugs that have incorporated a radioactive atom for the purpose of either diagnostic imaging or radiation therapy (this presentation will not cover the radiation therapy aspects of radiopharmaceuticals). The properties of the drug are selected to ensure that the delivery is to a specific cellular target, providing high-quality images of physiological processes. The manufacturing of radiopharmaceuticals must occur within a good manufacturing practice (GMP) environment to ensure safety, regardless of whether the manufacturer is a commercial supplier or an in-house facility. GMP regulations are in place to ensure that the finished radiopharmaceutical meets the key components of product quality: safety, efficacy, purity and uniformity. Positron Emission Tomography (PET) utilizes short-lived radioisotopes, with half-lives on the order of minutes to hours, and thus have short shelf lives. As such, commercial manufacturing is not always practical and in-house production is sometimes necessary due to the just-in-time nature of PET drug manufacturing. This is a very different environment than MRI contrast agents, which are widely available commercially and can be stocked well in advance of the imaging study. In addition, only a handful of PET radiopharmaceuticals have been approved for clinical use and a great number of PET radiopharmaceuticals are administered as part of a clinical trial rather than for routine clinical use. It is imperative that PET radiopharmaceutical regulations are followed when performing PET/MRI studies. Unfortunately, there is not a harmonized framework for PET radiopharmaceutical regulations, so it is necessary to understand the regulations that are specific to a local region in order to assure compliance.

In order to understand the scope of PET radiopharmaceutical regulations, it is helpful to look at the examples of how some countries/regions regulate PET radiopharmaceuticals.

Australia: The Therapeutic Goods Administration (TGA) oversees the production of all medicinal products, including radiopharmaceuticals. The guidelines provide satisfactory licensing requirements for the production of radiopharmaceuticals and include Australian Registry for Therapeutic Goods (ARTG) numbers for individual drugs. Radiopharmaceuticals without assigned ARTG numbers can be manufactured by commercial suppliers for a specific patient study under the Special Access Scheme (SAS). New radiopharmaceuticals manufactured in-house are usually exempt from licensing by TGA. Instead, the local Institutional Review Board (IRB) controls the oversight of these radiopharmaceuticals. These radiopharmaceuticals must comply with United States Pharmacopoeia and/or British Pharmacopoeia regulations and the synthesis modules used for manufacturing must be approved.

European Union (EU): The manufacture and use of radiopharmaceuticals for both clinical and research use are regulated by several European bodies and by national authorities. The European Commission EudraLex Volume 4 “Guidelines for Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use” describes the rules for manufacturing medicinal products, including radiopharmaceuticals and is in effect for all Member States. The European Medicine Agency (EMEA) is responsible for evaluating the applications for marketing authorizations of new drugs. Radiopharmaceuticals used in clinical trials are subject to the rules of the nation under which the trial is being conducted and vary from nation to nation within Europe.

Japan: The Ministry of Health, Labour and Welfare (WHLW) and the Pharmaceutical and Medical Device Agency (PMDA) are responsible for the approval of radiopharmaceuticals in Japan. In order to meet GMP requirements, radiopharmaceuticals should be manufactured using an approved synthesis module with rigorous process controls and quality assurance that meets the guidelines and monographs published by the Japanese Society of Nuclear Medicine (JSNM).

United States: PET radiopharmaceuticals must be manufactured under Section 212 of Title 21 of the Code of Federal Regulations (21 CFR 212). This standard applies to approved PET radiopharmaceuticals as well as those that are in Phase III and IV clinical trials. PET radiopharmaceuticals being used in earlier phase clinical trials have the option of being manufactured under either 21 CFR 212 or Chapter <823> of the United States Pharmacopeia (USP, 32nd edition, 2009). There are two appropriate pathways when conducting a clinical trial with radiopharmaceuticals: the Radioactive Drug Research Committee (RDRC) or Investigational New Drug (IND) application. The RDRC is a local committee that is allowed to approve initial phases of clinical trials under certain conditions in place of FDA approval. An IND is needed to perform any radiopharmaceutical clinical trial that is not being performed under RDRC oversight.

While regulations vary across the globe, the general framework is the same. PET radiopharmaceuticals in routine clinical use will have been approved by the appropriate regulatory body and should be available by either commercial or in-house suppliers. It is important to verify that the supplier has the appropriate approvals from the regulatory body before the PET radiopharmaceutical is purchased/used in diagnostic imaging studies. PET radiopharmaceuticals for use in clinical trials will require a more rigorous approach. It is imperative that the imaging site is well versed in the local regulations concerning the use of radiopharmaceuticals in clinical trials and follows due diligence to ensure compliance with all local laws.