Regulatory aspects of PET radiopharmaceutical production in the United States

Abstract

The Food and Drug Administration (FDA) Modernization Act (the Modernization Act) of 1997 directed FDA to establish current good manufacturing practice (CGMP) requirements for positron emission tomography (PET) drugs. As directed by the US Congress in the Modernization Act, the costly CGMP regulations which the FDA applies to large pharmaceutical manufacturers are not appropriate for the PET drugs due to the unique properties of these drugs mainly the short half-lives. In consideration of the unique nature of PET drugs and PET drug production, FDA instituted specific CGMP requirements in 21 Code of Federal Regulations (CFR) part 212. Sections 1 and 2 of this book chapter illustrate the significant different aspects and the rationales for such differences between part 212 and parts 210/211 which are the CGMP requirements for non-PET drugs. The PET drug CGMP regulation found in part 212 also provides a more flexible regulatory framework for investigational PET drugs for human use produced under an investigational new drug application (IND) in accordance with part 312 and PET drugs produced with the approval of a Radioactive Drug Research Committee (RDRC) in accordance with part 361. The PET CGMP requirements for these PET drugs can be met either by compliance with part 212 or by producing such drugs in accordance with the 32nd edition of the United States Pharmacopeia (USP) General Chapter <823>, “Radiopharmaceuticals for Positron Emission Tomography - Compounding," which was published in 2009. In 2012, USP revised and renamed this General Chapter <823>, “Positron Emission Tomography Drugs for Compounding, Investigational, and Research Uses." FDA is currently considering whether to amend the PET CGMP regulations to incorporate this revised chapter into part 212. Section 4 describes format/content of the revised USP General Chapter <823> which is very much in line with part 212 and offers more flexible requirements than the <823> in 32nd USP. FDA expects to perform a CGMP surveillance inspection of each PET facility once every 2 years on average, but may visit some sites more than once every 2 years when warranted, such as when the site is named in an application for a new type of PET drug product or has undergone substantial change. As part of the drug approval process, a preapproval inspection (PAI) will be performed by the FDA inspector(s) to provide assurance that a PET drug production facility that is named in a drug application is capable of producing the PET drug in accordance with CGMPs and that the submitted application data are reliable, accurate, and complete. Section 5 summarizes the major deficiencies identified by the FDA inspectors during their 2013 and 2014 inspection programs at various PET drug production facilities in the United States.