FAQs: <825> Radiopharmaceuticals

Last updated: May 31, 2019

The following are responses provided by members of the USP Compounding Expert Committee. Responses have been provided for informational purposes only, and should not be construed as an official interpretation of USP text or relied on to demonstrate compliance with USP standards or requirements.

2. What is a radiopharmaceutical?

A radiopharmaceutical (radiopharmaceutical preparation/radioactive drug) is defined as a finished dosage form that contains a radioactive substance in association with one or more ingredients and that is intended to diagnose, stage a disease, monitor treatment, or provide therapy. A radiopharmaceutical includes any non-radioactive reagent kit or radionuclide generator that is intended to be used in the preparation of any such substance. The terms "radiopharmaceutical" and "radioactive drug" are used interchangeably.

Radiopharmaceuticals are controlled by the U.S. Nuclear Regulatory Commission (NRC) or NRC-contracted agreement state agency because they contain radioactive material. In addition, they fall under the control of the U.S. Food and Drug Administration (FDA) because they are prescription drugs.

3. Are radiopharmaceuticals classified as hazardous drugs because of the radiation hazard?

No. The National Institute for Occupational Safety and Health (NIOSH) does not classify radiopharmaceuticals as hazardous drugs. NIOSH will continue to defer to the NRC for current and future radiopharmaceuticals because special handling is already required by NRC.

4. What is the purpose of this chapter?

The purpose of the chapter is to provide uniform minimum standards for the preparation, compounding, dispensing, and repackaging of sterile and non-sterile radiopharmaceuticals for humans and animals that occur as part of state-licensed activities (e.g., the practice of pharmacy and the practice of medicine). The chapter describes facilities and engineering controls, personnel training and qualifications, and procedural standards for processing radiopharmaceuticals in nuclear pharmacies, nuclear medicine areas in hospitals and clinics, and other healthcare settings that utilize radiopharmaceuticals. For sterile radiopharmaceuticals, these standards balance aseptic handling practices with radiation protection practices to describe appropriate strategies to maintain patient safety while also ensuring the safety of individuals performing these activities.

5. Why and how was this chapter developed?

The chapter was developed in response to public comments associated with the 2015 proposed revision of <797>, a white paper published in 2016 by the Society of Nuclear Medicine and Molecular Imaging, and a 2017 Stakeholder Workshop held by USP. All emphasized the unique characteristics of radiopharmaceuticals that make compliance with <797> difficult or impossible.

This chapter was developed by an Expert Panel composed of members from the USP Chemical Medicines 4 Expert Committee (which oversees radioactive drugs), the USP Compounding Expert Committee, FDA and Health Canada, and practicing nuclear pharmacists.

The draft chapter was made available for public comment in July 2018. Public comments were received through November 2018. The final chapter addressing all the public comments is scheduled for release June 1, 2019 with an official date of December 1, 2019.

6. To whom do the standards in General Chapter apply?

The chapter applies to all individuals who prepare, compound, dispense, or repackage radiopharmaceuticals. These individuals consist of authorized nuclear pharmacists (ANPs), and authorized user (AU) physicians, as well as individuals working under their supervision. This includes, but is not limited to, student pharmacists, nuclear pharmacy technicians, nuclear medicine technologists and students, and physician residents and trainees.

The chapter also applies to all practice settings where radiopharmaceuticals are prepared, compounded, dispensed, or repackaged. Practice settings include state-licensed nuclear pharmacies, federal nuclear pharmacy facilities, not limited to nuclear medicine departments in hospitals and clinics, nuclear cardiology clinics, and other specialty clinics handling radiopharmaceuticals.

7. Are radiopharmaceuticals compounded by 503B facilities or conventionally manufactured in FDA-registered drug establishments considered active pharmaceutical ingredients (APIs)?

No. The term "API" refers to a bulk drug substance (pure chemical substance), usually in powder or liquid form, which is intended to be used in compounding. API is distinguished from finished dosage forms. Ingredients or components used for compounding radiopharmaceuticals typically are not API bulk drug substances.

8. How do I know what are requirements versus recommendations in the chapter?

Generally, requirements in a General Chapter are conveyed by use of the terms "must" or "shall". Recommendations are conveyed by use of the terms "should" and "may".

9. What does "official date" mean?

The USP "official date" indicates the date by which affected users are expected to meet the requirements of a particular standard. Ensuring compliance with the requirements of these standards is the responsibility of regulators such as the FDA, states, and other government authorities. USP has no role in enforcement.

10. When will General Chapter become official?

The official date of <825> will be December 1, 2019, which is aligned with the official dates of <795> and <797>.

11. Are the temperatures in the chapter expressed in degrees Fahrenheit or Celsius?

Unless otherwise specified, all temperatures in the USP-NF are expressed in degrees centigrade (Celsius) (see also General Notices 8.180 Temperatures).

12. Can the chapter be adopted before December 1, 2019 in my facility?

Yes. Early adoption of the standard is allowed (see General Notices 3.1 Applicability of Standards).

13. Have there been changes between the proposal in PF44(5) Sep-Oct 2018 and the official version as a result of public comments?

Yes. Based on the public comments, changes have been made to the chapter. For example, requirements for immediate use preparations have all been presented as new section 3. Immediate Use of Sterile Radiopharmaceuticals. Another example of change is that the frequency for requalification of media fill competency has been increased from 6 months to 12 months. For detailed information on the changes made in response to public comments, please see the Commentary.

14. Is administration of radiopharmaceuticals to patients in the scope of the chapter?

No. The intent of the chapter is to provide uniform minimum standards for the preparation, compounding, dispensing, and repackaging sterile and nonsterile radiopharmaceuticals that occur in nuclear pharmacy and the practice of medicine. Administration is out of scope.

15. Is kit-splitting (fractionation) allowed per the chapter?

Yes. Kit splitting is defined in the chapter as the act of dividing the contents of kit vials and transferring aliquots into other containers for storage and subsequent radiolabeling. 11.2 Sterile compounding states that kit-splitting may be used to meet patient need. For example, the contents of a kit vial can be reconstituted with 0.9 % sodium chloride injection and aliquoted into other containers for storage and subsequent radiolabeling. The individual must consider all possible interactions of kit components with these other containers (e.g., container walls, closures), as well as possible alterations in stability (e.g., physical and chemical stability) that may affect radiolabeling yields of performance parameters when determining an appropriate BUD. The Glossary includes definitions for Dose-splitting and Kit-splitting. The chapter allows dose-splitting under certain circumstances. The descriptions of all the requirements for dose-splitting are discussed in sections 3. Immediate use of Sterile Radiopharmaceuticals, and in the Glossary.

16. Why is this chapter needed? Have there been published reports of patient harm from mishandled radiopharmaceuticals?

This chapter describes appropriate strategies to maintain patient safety while also ensuring the safety of individuals performing these activities.

Yes, there have been published reports of patient harm from mishandled radiopharmaceuticals. Patel, et al. reported 16 patients who developed hepatitis C virus infections from contaminated radiopharmaceuticals used in myocardial perfusion studies (Patel PR, et al. Hepatitis C Virus Infections From a Contaminated Radiopharmaceutical Used in Myocardial Perfusion Studies. JAMA. 2006; 296(16):2005-2011.) Moore, et al. reported several patients who developed hepatitis C virus infections from improper handling practices in a nuclear cardiology clinic (Moore ZS, et al. Transmission of Hepatitis C Virus During Myocardial Perfusion Imaging in an Outpatient Clinic. Am J Cardiol. 2011:108;126-132.)

17. How do the chapter requirements interface with NRC regulations and RAM license conditions?

As stated in the Introduction, other regulations (e.g., NRC) must be followed in addition to the standards in the chapter. In other words, nothing in the chapter supersedes NRC regulations and RAM license requirements. For example, Section 2 states: "As per RAM license requirements, individuals must wear body and, as required, extremity dosimeters (e.g., a ring worn on a finger) for long term monitoring of personnel radiation exposure… Any extremity dosimeter must be worn underneath the gloves and must not interfere with proper fit of gloves." As another example, Section 5.7 states: "All RAM users must comply with the conditions specified in their approved RAM license application and regulations, and RAM license conditions may supersede the requirements for environmental controls described in this section." For sterile radiopharmaceuticals, the chapter balances aseptic handling practices with radiation protection practices to describe appropriate strategies to maintain patient safety while also ensuring the safety of individuals performing these activities.