FAQs: <825> Radiopharmaceuticals

1. 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 term "radiopharmaceutical" and "radioactive drug" are used interchangeably.

Because they contain radioactive materials, radiopharmaceuticals fall under the control of the U.S. Nuclear Regulatory Commission (NRC) or NRC-contracted agreement state agency. Also, because they are prescription drugs, radiopharmaceuticals fall under the control of the U.S. Food and Drug Administration (FDA).

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

No. National Institute for Occupational Safety and Health (NIOSH) definition of hazardous drugs excludes radiopharmaceuticals, which are regulated by the Nuclear Regulatory Commission.

3. What is the purpose of <825>?

The purpose of <825> 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 practices of pharmacy and medicine). <825> 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 that provide assurance of maintaining patient safety while also ensuring the safety of individuals performing these activities.

4. Why and how was <825> developed?

<825> was developed in response to public comments associated with the 2015 proposed revision of <797>, a white paper in 2016 by the Society of Nuclear Medicine and Molecular Imaging, and a 2017 Stakeholders Workshop held by USP, all of which emphasized the unique characteristics of radiopharmaceuticals which make compliance with <797> difficult or impossible.

<825> 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, Health Canada, nuclear pharmacists and a nuclear medicine technologist.

The draft of <825> was made available for public comment in July 2018. Public comments were received through November 2018. The final version addressing all the public comments was released June 1, 2019 with an official date of December 1, 2019.

5. To whom and in what settings does <825> apply to?

<825> applies to all individuals who prepare, compound, dispense or repackage radiopharmaceuticals. Applicable individuals consist of authorized nuclear pharmacists (ANPs), and authorized user (AU) physicians, as well as individuals working under their supervision. This includes, but not limited to, student pharmacists, nuclear pharmacy technicians, nuclear medicine technologists and students and physician residents and trainees.

<825> also applies to all practice settings where radiopharmaceuticals are prepared, compounded, dispensed or repackaged. Practicing settings include state-licensed nuclear pharmacies, federal nuclear pharmacy facilities, but not limited to nuclear medicine departments in hospitals and clinics, nuclear cardiology clinics and other specialty clinics handling radiopharmaceuticals.

6. 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.

7. How do I know what are requirements versus recommendations in <825>?

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

8. 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, other government authorities, and accreditation/credentialing organizations. USP has no role in enforcement.

9. When will General Chapter <825> become official?

Please see the Notice of Intent to Revise.

10. Are the temperatures in <825> 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).

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

Yes. Based on the public comments, changes have been made to <825>. For example, requirements for immediate use preparations have all been presented as new section 3. Immediate Use of Sterile Radiopharmaceuticals. Another example of the change is the time interval for requalification of media fill competency has been increased from 6 months to 12 months. For detailed information on the changes due to public comments, please see the commentary.

12. Is Administration to the patients in the scope of <825>?

No. <825> explicitly states that it does not cover the "administration of radiopharmaceuticals to patients."

13. Is kit-splitting (fractionation) allowed per <825>?

<825> defines standards that must be met if kit splitting is performed. In <825>, kit splitting is defined as the act of dividing the contents of kit vial and transferring aliquots into other containers for storage and subsequent radiolabeling. Section 11.2 states that kit-splitting may be used to meet the 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. See Table 7 for the preparation conditions for sterile radiopharmaceuticals.

14. Why is <825> needed? Have there been published reports of patient harm from mishandled radiopharmaceuticals?

This chapter describes appropriate standards that provide reasonable assurance of maintaining patient safety while also providing reasonable assurance for the safety of individuals performing these activities.

There have been published reports of patient harm form mishandled radiopharmaceuticals. Patel, et al. reported 16 patients who developed hepatitis C virus infections from a contaminated radiopharmaceutical 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.)

15. How do <825> 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 <825>. In other words, nothing in <825> supersedes NRC regulations and RAM license requirements. For example, in Section 2 it 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 "[a]ll 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, <825> balances aseptic handling practices with radiation protection practices to describe appropriate strategies that provide assurance of maintaining patient safety while also ensuring the safety of individuals performing these activities.

16. Do students and trainees need to perform gloved fingertip testing and media fill testing prior to preparing sterile radiopharmaceuticals beyond immediate use?

Yes, section 4.1 states: "Personnel must prove competency, as applicable to their job functions, prior to performing radiopharmaceutical aseptic tasks that are beyond immediate use." Specifically in the media fill section it states: "Media-fill testing is necessary for all personnel who prepare, compound, dispense, and repackage sterile radiopharmaceuticals." Section 4.3 describes the situations when students or visitors do not have to prove competency "Other personnel or visitors (e.g., auditors, regulators, student observers) must comply with garbing SOPs but do not need to prove competency." If the student or trainee will prepare, compound, dispense, or repackage a sterile radiopharmaceutical beyond immediate use (in an ISO class 5 PEC) then they must comply with the aseptic qualifications in section 4 including aseptic technique training, gloved fingertip testing, and media fill testing.

17. Can radiopharmaceuticals be prepared for immediate use if the worker fails the media fill challenge?

Yes, section 3 states: "Does not require personnel to complete the aseptic qualifications as detailed in section 4.1 (e.g., aseptic technique training with documented assessment, media fill challenge, gloved fingertip testing)." so a worker can prepare radiopharmaceuticals for immediate use regardless of the results of their media fill challenge. Nonetheless, some regulatory authorities and accreditors expect documented competency for performance of critical activities, so documentation of training and performance assessment for radiopharmaceutical preparation for immediate use is recommended.

18. Does the media fill proctor need to have specialized or additional training?

Section 4.1 specifies that the media fill challenge will be observed by a "designated person". The designated person is defined as: "One or more individuals assigned to be responsible and accountable for the performance and operation of the radiopharmaceutical processing facility and for personnel who prepare, compound, dispense, and repackage radiopharmaceuticals." The designated person must be appropriately trained in their area of supervision.

19. If a media fill challenge is performed in one facility, does it need to be repeated in every facility the worker works in?

Section 4.1 states "Personnel must prove competency, as applicable to their job functions, prior to performing radiopharmaceutical aseptic tasks that are beyond immediate use. These qualifications may be conducted at a different site if all SOPs are identical for the applicable job function." Media fill testing is one component of competency qualification, so it need not be repeated in every facility the worker works in as long as all SOPs are identical for the applicable job function. Nonetheless, some regulatory authorities and accreditors may require performance of qualification testing at each facility, so personnel are responsible for knowing and following any such requirements.

20. Does the Y-90 microspheres v-vial need to be prepared in an ISO 5 PEC if used beyond 1 hour of preparation?

Yes, intravascular radioactive devices (e.g., radioactive microspheres for intravascular brachytherapy) are supplied as a sterile device and should be handled with appropriate aseptic handling practices to maintain sterility prior to administration. Section 3 states "All components involved (e.g., Tc-99m sodium pertechnetate syringe or vial, final prepared radiopharmaceutical kit vial, diluent vial) must be discarded within one hour of being punctured or after use for a single patient administration, whichever is first." so if the Y-90 microspheres are not used within 1 hour of the first puncture of the vial they will need to be discarded. If the facility wants to prepare and use the Y-90 microspheres (or any radiopharmaceutical) beyond 1 hour, an ISO 5 PEC in an SRPA is required. See Table 7.

21. Does splitting a unit dose into 2 doses require an ISO 5 PEC?

Yes. See section 3, which states "Dose splitting (splitting a unit dose for administration to more than one patient) may not be performed as immediate use; if performed, dose splitting must be performed in an ISO class 5 PEC in either an SRPA or in an ISO class 8 or better buffer area."

22. If the "bulk" Tc-99m pertechnetate vial obtained for contingency usage is used to prepare a radiopharmaceutical for immediate use, can it be saved for additional patient studies?

No, see Section 3, which states "All components involved (e.g., Tc-99m sodium pertechnetate syringe or vial, final prepared radiopharmaceutical kit vial, diluent vial) must be discarded within one hour of being punctured or after use for a single patient administration, whichever is first." Therefore, any residual content of all vials utilized must be discarded after 1 hour so it cannot be saved for additional patient studies.