The practice of nuclear medicine has significantly evolved from its modest beginnings in 1946, with over 50 novel FDA-approved radiopharmaceuticals currently available for imaging diagnostics and therapeutic use.1 Today, nearly every hospital’s radiology department has a nuclear medicine unit that receives these unique pharmaceuticals from contracted authorized nuclear pharmacists and their staff. The increasing use of radiopharmaceuticals emphasizes the need for safe practices and standards to minimize the unintended exposure of ionizing radiation to workers, patients, and the environment.

Due to the uniqueness of radiopharmaceuticals and the lack of detail regarding nuclear pharmacy in USP <797>, nuclear medicine professionals have historically experienced difficulty in maintaining compliance with available safety standards (see the TABLE). While current guidance, USP <825>, is not yet compendial, accrediting bodies are expected to actively require compliance with the new USP <825> standard as soon as it becomes enforceable.2 As such, pharmacy should begin to adopt these pending policies for the safety of patients and providers and to ensure future compliance.

Click here to view a larger version of this TABLE.

Key Elements of USP <825>

Due to the exclusion of radiopharmaceuticals in the 2014 revision of USP <795>, several agencies and stakeholders petitioned the United States Pharmacopeial Convention to create a new chapter that met the specific needs of handling radiopharmaceuticals, both sterile and non-sterile. When the Convention asked stakeholders why nuclear medicine was different, the following four reasons were given:3

• Short half-lives: The amount of radioactivity added to a syringe must be mathematically greater than the amount to be administered at the time of the dose due to isotope decay.
• Remote handling: Radioactive materials must be handled with equipment that increases the distance from the operators.
• Radiation shielding: Lead and tungsten shielding must be used to protect the preparer from exposure (See FIGURE 1).
• Electronics: Electronics and computers are needed to detect and measure radiation.

Thus, during the revision process of USP <797>, a new reference chapter was created, USP <825> Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging, that adds an expanded scope and is specific to the nuances of radiopharmaceuticals while also adding the concepts and disciplines of radiation safety.4

There are several key differences between USP chapters <797> and <825>, with the latter focusing on:

• Scope of Practice: USP <825> applies to all individuals who prepare, compound, dispense, or repackage radiopharmaceuticals, both sterile and non-sterile. The practice settings include nuclear medicine departments in hospitals and clinics, nuclear pharmacies, nuclear cardiology clinics, and other specialty clinics.
• Radiation Safety: Among the main differences between the two chapters are the requirements for radiation safety. Although exposure to ionizing radiation cannot be avoided entirely, it can be minimized through a robust radiation safety program. As Low as Reasonably Achievable (ALARA) is the goal for nuclear medicine workers. There are four key elements in achieving ALARA:
  • Time: Radiation exposure is directly proportional to the quantity of radioactive material (RAM) handled and the time spent handling it; therefore, minimizing the handling time will minimize the radiation exposure.
  • Distance: Radiation exposure follows the inverse square law; increasing the distance from radioactive materials will decrease the exposure by the square of the distance. Thus, operators may utilize techniques to increase distance (eg, tongs or other remote handling tools).
  • Shielding: Personnel exposure to radiation decreases with the use of shielding materials, such as lead and tungsten syringe shields and vials shields.
  • Radiation Contamination Control: Radioactive materials contamination, such as spills, drips, sprays, and volatility, is a safety concern, and materials such as disposable absorbent pads that are low-lint are used to contain and quickly remove contamination. In addition, vertical laminar airflow hoods are utilized to ensure that radiative contamination does not blow at the operator.
• Facilities and Environmental Controls: Whereas USP <797> defines a segregated compounding area (SCA) as an area of unclassified air quality with a PEC, USP <825> instead has a segregated radiopharmaceutical processing area (SRPA) with a PEC in ISO class 8 air quality, which is necessary to protect the eluting of the Tc-99m/Mo-99 generators needed to prepare many radiopharmaceuticals.
• Microbiological Air and Surface Monitoring: Whereas USP <797> has microbiological sampling occurring under dynamic or simulated conditions, USP <825> instead suggests that this process occurs after the radiopharmaceutical processing but prior to cleaning and disinfecting. This change aims to better protect the monitoring technicians from being exposed to radioactive materials.
• Cleaning and Disinfecting: After microbiological air and surface sampling has been conducted, radiation safety must be observed before the cleaning and disinfecting of the buffer area and anteroom can occur. This process must include the following steps:
  • First, the absorbent paper in the PEC must be removed and checked for radioactive contamination with a Geiger counter, and any contaminated paper must be placed in an appropriate lead barrel.
  • All surfaces inside and surrounding the PEC must be checked for contamination with a Geiger counter and wipes must be taken and sampled for activity.
  • If contamination is found, it must be thoroughly decontaminated. If the levels of radiation are unacceptable, lead covered in plastic must cover the area for 10 half-lives of the isotope.
• Master Formulation Records: When doses are changed or altered, a master formulation record (MFR) is required. For example, when a diagnosis is needed in cases of diabetic gastroparesis, Tc-99m sulfur colloid is commonly added to scrambled eggs for consumption. The data needed for the MFR includes but is not limited to:
  • Name of the radiopharmaceutical
  • Name, identity, strength, purity, and quality of ingredients
  • Range of radioactivity
  • Range of volume
  • Quality control tests to be performed for final release
  • Reference source for BUD assignment and storage conditions
  • Equipment to be used and detailed procedures
    • For this example, what kind of frying pan is used and what kind of cooking is necessary to make the edible radioactive eggs for the patient to enjoy

Case Study

Cone’s Approach to <825> Compliance

Moses H. Cone Memorial Hospital is a 628-bed facility serving the Greensboro, North Carolina area that sought to achieve USP <825> compliance ahead of the formal adoption of regulations. The first step toward this goal was developing relationships between the pharmacy and nuclear medicine departments. It quickly became apparent that both of the departments had the necessary expertise and experience to employ a cooperative approach toward achieving USP <825> compliance.

A site visit and walk-through of the nuclear medicine hot lab were performed to make initial observations. Next, a broader team was formed to discuss USP <825> and its impact on the organization. External stakeholders were invited to this meeting to provide initial training and education on the new standard. Next, a gap analysis was performed that led to sharing of information between the two departments to aid in compliance. This included policies and procedures, master formulation record examples and templates, standard work for primary engineering control cleaning, hood certification, and garbing. The team developed a formal USP <825> Compliance Guideline for the health system and formulated a USP <825> subcommittee of the Pharmacy & Therapeutics (P&T) committee. Lastly, all existing utilized radiopharmaceuticals were presented to P&T for approval.

As legend drugs, all radiopharmaceuticals used in the nuclear medicine department should be included on the hospital formulary. At Moses H. Cone Memorial Hospital, it was determined that the pharmacy department should be responsible for updating the formulary with the current radiopharmaceutical use. This process involved several key steps:

• Engage with the director of pharmacy to state the intent of bringing the hospital formulary current with radiopharmaceutical use.
• Collaborate with nuclear medicine staff and determine where pharmacy can be involved.
• Submit a formal intent to have radiopharmaceuticals evaluated at the P&T committee.
• Perform USP <825> gap analysis in collaboration with the nuclear medicine department.
  • Start with the list of all FDA-approved radiopharmaceuticals (currently, there are 55 on the market).
  • Compare the list with radiopharmaceuticals used within the organization.
  • Compare the list with the hospital formulary to determine any gaps.
• Form a radiopharmaceutical subcommittee of P&T that contains both nuclear medicine and pharmacy department representation.
  • Membership: We chose to include an imaging specialist (co-chair), a radiologist, the director of radiology, the director of environmental health/radiation safety, and a staff pharmacist (co-chair).
  • Meeting Cadence: This subcommittee has biannual meetings, which are useful to chart the progress being made toward adding new radiopharmaceuticals on formulary and to communicate which ones should be prioritized for addition.

When creating a P&T presentation, analyze the experience of current P&T committee members. Consider adding additional background and context, if the committee does not have familiarity or experience with radiopharmaceuticals. It is important to make the concepts of nuclear medicine relatable. As most radiopharmaceuticals are diagnostic in nature, images can be an effective way to illustrate how the radiopharmaceutical is used.

Future Directions

Efforts toward compliance in advance of the USP <825> official enforcement date allow for the preparation, education, and protection of staff, even while the chapter is only informational. By working toward compliance, pharmacy will gain clarity about the extent of its involvement. While a health system’s department of pharmacy needs to be aware of how dispensing, labeling, and purchasing are performed, carrying out these activities is best left to the nuclear medicine department to execute under their expertise. Overall, USP <825> will help departments of pharmacies better understand what is going on behind the door labeled “Caution–Radioactive”, improving safety for patients and staff.

References

1. Cardinal Health Nuclear Pharmacy Services. FDA-approved Radiopharmaceuticals - Cardinal Health. [White Paper]. Cardinal Health. www.cardinalhealth.com/content/dam/corp/web/documents/fact-sheet/cardinal-health-fda-approved-radiopharmaceuticals.pdf.
2. Cardinal Health Nuclear Pharmacy Services. (2020). Director of Pharmacy and Nuclear Medicine Oversight: An FAQ for the Director of Pharmacy (DOP) [White Paper]. Cardinal Health. www.cardinalhealth.com/content/dam/corp/web/documents/fact-sheet/cardinal-health-usp-825-faqs-dop.pdf.
3. Cardinal Health Nuclear Pharmacy Services. (2019). A New Chapter for Nuclear Medicine: USP <825> addresses the unique challenges of radiopharmaceuticals in a dedicated chapter for the first time [White Paper]. Cardinal Health NPS.
4. USP Chapter <825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging. The United States Pharmacopeia. United States Pharmacopeial Convention; 2019.

Christopher deHoll, PharmD, BCSCP is a sterile products clinical pharmacist at Moses H. Cone Memorial Hospital in Greensboro, North Carolina. He serves as co-chair for the Pharmacy & Therapeutics Radiopharmaceutical Subcommittee.

Kevin Hansen, PharmD, MS, BCPS, BCSCP is the system-wide director of pharmacy at Cone Health, based in Greensboro, North Carolina. He earned his doctor of pharmacy degree from LECOM and completed a PGY1/PGY2 health-system pharmacy administration and leadership presidency program at the University of North Carolina Medical Center.

SIDEBAR

What is a Radiopharmaceutical?

The basis of all safety standards begins with an understanding of the specific needs of nuclear pharmacy. Key to this understanding is the recognition that in its essence nuclear pharmacy is still pharmacy—a nuclear drug acts just like a nonnuclear drug. However, the pharmaceutical part of the radiopharmaceutical is pharmacodynamically inert and has no effect on the human body; its usefulness derives instead from its pharmacokinetic profile.

The radioactive portion of the radiopharmaceutical is the radioisotope. This is the physically unstable atom that is bound to the pharmaceutical that gives the desired effect. Diagnostic radioisotopes emit gamma radiation, which is a penetrating form of ionizing electromagnetic radiation that is similar to X-rays. Like X-rays, gamma radiation travels through and outside the body from the organ of interest in which the radiopharmaceutical has localized and concentrated and is taken up by a gamma scintillation camera (See FIGURE 2). Very little energy is taken up by the body, and the amount that is absorbed is well within safe limits as determined by the Nuclear Regulatory Commission.

A majority of radiopharmaceuticals are diagnostic. The advantage of diagnostic nuclear medicine imaging is not in revealing the structure of the body or an organ, but rather in demonstrating metabolism and perfusion. Diagnostic radiopharmaceuticals are commonly used in cardiology to perform nuclear stress tests. In cases like unstable angina, it is vital to be able to evaluate if the perfusion of the coronary arteries worsens as the heart is stressed and the oxidative need of cardiac tissue increases. Tc-99m sestamibi, Tc-99m tetrofosmin, Tl-201 thallous chloride, and Rb-82 rubidium chloride are used to image the heart’s coronary artery perfusion when at rest and when at stress. Comparing the two sets of images aids cardiologists in determining if a patient’s coronary arteries are acutely occluded and whether reperfusion therapy and surgery will be effective.

One radiopharmaceutical that is essential to cancer imaging is F-18 fludeoxyglucose (FDG), which is sometimes referred to as radioactive sugar. Glucose is taken up quickly by the brain and by any rapidly growing cancer. This is used in positron emission tomography (PET), and these scans can demonstrate the effectiveness of the therapy. Other radiopharmaceuticals that incorporate F-18 as their radioisotope have developed very selective and specific pharmaceutical moieties to image formerly elusive disease states.

Therapeutic radioisotopes emit a particle with energy and mass that slices and destroys cellular DNA, killing the cells and tissue surrounding the radiopharmaceutical. These therapeutic particles are expressed as either beta radiation, which is an emitted electron, or as alpha radiation, which is a helium atom composed of two protons and two neutrons. Alpha radiation is roughly 8,000 times as large as beta radiation.