As with all compounded sterile preparations (CSPs), radiopharmaceuticals fall under the standards put forth in USP Chapter , and it is up to pharmacy to ensure that both the radionuclides and the non-radioactive medications that are handled, prepared, and stored in the nuclear medicine department meet these standards. While managing compliance of radiopharmaceuticals with requirements presents some unique challenges because of the nature of these drugs, these challenges are quite manageable, and, in fact, are similar in many ways to those faced with hazardous drugs.
Overview of Radiopharmaceuticals
Although some radiopharmaceuticals are used as therapeutic agents, the vast majority is used for diagnostic purposes. A diagnostic radiopharmaceutical contains a tracer quantity of product to which the radioactive agent will be attached during the radiolabeling process. Since such a small amount is injected into the patient, unlike other pharmaceuticals, radiopharmaceuticals do not produce physiologic effects in the body.
The artificial radionuclides (also known as radioisotopes) used by nuclear pharmacies to create a radiopharmaceutical are generally produced in a cyclotron or some other particle accelerator, where the stable nucleus of the starting material is bombarded with specific particles (neutrons, protons, electrons, or some combination of these). This causes the nucleus of the starting material (inorganic element) to become unstable; in order to return to stability, it will emit radioactivity. Examples of elements used to emit radioactivity include fluorine (18-F), molybdenum (99-Mo), cobalt (57-Co), iodine (131-I), and xenon (133-Xe).
The type of emission (alpha, beta, or gamma) that is released will determine whether or not the radionuclide will be useful for imaging or treating a patient. A procedure known as tagging combines the radioactive source to a compound that localizes in a specific area of the body; the compound will carry the radionuclide to the targeted organ (eg, brain, heart, or liver). By using a gamma camera, a specific detection device that images gamma radiation, it is possible to detect the emissions given off by the radionuclide and create images of the relative distribution of the radioactive source in the body.1
In most nuclear pharmacies, the nuclear pharmacist is responsible for obtaining the desired radioactive material, either directly from a manufacturer, or via an in-house generator system. Depending on the capabilities or available resources within hospitals, some may outsource their need for radiopharmaceuticals from nuclear pharmacies licensed to provide bulk vials of radiopharmaceuticals, which will be used to prepare patient-specific doses.
The most commonly used radionuclide in nuclear medicine procedures is technetium-99m (Tc-99m), which is generated from the decay of molybdenum-99. However, the international supply of technetium has been in short supply for almost two years because of reactor maintenance and fuel conversion procedures at reactors that produce molybdenum-99.
Within the molybdenum-99/technetium-99m generator, molybdenum-99 is adhered to an aluminum column that is heavily shielded in lead. As the molybdenum-99 decays, it forms technetium-99m, which is retained on the column until the generator is milked by passing sterile sodium chloride for injection over the column. The eluate (the solution, now containing the desired radionuclide) is collected in a shielded evacuated vial. After performing quality assurance tests on the eluate, it can be used in the preparation of the final radiopharmaceutical CSPs.
USP Requirements for Radiopharmaceuticals
The section of USP addressing the requirements for radiopharmaceuticals as CSPs is based on specific and detailed recommendations from an advisory panel of nuclear pharmacists. The section clarifies details and exemptions for radiopharmaceutical compounding, especially in regards to microbial contamination risk levels.
Determining the risk level of CSPs prepared in a nuclear pharmacy is one of the most important aspects of the section. Keep in mind that both radionuclides and non-radioactive medications are handled, prepared, and stored in nuclear pharmacies. Table 1 provides a list of common radionuclides and traditional drugs that are prepared and dispensed with their corresponding risk levels.
Radiopharmaceuticals are not batched in the same way as traditional medications because of the half-life of the radionuclides. USP specifies that all drugs have 90% to 110% of their potency to still be stable. So if a drug is exposed to adverse conditions but still retains 90% to 110% of its potency it can be used. All radionuclides have specific half-lives that range from seconds to years. Technetium-99m has a half-life of six hours, meaning that the amount of the radioactive material will decrease by 50% every six hours. A 25-millicurie (mCi) dose of technetium-99m compounded at time zero will only be 12.5 mCi at six hours, 6.25 mCi at 12 hours, etc. Therefore, most radionuclides are prepared and administrated within 18 to 24 hours after compounding.
Radiopharmaceuticals are prepared and handled as either single-dose containers or multiple-dose containers. Radiopharmaceuticals compounded from sterile components in closed sterile containers and with a volume of 100 mL or less for a single-dose injection, or not more than 30 mL taken from a multiple-dose container, shall be designated as, and conform to, the standards for low-risk level CSPs.3 Chapter requires low-risk CSPs to be prepared within an ISO Class 5 primary engineering control. Due to the inherent risks associated with handling radiopharmaceuticals, the ISO Class 5 environment used for aseptically compounded preparations is a specially-designed, lead-lined, negative-pressure vertical airflow hood biological safety cabinet (BSC). Although not all radiopharmaceuticals are classified as hazardous drugs, the engineering controls and work practices are intended to ensure the safety of the CSP as well as protect the operator from exposure to radioactivity, similar to those required when handling hazardous drugs. Several of the radionuclides are volatile and must be handled using engineering controls that exhaust externally out of the building.
The US Nuclear Regulatory Commission’s requirement that radiation exposure for those that handle this material be “as low as reasonably achievable” (known as ALARA) challenged the traditional sterile compounding practices—such as removing or minimizing paper or particle-generating components. The assembly and use of lead brick barriers and berms and the use of absorbent paper, while important for ensuring radiation safety, are known to generate particles and are difficult to properly clean. It was generally believed that it was not possible to achieve the air cleanliness requirements of ISO Class 7 for buffer areas as required in traditional sterile compounding facilities. Exemptions were granted and Chapter now requires that molybdenum-99/technetium-99m generators be stored and eluted in an ISO Class 8 or cleaner air environment that will permit special handling, shielding, and airflow requirements.
Nonetheless, it is possible to place a molybdenum-99/technetium-99m generator within an ISO Class 5 BSC and not require the construction of an ISO Class 8 buffer and ante area if the radiopharmaceuticals in use can be compounded under the low-risk CSP standards with a 12-hour or less BUD criteria. As such, a segregated compounding area can be established with minimized expense.
Despite these exemptions, personnel who handle, compound and/or store radiopharmaceuticals are required to comply with all of the other requirements in the chapter. This includes employee training, aseptic technique assessment via media fills, cleaning, environmental sampling, and documentation.
Safety Regulations for Radiopharmaceuticals
The US Nuclear Regulatory Commission (NRC) is the federal agency responsible for
regulating the safe use of radioactive materials. The areas of focus for the NRC include:
licensing, training requirements, proper use and calibration of equipment, establishment and maintenance of a strong radiation safety program, bioassays, shipping and receipt
of radioactive material, labeling of radioactive material, recordkeeping, and contamination control. The actual regulatory requirements can be found at the agency’s Web site:
The cornerstone of a robust radiation safety program is the idea of ALARA, which stands for “as low as reasonably achievable.” It is a radiation safety principle for minimizing exposure to radiation doses and release of radioactive materials by employing all reasonable methods. ALARA is both a sound safety principle and a regulatory requirement for all radiation safety programs.2
In order to protect radiation workers and the public when dealing with radionuclides,
three primary methods are used: time, distance, and shielding. Time involves minimizing the duration of exposure and, as such, most handling and compounding of radiopharmaceuticals is done as quickly as possible. Distance involves maximizing the distance between the source of radiation and the operator. Shielding involves the use of materials that slow down or block the radioactive emissions of the radionuclides.
Personnel monitoring devices are worn by radiation workers and other staff members at risk for exposure as a means to measure any exposure. Ring badges worn on the finger are very effective as the hand is most likely to be exposed to radiation during the handling, compounding, and storage of radionuclides. Whole body badges are also worn to measure the amount of radiation that the operator receives over time. The NRC has established Annual Radiation Dose Limits, which is expressed as REM, for various parts of the body.
While complying with USP requirements for radiopharmaceuticals is not the same as traditional CSPs, it is a very manageable process, analogous to the practices pharmacy has developed for safely managing hazardous drugs. Once pharmacy develops an understanding of the special requirements for handling these drugs safely, implementing measures to ensure compliance to Chapter is relatively easy and inexpensive. As with traditional drugs, those preparing radiopharmaceuticals should always keep the patient in mind and take great care to ensure the identity, strength, purity, and sterility of this special class of CSPs.
Eric S. Kastango, MBA, RPh, FASHP, is the president, CEO, and owner of Clinical IQ LLC, a provider of customized process and educational strategies for the pharmaceutical, medical device, and health care industries. A member of USP’s Sterile Compounding Committee, he has practiced in the field of both hospital and home care pharmacy since 1980.
Kara Duncan Weatherman, PharmD, BCNP, FAPhA, is assistant professor of nuclear pharmacy at Purdue University. She received her PharmD from Purdue University, and has been a board-certified nuclear pharmacist since 1996.