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, 2020.

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; December 1, 2020.

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, <825> does not address if it needs to be repeated in every facility the worker works in. 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.

(“Bulk technetium” is a commonly used name for a container (vial or syringe) supplied from a nuclear pharmacy to a nuclear medicine department or clinic, for use in preparing a radiopharmaceutical for contingency or urgent use. If handled for “immediate use”, the sodium pertechnetate can be used only for a single patient. If desired to be used as a multidose container, the bulk technetium container must be handled in an ISO 5 PEC in a radiopharmaceutical segregated processing area or buffer area along with following the additional requirements for training/competency testing, garbing, gowning, cleaning, environmental monitoring, etc. Hence, most facilities may choose to use “bulk technetium”only as a single-dose container for immediate use for a single patient. Instead of one large container of “bulk” technetium, many facilities find it more appropriate to obtain two or more smaller single-use containers of technetium for contingency use.)

23. What cleaning agents are appropriate for areas potentially contaminated with bodily fluids, e.g., blood?

Specification of particular cleaning agents is outside the scope of <825>. Individual facilities should create internal SOPs to provide training and direction to personnel concerning cleaning, disinfecting, and applying sporicidal agents. Consult product labeling, industrial hygienist, environmental health safety officer, OSHA.gov, or https://www.cdc.gov/infectioncontrol/pdf/guidelines/environmental-guidelines-P.pdf for more information.

24, What PPE should be worn when cleaning with a sporicidal agent?

Specification of a particular PPE is outside the scope of <825>. Individual facilities should create internal SOPs to provide training and direction to personnel concerning cleaning, disinfecting, and applying sporicidal agents as described in section 7. Cleaning and Disinfecting. Consult product labeling, industrial hygienist, environmental health safety officer, OSHA.gov, or CDC.gov for more information.

25. Do gloves need to be sterile?

The use of sterile gloves is dependent on the activity beingperformed. When working within an SRPA or buffer room, Section 4.5 requires sterile gloves to be donned, as wearing sterile gloves reduces the bioburden brought into the SRPA or buffer room. When performing immediate use drug preparation, Section 4.4 states “either don sterile gloves or don nonsterile disposable gloves and then disinfect the gloves with sterile 70% IPA”. Sterile gloves are not required for immediate use.

26. Should gloves be over or under the gown sleeve?

Gloves should be over the gown sleeve per Section 4.5, which states: “Gloves must completely and snugly cover the ends of the gown cuffs so that skin on the wrists and upper hands is completely enveloped.” Users should be reminded that the individual performing the task is considered the highest source of potential particle shedding that can result in microbial contamination.

27. . Is a fume hood or vent hood the same thing as an ISO 5 PEC?

As stated in the glossary a PEC is: “A device or zone that provides an ISO Class 5 air quality environment for sterile processing.” Table 1 specifies the particles in ISO Class 5 air quality to be less than 3520 particles/m3 for the number of particles ≥0.5 µm measured under dynamic operating conditions through the use of high efficiency particle (HEPA) filter. In contrast, a fume hood does not contain a HEPA filter and exhausts volatile chemicals or radioactivity out of the room to protect the operator but does not protect the sterile radiopharmaceutical from bacterial or fungal contamination. Sometimes a fume hood is required by a RAM license, but it cannot be considered a PEC for sterile drug preparation.

28. Can a fume hood be retrofitted into an ISO 5 PEC?

No, because the standard equipment to qualify for an ISO 5 PEC is specialized and cannot be added to an established fume hood setup.

29. Can the area used for radiolabeling food be used for immediate use red cell labeling or other sterile radiopharmaceuticals if cleaned first?

Yes, if the area is used for only one activity throughout the time of handling and then cleaned before it is used for another activity.

Section 3 Immediate Use of Sterile Radiopharmaceuticals states “Area for sterile preparation and/or dispensing must be functionally separate from nonsterile compounding area (e.g., radiolabeling food) during the time of use.”

Section 11.1 Compounding Non-sterile Radiopharmaceuticals states “Areas designated for nonsterile compounding must be cleaned and uncluttered and separated from areas designated for sterile radiopharmaceuticals.”

Section 10.4 Preparation of Radiolabeled Red Blood Cells for Immediate Use states “A dedicated space for blood handling must be designated through the entirety of the blood radiolabeling process. This area must be free from clutter and not used for any other radiopharmaceutical preparation or handling until the completion of cleaning and disinfection.”

30. Can an SRPA be inside a hot lab?

Yes, if the SRPA meets the requirements specified in Section 5 Facilities and Engineering Controls for an SRPA it can be a subsection of the hot lab. Per the definition in the glossary, a hot lab is “Unclassified radiopharmaceutical processing area located within a hospital or clinical site that is only appropriate for immediate use radiopharmaceuticals if there is not an ISO 5 PEC within SRPA located within the area.”

31. Section 5.7 in USP states “All pressure monitoring devices must be tested for accuracy and required performance at least every 6 months.” Does “tested for accuracy and required performance” imply re-certification or re-calibration of the pressure monitoring device itself? What is the protocol if the device can only be re-certified if it is returned to the vendor (meaning out of commission for some time)? Can this requirement be fulfilled by testing the device against a handheld pressure measurement unit?

<825> does not describe how such testing is to be performed. Comparison with a calibrated/certified handheld measuring device could be an acceptable option. The end user should discuss this with the cleanroom certifier.

32. Is QC testing required for radiopharmaceuticals prepared under the immediate use provision?

<825> Section 3 is not fully prescriptive on all factors. In Section 8. Assigning BUD, there is discussion of factors that must be considered in determining BUD, including maintenance of radiochemical purity (which may require studies of QC testing over time), but this would rarely be applicable for Immediate Use. In Section 9. Documentation, it requires that records be maintained for “End product radiochemical and other testing, as applicable, results of preparations, preparations with minor deviations, and compounded preparations.” For some radiopharmaceutical kits, the package insert preparation instructions require QC testing, but for other radiopharmaceutical kits they do not. Section 10.2 Preparation with Minor Deviations includes a requirement for “appropriate in-house QC testing, designed to validate the radiochemical purity of the product for the entirety of the BUD or is supported by appropriate peer-reviewed publications for the minor deviation utilized.”

Apart from <825>, QC testing should be performed as a professional standard of practice (for example, see document from SNMMI; the American College of Radiology and the American Pharmacists Association).

33. If a drug that has biological distribution in its USP monograph is fractionated under the 96- hour compounding standard (Table 7) of what parameters need to be checked before using the fractionated product?

<825> does not specify what quality testing parameters are to be performed for compounded radiopharmaceuticals. As an example, if a user is fractionating a container of a conventionally manufactured, lyophilized drug product, Section 8. Assigning a BUD,states “the individual responsible for the manipulation assigns the BUD based on established testing data, either performed in-house or obtained from peer reviewed literature. Section 8 also states that the BUD is also dependent on maintenance of appropriate quality and purity, including radiochemical purity, radionuclidic purity, and other applicable parameters as specified in individual monographs or as clinically appropriate. In addition section 11.2 states “The individual responsible 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 stability, chemical stability) that may affect radiolabeling yields or performance parameters, when determining an appropriate BUD. Systematic QC testing is required to validate the appropriateness of a particular BUD. If a drug product is compounded with non-sterile components, section 11.3 Sterile Compounding Using a Nonsterile Drug Substance or Components applies

34. Certain imaging protocols require radiopharmaceuticals to be re-assayed in the SRPA or buffer room. How does apply?

This is dependent on the location of the dose calibrator. Section 7.6 Cleaning and Disinfecting Items from Patient Care Areastates “Syringes that have been used in a patient care area must not be brought back into the classified area (e.g., buffer or ante-room) or SRPA for re-assaying or disposal unless the syringe in sealed inside an impervious container (e.g., sealed plastic bag) that is disinfected prior to entry into the classified area or SRPA.” Users should consult their epidemiology/infection control experts for proper application of standards.

35. What are the cleaning and ALARA requirements for unit dose pigs and product vial shields that are received from an outside source (e.g. nuclear pharmacy, manufacturer) before they are further relocated to specific areas (e.g. L-block) within a hot lab for further manipulation?

Radioactive material licensing commitments involve keeping worker exposures within the expectations of ALARA principles. Therefore, ALARA practices should always be considered when dealing with radioactive materials. If the hot lab has no SRPA or PEC, there would be no restrictions or further requirements (e.g. cleaning) before moving the pigs and product vial shields to areas within the hot lab where further manipulation of the radiopharmaceuticals could take place.

36. What are the cleaning and ALARA requirements for the facility’s own unit dose pigs, syringe shields and vial shields that are maintained as part of a hot lab’s inventory (e.g. never returned to a commercial source) before they are relocated to specific areas (e.g. L-block) within a hot lab for further manipulation?

Radioactive material licensing commitments involve keeping worker exposures within the expectations of ALARA principles. Therefore, ALARA practices should always be considered when dealing with radioactive materials.

If the hot lab has no SRPA or PEC, there would be no restrictions or further requirements (e.g. cleaning) before moving the pigs or shields to any specific areas within the hot lab. However, sections 7.6 and 10.4 of the chapter specify that there are cleaning expectations for equipment exposed to patient care areas and/or blood-borne pathogens. Facilities should have their own procedures to account for these relocations.

37. In an outpatient clinic with no associated pharmacy, and therefore no Director of Pharmacy, who is the responsible person for radiopharmaceuticals?

The Authorized User Physician is responsible for radiopharmaceuticals. Section 1. Introduction states: Applicable individuals consist of authorized nuclear pharmacists (ANPs) and authorized user (AU) physicians, as well as individuals working under their supervision.

38. In the broad category of cleaning and disinfecting, section 7.1 states that ONLY the 70% IPA used in the ISO 5 PEC be sterile; however, in section 7.4 it reads to use sterile 70% IPA.

A sterile or nonsterile cleaning and disinfecting agent may be used but if the disinfectant agent is not sterile, the process must be followed with a sterile 70% IPA.

39. If an area in a hospital is designated as “Radiopharmacy”, does it then require a Pharmacy Sterile compounding license and a qualified Pharmacist to be involved with compounding of these products?

Depending on the state, “radiopharmacy” may be used synonymously with “nuclear pharmacy” vis-à-vis licensing by the state board of pharmacy. In a nuclear medicine department or clinic, the common term “hot lab” is used to denote an area for radiopharmaceuticals but is not a pharmacy per se that would require separate licensure from the state board of pharmacy. In either situation, compounding is performed under the supervision of an Authorized User Physician or Authorized Nuclear Pharmacist.

40. Does compounding include radiolabeling of kits according to the package insert?

No, please refer to the Glossary in for USP’s definitions of radiopharmaceutical compounding, preparation, and preparation with minor deviations.

41. Can patient specific doses be prepared for immediate use with contingency Tc-99m sodium pertechnetate?

Yes, allows preparation (including preparation with minor deviations) and/or dispensing that is limited to use for a single patient. Please refer to Section 3. Immediate Use of Sterile Radiopharmaceuticals for more details.

42. For radiopharmaceutical kits prepared under immediate use conditions, must radiochemical purity (RCP) testing be performed?

RCP testing may be fulfilled at the point of care before administration, or through a systematic validation of preparation procedures that ensure RCP. The term Preparation includes not only the process of following the manufacturer’s recommendations, but also includes preparations with deviations from the manufacture’s recommendations. USP Section 10. on Preparation states: “The individual responsible for preparing the radiopharmaceutical(s) must ensure that the final preparation complies with quality and purity specifications throughout the assigned BUD. This includes, as appropriate for the preparation, radionuclidic purity, radiochemical purity (RCP), chemical purity, and physical and chemical properties” (Italics added for emphasis). The FDA approval process is based on labeling instructions directed to maintain stability throughout the “use by” time. Some radiopharmaceuticals approved before 1990 do not have RCP testing mentioned in their product labeling. The physician or pharmacist is responsible for ensuring that the radiopharmaceutical meets the quality and purity intended by the manufacturer and is responsible for documentation as stated in Section 9. Documentation as applicable to the category of preparation. In these situations, the USP monograph or other equivalent testing method used to ensure the stability throughout the BUD should be sufficiently rigorous to allow statistical confidence in the results.

43. Is the BUD limited to one (1) hour or less for immediate use?

Yes, specifies that the BUD for immediate use is one hour. Please refer to Section 3. Immediate Use of Sterile Radiopharmaceuticals and information in Table 7.

44. Is a biosafety cabinet required for xenon?

A biological safety cabinet (BSC) is NOT appropriate for Xenon gas – rather, radioactive gases should be stored and handled in a chemical fume hood or as otherwise described in the facilities specific Radioactive Material (RAM) license.

45. Does a Containment Segregated Compounding Area need to comply with and include a biosafety cabinet or glove box?

A Containment Segregated Compounding Area (C-SCA) is a facility defined in USP Hazardous Drugs — Handing in Healthcare Settings and is not the facility design allowed in .

46. Should the Segregated Radiopharmaceutical Processing Area be positive pressure to comply with USP 825, and include a Biosafety cabinet or Glove box?

A Segregated Radiopharmaceutical Processing Area (SRPA) does not specify pressure differentials; these must comply with conditions described in the facility’s Radioactive Material License. A SRPA must include an ISO 5 PEC (e.g., vertical laminar airflow workbench or Class II Biological Safety Cabinet) for radiopharmaceutical processing activities; a glove box is not acceptable.

47. Should the “Hot Lab” be negative pressure to the Segregated Radiopharmaceutical Processing Area and the corridor?

<825> does not specify pressure differentials for the “hot lab”, Segregated Radiopharmaceutical Processing Area (SRPA), or other non-classified areas; pressure differentials must comply with conditions described in the facility’s Radioactive Material License.

48. Is an anteroom or ante area required for a Segregated Radiopharmaceutical Processing Area?

No, an ante-room is not required for a Segregated Radiopharmaceutical Processing Area (SRPA). An ante-room is only required for entry into a buffer area (sometimes referred to as a cleanroom).

49. For Immediate Use of Sterile Radiopharmaceuticals, it states “All components involved (e.g., Tc-99m sodium pertechnetate syringe or vial, final prepared radiopharmaceutical kit vial, diluent vial) must be discarded within 1 hour of being punctured or after use for a single patient administration, whichever is first.” Instead of “discarded”, can a radioactive component be used for instrument quality control?

Yes. Discarded radioactive material cannot be used for patients, but it may be used for nonpatient use such as instrument testing or as an external imaging source.

50. What cleaning procedures are required for hot labs?

Section 10.4 Radiolabeling of Red Blood Cells for Immediate Use says, “A cleaning and disinfecting procedure with an appropriate agent(s) must be used to decontaminate the area and equipment prior to and after the radiolabeling is complete and all disposable components have been discarded.” Cleaning for other activities performed in the hot lab is outside the scope of . This question falls within the general area of infection control. Each facility should develop and follow appropriate infection control policies and procedures in line with professional practice guidelines and accreditation standards.

51. What cleaning should be performed on equipment used or exposed in a patient care area?

Each facility should develop and follow appropriate infection control policies and procedures in line with professional practice guidelines and accreditation standards with consideration of Section 7.6 Cleaning and Disinfecting Items from a Patient Care Area, which provides information on cleaning and disinfecting items returned to a classified area (e.g., buffer or ante-room) or SRPA.

52. Can heat-treated red blood cells that are subsequently damaged be considered a minor deviation, and can these Tc-99m RBCs be used under the Immediate Use parameters spelled out in section 3?

Yes, heat treatment of red blood cells is considered a minor deviation and can either be assigned a BUD or given as an immediate use if all processes are done within one hour.

53. It is unclear whether nuclear medicine departments in hospitals need to follow USP standards because they are not nuclear pharmacies.

The Introduction section of states “This chapter applies to all practice settings where radiopharmaceuticals are prepared, compounded, dispensed, or repackaged. Practice settings consist of state-licensed nuclear pharmacies, federal nuclear pharmacy facilities, and other healthcare facilities, including, but not limited to: nuclear medicine departments in hospitals and clinics, nuclear cardiology clinics (fixed or mobile), and other specialty clinics.” goes on to state that “This chapter 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 is not limited to, student pharmacists, nuclear pharmacy technicians, nuclear medicine technologists and students, and physician residents and trainees.”

54. Is it permissible to prepare kits utilizing Ge-68/Ga-68 generators outside an ISO Class 5 environment?

As noted in Table 7, a secondary engineering control environment with an ISO 8 total airborne particle count is appropriate for eluting Ge-68/Ga-68 generators. Any Ge-68/Ga-68 generator eluent container or tubing assembly/connections should take place within an ISO Class 5 PEC. Additional manipulations of the product, including but not limited to withdrawing a quality control sample, buffering the preparation, etc., must be performed in an ISO 5 environment.

55. I work in a PET drug manufacturing facility that produces a variety of products under ANDAs, INDs, and RDRC approval. In addition, the half-lives of the PET drugs range from 10 minutes to more than 110 minutes. For short-lived products, a single batch is used for a single patient dose. For longer-lived products, a single batch is used for multiple patient doses. For these scenarios, would you please explain the difference between septum punctures that occur under manufacturing and if they matter for purposes of , especially with regard to the Immediate Use provisions of ? It is stated in the chapter that “[T]his chapter does not apply to manufacturing of approved radiopharmaceuticals (e.g., NDA, ANDA, BLA) in FDA-registered manufacturing establishments or Manufacturing of radiopharmaceuticals as investigational agents (e.g., IND, RDRC). In each of these scenarios, …the further processing and manipulation of the drug product after release falls within the scope of this chapter.”

Punctures made for QC testing are considered pre-manufacturing release and do not apply to <825>

56. For the immediate use category, does the lab coat need to be cleaned dally or does a disposable lab coat need to be used?

In section 4.4, Hand Hygiene and Garbing for Immediate Use Preparation, it states to “…don a clean coat or gown that has not been exposed to a patient of patient care area…” and “a different lab coat must be worn to care for a patient than the coat/gown used for radiopharmaceutical preparation.” Each facility should develop policies and procedures on the use and donning of lab coats or gowns consistent with the provisions of this chapter.

57. Does a facility that produces radiopharmaceuticals not intended for human or animal use need to follow the provisions of ?

No. The Introduction of <825> states, “This chapter is intended to provide uniform minimum standards for the preparation, compounding, dispensing, and repackaging of sterile and nonsterile radiopharmaceuticals for humans and animals that occur as part of state-licensed activities.”

58. Does the “designated person” have to be someone from the pharmacy department?

No. The Glossary defines the Designated Person 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.” It is the facility’s responsibility to choose a qualified individual to serve as the Designated Person. The chapter does not require a specific number of Designated Persons per site or the discipline of the person(s) designated.

59. What is an Expert Panel vs. Expert Committee?

An Expert Panel is an advisory body formed to provide additional expertise on specific compendial topics and to inform the development of standards by an Expert Committee. An Expert Panel develops recommendations for an Expert Committee; an Expert Panel does not vote on standards.

60. What QC testing is required for RP preparation, preparation with minor deviations, and compounding?

Section 10 Preparation states, “The individual responsible for preparing the radiopharmaceutical(s) must ensure that the final preparation complies with quality and purity specifications throughout the assigned BUD.” Section 10.2 Preparation with Minor Deviations further states, “This requires appropriate inhouse QC testing, designed to validate the radiochemical purity of the product for the entirety of the BUD or is supported by appropriate peer-reviewed publication for the minor deviation utilized.”

Section 11.2 Sterile Compounding states, “In some cases, this may require systematic QC testing over time to validate the appropriateness of a particular BUD.” In regard to kitsplitting or fractionation of a conventionally manufactured vial the chapter states, “Systematic QC testing is required to validate the appropriateness of a particular BUD.”

Section 11.3 Sterile Compounding Using a Nonsterile Drug Substance or Components states, “a sterilization procedure and testing described in <85> must be performed. The designated person for compounding is responsible for ensuring that the final preparation complies with pre-established standards or acceptance criteria for identity, quality, and purity, and must consider all possible interactions between the components such as altered chemical stability, radiochemical stability, solubility,or other parameters…in determining the BUD. This may require testing to validate the appropriateness of a particular BUD.”

61. Can an oral Tc-99m sulfur colloid unit-dose be split into multiple syringes for multiple patients for non-sterile compounding (e.g., radiolabeling food) without an ISO 5 PEC?

Non-sterile compounding does not require an ISO 5 PEC. Section 3 Immediate Use of Sterile Radiopharmaceuticals is only for sterile radiopharmaceuticals.

62. Can a unit-dose of technetium-labeled radiopharmaceutical (e.g., Tc-99m sestamibi, Tc-99m tetrofosmin, sterile filtered Tc-99m sulfur colloid) be divided into multiple syringes without an ISO 5 PEC if to be used for one patient and administered within an hour of the division of the dose?

Section 3 allows for:

  • Manipulations for any unit doses (e.g., decreasing the dosage, needle changes) or dispensing for one patient (e.g., withdrawing a dose) is allowed.
  • Must be administered within 1 hour of the first container puncture or exposure of any critical site involved (e.g., syringe tip, needle hub or needle) to ambient air, whichever is first.
  • All components involved (e.g., …diluent vial) must be discarded within 1 hour of being punctured or after use for a single patient administration, whichever is first.”
63. Is a master drug formulation record required to use an FDA-approved radiopharmaceutical for an unapproved use?

Section 9.1 states that an"MFR is required only for a preparation with minor deviations or compounding". Approved and unapproved indications of radiopharmaceuticals relates to the procedure and usage of the drug which is beyond the scope of the preparation or compounding of the drug. An MFR is required if the radiopharmaceutical is prepared with a minor deviation or compounded regardless of whether the indication is approved or not in the FDA prescribing information.

64. What is a minor deviation and who defines it?

<825> defines preparation with minor deviation as: The act of preparing a conventionally manufactured kit with a conventionally manufactured radionuclide with volume, and/or radioactivity, and/or step-by-step deviations from the manufacturers recommended labeling while ensuring that the final preparation maintains appropriate radiochemical and radionuclidic purity for the entirety of the BUD. Examples of minor deviations include, but are not limited to, altering the amount of activity or volume added to the vial, changes in step-by-step operations (e.g., dilute Tc-99m solution after, rather than before, addition to the vial, use of a venting needle or filter), using alternative devices or equipment (e.g., a heating block rather than a hot water bath), and using alternative radiochemical purity testing methods.

This definition is adapted from published FDA Guidance.

65. What are considered cosmetics?

Cosmetics are defined in the Federal Food, Drug, and Cosmetic Act as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance.” [FD&C Act, § 201(i)] It would not be feasible to list all the different types of cosmetics. Section 4.5 Hand Hygiene and Garbing for Buffer Areas and Segregated Radiopharmaceutical Processing Area specifically mentions cosmetics.

66. USP states that “cleaning must be performed in the direction of most to least clean areas”. Does this indicate that you would clean the PEC before the buffer area or SRPA that contains the PEC?

This reference is specific to the individual area involved (i.e., PEC, buffer area, ante room, SRPA). Cleaning should be done to prevent inadvertent contamination of another recently cleaned area. However, the designated person(s) is responsible for making any decision on a facility basis.

67. When should cleaning and disinfecting around a molybdenum-99/technetium-99m generator be performed?

All cleaning activities should be followed according to Table 5. The molybdenum99/technetium-99m generators would fit into “Work Surfaces(s) outside the PEC” or “Storage shelving and storage bins.” Most molybdenum-99/technetium-99m generators have horizontal surfaces that are used frequently during the aseptic elution process. The utilization is more critical than that of storage space. Therefore, the cleaning should be performed daily using ALARA techniques such as extension tools appropriate for the conditions of the generator and of the cleaning and disinfecting materials used. SOPs should reflect current facility practices.

68. Can the blood-collection syringe, containing anticoagulant/settling agent syringe (e.g., heparin/hetastarch), be prepared in an ambient air hot lab for white blood cell radiolabeling?

No; due to BUD requirements. White cell labeling cannot be done under the parameters of immediate use, and appropriate conditions for manipulation of all components are stated in Table 7.

69. When is a CoA required for radiopharmaceutical sterile compounding?

When a sterile radiopharmaceutical compounding activity involves the use of a bulk drug substance (which includes a radionuclide, a ligand, or other substance such as a precursor that becomes an active ingredient in the final radiopharmaceutical), Section 11.3 states that it “must comply with standards of an applicable USP or NF monograph, if one exists, or be a component of an approved drug product. Each bulk drug substance should be manufactured by drug establishments registered with FDA and be accompanied by a valid CoA or equivalent testing procedures.”

70. Why are sterile radioactive intravascular devices such as Y-90 microspheres included in USP ?

USP <825> was written to provide standards for the preparation, compounding, dispensing, and repackaging of radiopharmaceuticals, including all sterile radioactive material that must maintain sterility through manipulations prior to administration. A sterile radioactive product can be a drug or device and may be classified in several ways (e.g., radiopharmaceuticals, radioactive biologics, radioactive unsealed sources, and radioactive devices for intravascular brachytherapy). Since the FDAapproved labeling often does not address the environment for preparation and dispensing, or the appropriate Beyond Use Date (BUD) to be assigned after the manufacturer’s vial has been punctured, USP <825> was written to establish minimum standards for these subsequent processing activities. From a manipulation standpoint, there arguably are no differences between the manipulation of the SIRSpheres Y-90 microspheres device in suspension (expiration time of 24 hours after calibration) and the dispensing of ioflupane I-123 (expiration time of 7 hours after calibration), In-111 DTPA (expiration time of 8 days after calibration), or any other radioactive sterile injection or suspension (e.g., Tc-99m MAA). Each of the referenced products requires appropriate aseptic handling and radiation safety to process the patient dose from the manufacturer’s vial, diluting if necessary, to create a final dose form appropriate for parenteral administration.

71. What is the BUD for sterile intravascular devices?

The post-calibration expiration period for a manufacturer’s product is not the same as a BUD. The BUD is the assigned date and time beyond which the prepared, patient-ready radiopharmaceutical or radioactive product must not be administered, as determined by the designated person (e.g., authorized nuclear pharmacist, authorized user). The assigned BUD for the final dosage form for the patient (i.e., the patient dose, diluted if necessary, in a syringe or vial ready for administration) is determined by the physical environment utilized while handling the sterile radioactive material (see USP <825>, Table 7). If the sterile v-vial is prepared or dispensed in ambient air, such handling must follow section 3 of <825>, related to the immediate use of sterile radiopharmaceuticals, and will have a BUD of 1 hour from the time of puncturing the manufacturer's vial. If the sterile intravascular device is prepared or dispensed in an ISO 5 PEC located in a SRPA or buffer room with an ante room, a longer BUD can be assigned as described in Table 7 of the chapter (i.e., 12 hours, 24 hours, or 96 hours, based on the table’s specific requirements).

72. If a unit dose is dispensed or repackaged from a sterile multi-dose radiopharmaceutical with a preservative (e.g., Tl-201 thallous chloride, Ga-67 gallium citrate) within an ISO 5 PEC in an SRPA or buffer room with ante room does the BUD on the multi-dose vial need to be adjusted after puncturing the vial?

This dispensed or repackaged unit-dose must follow the BUD provisions within Table 7. Once a multi-dose container is punctured, the manufacturer’s expiration date no longer applies; a beyond-use date must be applied. The multidose container with preservative must be used within 28 days unless otherwise specified by the manufacturer-labelling (see Multidose Containers, <659> Packaging and Storage Requirements)

73. Does USP require a certificate of analysis for an FDA approved product if you are preparing with minor deviations or compounding?

Under 9.1 Master Formulation Record it states an MFR is required for a preparation with minor deviations or compounding; examples of data that must be included are name, identity, strength, purity, quality, and quantity of ingredients with validated documentation (e.g., CoA). While a CoA is an example of one type of validated documentation, the Prescribing Information of the FDA approved product is also a valid example.

74. If the external eluent must be punctured prior to the elution, in what environment should this take place (e.g. external HCl, removing volume from a normal saline vial)?

Puncturing and adjusting the volume of an eluent (e.g. normal saline vial, external HCl) must take place in the ISO Class 5 PEC before being used to elute the generator.

75. Is the Designated Person required to sign off on anything, similar to the Quality Assurance Specialist in a manufacturing facility?

Section 14 QUALITY ASSURANCE AND QUALITY CONTROL says, “A designated person must ensure that the facility has formal, written QA and QC programs that establish a system of:

  1. Adherence to procedures,
  2. Prevention and detection of errors and other quality problems,
  3. Evaluation of complaints and adverse events, and
  4. Appropriate investigations and corrective actions.

The SOPs must describe the roles, duties, and training of the personnel responsible for each aspect of the QA program. The overall QA and QC program must be reviewed at least once every 12 months by the designated person. The results of the review must be documented, and appropriate corrective action taken, if needed.” As described, the designated person must document the annual review of the quality assurance and quality control program. This is the only section of the chapter requiring documentation from the Designated Person.