USP General Chapter <825> Update

June 9, 2022

USP <825> FAQs 

The following are frequently asked questions by our membership regarding USP<825>. The Committee on Radiopharmaceuticals (COR) answered these questions noting that each facility may have their own internal procedures. The USP reviewed these questions and referenced their own corresponding FAQ answers for each. The USP only officially endorses their own FAQ list found on their website.

  1. Are multiple dose calibrator and L-shield setups required?

The fast answer is not unless you prepare tagged RBCs. You would have to clean and disinfect the sleeve and dipper every time you assay a "non-sterile" dose (e.g. re-assaying a dose, assaying a tagged WBC Dose or tagged RBS dose). If you routinely label blood components ( i.e. RBC or WBC), you should consider delegating a separate sleeve  and dipper for these blood product procedures. USP <825> states that dedicated equipment must be used for blood radiolabeling procedures (e.g., L-block, syringe shield, vial shield, forceps, needle re-capper).

If a dedicated dose calibrator is not available, then a means of preventing the blood container(s) from contaminating the dose calibrator or a cleaning and disinfecting procedure with an appropriate product must be used to decontaminate the dipper and liner of the dose calibrator following the radioassay.

  1. Can plastic gowns be used for clean lab coats? 

Yes, plastic gowns or other non-shedding clean frocks can be used as long as you don't wear your patient area lab coat under it.  This may be something that is specified by a particular institution's policy as to what type of garb is considered acceptable.

  1. Does an in-house pharmacy oversee compliance? 

Officially, Yes. The director of pharmacy is responsible for all drugs used in your institution. Often Pharmacy departments will have limited experience with radiopharmaceutical preparations. You should establish collaborative relationships with your Pharmacy department as a resource on current radiopharmaceutical practices that occur in your Nuclear Medicine practice area.

  1. If a commercial radio pharmacy (such as Cardinal Health) prepares the hard-boiled Tc Sulfur Colloid egg for Gastric Emptying exam, for a client, is the client require to have a copy of the "Master Drug Formulation Record" from the radio pharmacy for the patient's health record? 

No.  The pharmacy will have to create a MDF for their internal preparation of the egg mixture. If you are receiving a "unit dose" from the pharmacy, it is no different than any other radiopharmaceuticals that you receive. You will have to still handle this as a non-sterile unit dose in your facility however, so you will need to make sure any handling or manipulations are separate from your sterile preparation area. If this is not possible, you will need to thoroughly clean the area (workstation, dose calibrator etc.) after handling the gastric dose and before handling any other sterile product.

5a. Does dose manipulation (i.e. changing the needle, removing volume, adding volume) require gowning, sterile gloving, and cleaning similar to kit preparation? 

If being prepared as immediate use in ambient air, you just need to follow <825> section 4.4 Hand Hygiene and Garbing for Immediate Use Preparations. Radiopharmaceuticals may be prepared and dispensed as immediate use, and the precautions related to personal hygiene to be followed must include the following:

  • Hand hygiene: Wash hands and arms to the wrists with soap and water or use a suitable alcohol-based hand rub with a time based on institution policies to reduce bioburden on the hands.
  • Garbing: Immediately after hand hygiene, don a clean coat/gown that has not been exposed to a patient or patient care area, and either don sterile gloves or don nonsterile disposable gloves and then disinfect the gloves with 70% sterile isopropyl alcohol (IPA). [NOTE—A different lab coat must be worn to care for a patient than the coat/gown used for radiopharmaceutical preparations.]

See USP FAQ sections regarding immediate use activity and immediate use garbing

5b. What are the steps, in order, for donning/doffing PPE, cleaning etc. for this? 

For immediate use: Wash hands, don clean lab coat, then put on gloves. If non-sterile gloves are used, you must disinfect with 70% sterile Isopropyl alcohol and allow it to dry before preparing the radiopharmaceutical.

6. Our hospital is a few hours from our nuclear pharmacy so we received bulk Tc twice a day. The Pharmacy and I discussed delivering our Tc in multiple syringes to stay in compliance with USP <825>, yet that never happened. When I questioned this I was told they had no instructions on procedures yet from corporate, so we are still getting bulk Tc-99m. Any suggestions or information on a scenario such as this? 

See USP FAQ sections regarding immediate use

USP <825> 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.”

7a. If our physician is adding the lidocaine immediately prior to injection, what would we need to have in place? 

As long as you administer within 1 hour of the addition of the Lidocaine and you follow the hand hygiene, garbing and gloving outlined in USP <825> Section 4.4 this is acceptable.  Even though lidocaine would typically fall under USP <797> (since it is non-radioactive), because of the routine use in nuclear medicine, it was specifically included in USP <825>.

See USP FAQ section regarding immediate use

7b. If our physician is adding the lidocaine to sulfur colloid immediately prior to injection, do we need the ISO Class 5 PEC since it is technically compounding? Or does it fall under immediate use? 

It falls under immediate use.  Addition of lidocaine to sulfur colloid would normally be considered compounding, but it is specifically exempted as immediate use in UPS <825> since it is routinely done in nuclear medicine departments.

See USP FAQ section regarding immediate use

7c. If our physician is adding the lidocaine to sulfur colloid immediately prior to injection, and if it is immediate use, does the physician need to don a clean lab coat and sterile or gloves cleaned with 70% IPA prior to adding the lidocaine, or can he just wear regular gloves?

Yes. They need to follow USP <825> Section 4.4.

See USP FAQ section regarding immediate use

8. Do we need to use a different vial of lidocaine for each of the four syringes, or can the same vial be used? 

As a non radioactive this question falls under the 797 immediate use vial septa penetration restriction (<= 2 per vial).

9. Do you need to wear a separate, designated, lab coat to compound, if a Hot Lab is an “Unclassified Area?" 

Compounding isn’t allowed in a hot lab other than adding a non-radioactive drug like lidocaine to a radiopharm for a single patient and using within 1 hour. See USP <825> Sec. 4.4.

10. Can a single Y-90 dose be split to treat separate areas of the liver? 

As far as USP <825> is concerned, as long as it's for the same patient-yes. However, all manipulations must be done and administered to the patient within 1 hour of the first puncture of the vial if the manipulations are done under the immediate use provision.

11. How often do we need to clean behind the L-block and change the pads behind the L-block? 

The general practice is daily cleaning. Padding should also be changed daily. You should be monitoring for contamination as the day goes on. If blood products are handled, the absorbent material must be changed.

See the USP FAQ Cleaning Section. This answer is not covered in USP <825>. This is outside the scope of 825.

12. I want to know what the cleaning requirements are. How often should we be doing that? Is what we are doing now okay? 

Cleaning requirements are outlined in Table 5 in the USP <825> document.  Since most nuclear medicine departments don't have a primary engineering control (PEC), it can be assumed that most preparation and dispensing in an immediate use situation takes place on the countertop.  The best reference for cleaning would be found in the "work surfaces outside of the PEC" line.

13. Do we need to garb for the cleaning of the sleeve and dipper and changing of items behind the L-block? 

If you are going to manipulate the dose in any way, you have to wear a lab coat that has not been worn in a patient care area. Internal procedures should be developed.

14. We, nuc med techs, have food handlers certification that allows to cook eggs for Gastric Emptying studies. This is an unsterile procedure using sulfur colloid. Why do we still have to follow the guidelines for sterile compounding?

You do not have to follow  aseptic processing procedures but you still have to document that you are compounding an oral diagnostic perpetration in your MBR. See USP <825> Section 11.1 “Compounding non-sterile radiopharmaceuticals.”

15. If we have an on-site generator in the hot lab for emergent kit mixing, does the use of that need to be halted? 

Not necessarily, but if you plan on using one, there potentially will be some modification of your work area to allow for its use.  Table 7 in USP <825> outlines the preparation conditions for sterile radiopharmaceuticals, and radionuclide generators (non-direct infusion) do not require a primary engineering control (PEC) such as an ISO 5 laminar flow hood.  However, there are requirements for secondary engineering controls (SEC).  One method is to create segregated radiopharmaceutical preparation area (SRPA) which also must be shown to meet ISO 8 air quality requirements.  This may be space prohibitive in smaller departments.  It is also possible to keep a generator in a dedicated ISO 5 laminar flow hood and elute in that level of air quality.  If the Tc-99m vial is punctured outside of an ISO 5 environment though, the 1 hour time clock starts as soon as the first puncture occurs, essentially making the elution a single use.

See the USP FAQ SRPA Section

16. If a hot lab does not follow strict USP <797>rules (and is not <797> certified by pharmacy), does it need to follow <825> or need to be certified? 

Yes.  USP <825> will need to be followed for anyone that uses radiopharmaceuticals once it is designated as enforceable by USP.  Now that <825> has been released, it is up to the groups responsible for oversight and safety (perhaps the in-house pharmacy, accreditation agencies, etc.) to determine how it will be enforced until it is designated as an enforceable chapter by USP.  This will occur once USP <797> revision current under review is finalized by USP, as the revised chapter will refer radiopharmaceutical  compounding to USP <825>.

17. Is in-house QC testing for radiochemical purity required for immediate use kit preparation when the package insert is followed? 

See USP<825> FAQ Answer: <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).

18. Do kits have to be QC’d for single use on call within 1 hr. of administration? 

See USP<825> FAQ Answer: <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).

19. Is it okay to use Thallium multi-dose vials without a hood? 

No. This practice is  not allowed under the current USP<797> and is not allowed under USP<825>.

20. Do you have any protocols/schedules/forms for cleaning hotlab? And what is best to clean it with? 

Protocols are best written for your own hot lab configuration.  Daily cleaning with 70% sterile IPA is a good practice.  Weekly or monthly, a sporicidal agent should be used.  It is recommended that all cleaning agents used in ISO 5 PECs are sterile, including bleach. These sporicidal agents may leave behind cleaning solution residues which may require removal with sterile water or sterile 70% IPA after cleaning.  

21. Our hospital Nuc Med Dept gets our radiopharmaceuticals delivered from a pharmacy. Sometimes, however, we get add-ons. Can we still make kits, CCK, ultratag for mugas, etc., behind our L-block in the hot lab or does it have to be under a Laminar flow hood? 

The quick answer is yes-as long as you do it as Immediate Use and follow all the requirements stated in USP<825> for Immediate Use. Remember, the Rule of One (for one patient, administered within 1 hour). As a reminder, CCK is not a radiopharmaceutical and therefore falls under USP<797>.

22. We need to know for certain if chromatography is required for Immediate Use radiopharmaceuticals. Doing tagging QC on kits prepared for stat procedures is time consuming. 

See USP<825> FAQ Answer: <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. Validation of immediate use preparation quality may be established by review of appropriate peer reviewed publications and historical in-house qc data on preparations of immediate use kits as part of an ongoing testing program.

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).

23. I would like to know about the MFR and the compounding record for a simple gastric empty. I am unclear what needs to be done and how often. Do we create an MFR and then make a compound record each time or vice-a-versa? I have looked at MFRs for pharmacy and it is super extensive. We use Ensure, sulfur colloid and that is it. I am confused by all the other info it seems to ask.  

If you are mixing a prepared sulfur colloid dose with food in the hot lab, you will need a MFR.  This is simply a step-by-step protocol on how you make the labeled eggs.  It doesn't need to be quite as extensive as what you may see in other parts of your facility, but you do want to include enough information that someone would be able to prepare the same product by following those instructions and that anyone could go back after administration and be able to follow what you did when preparing the dose.  Make sure you incorporate generic statements for things that you may not know until you receive the dose from the pharmacy, along with a place to document what these values are.  You can use the same MFR template for every dose you prepare, and just fill out the key points each time you make them and keep that document on file in case there is ever an issue.

24. In regard to QC, are we required to QC RBC tagging for Multi Gated Acquisitions (MUGAs) or GI bleeds? If so what, free Tc? What strip? What solvents? 

Package insert quality control for radiolabeled RBC involves taking a small sample of the labeled final product, centrifuging it and comparing activity in the cell button (labeled cells) to the activity in the supernate (free Tc). Follow package insert quality requirements for percentage of activity required to be found  in the labelled cell button (  usual accepted requirement's = >90%).

25. I have been told that nurses can compound KINEVAC(R) in our scan room under USP <797> Immediate Use, apparently without any special garbing or competency on file. Is that an accurate interpretation? 

In general, sterile product competency of the nursing staff should be validated by protocols within the medical facility and are not specific to nuclear medicine.  If the nurse is approved for sterile compounding, they can compound in any area as an immediate use procedure.   If this is not being followed, the facility pharmacy will most often be the group that implements appropriate sterile product training.  Since KINEVAC is a non-radioactive drug, USP<825> does not apply and any handling or manipulation should be done under the USP<797> requirements for your facility.

This question is outside the scope of <825>

26. Please clarify storage requirements for 3-6 ounce bottles of IPA 70%. 

Stock bottles of IPA 70% should be stored per the SDS, formerly, MSDS data sheet that is provided by the manufacturer.  Once the bottle is opened however, it is no longer considered sterile.  Your facility infectious disease department most likely has facility specific requirements in use dating of cleaning supplies which in most cases would apply to the use of these products in the nuclear medicine department as well.

This question is outside the scope of <825>

27. Can you enter the hot lab with a lab coat that has been used around patients? Like when I receive a package, doing surveys and checking doses still in sealed lead pigs etc. Nothing to do with preparation. If yes, can the patient exposed lab coat be hung in the hot lab, while I don a clean one? 

Yes, as long as you are not preparing or handling a radiopharmaceutical.  It is recommended to hang the "dirty" lab coat outside the hot lab.

28. Is it ok for the RSO and/or delivery person (escorted by security) to enter the hot lab without a lab coat during deliveries? 

Yes, as long as these personnel do not enter the direct work area where drug manipulation, preparation, or compounding activities are being performed.

This question is outside the scope of 825

29. Why does USP <825> specify sterile 70% IPA?

See the USP FAQ Cleaning Section. 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

September 1, 2021 Update

USP published revisions to Compounding General Chapters <795> Pharmaceutical Compounding  Nonsterile Preparations and <797> Pharmaceutical Compounding – Sterile Preparations for an extended 150-day public comment period—until January 31, 2022. SNMMI is working to submit comment.

In addition, the USP Compounding Expert Committee (CMP EC) is hosting four Open Forum sessions in September 2021 and January 2022 to discuss questions from interested stakeholders. The CMP EC has also published several informational documents intended to supplement the proposed Chapters and explain the CMP EC’s rationale behind the revisions.

The registration to the open forum sessions can be done by clicking on the links below:

  • <795> Series registration
    • September 8, 2021 | 1:00 – 3:00 p.m. EDT
    • January 12, 2022 | 10:00 a.m. – 12:00 p.m. EDT
       
  • <797> Series registration
    • September 15, 2021 | 2:00 – 4:00 p.m. EDT  
    • January 19, 2022 | 10:00 a.m. – 12:00 p.m. EDT   

Revisions to chapters <795> and <797> reflect public health considerations, scientifically robust approaches, and numerous stakeholder engagement activities. The CMP EC engaged healthcare practitioners, regulators, academicians, and other key stakeholders in various sessions including semi-structured interviews with stakeholders, a small roundtable discussion with invited participants, and a broader open forum discussion. These engagements helped the CMP EC consider a wider range of perspectives to inform the revisions while maintaining scientific rigor and accounting for today’s public health and practice needs.

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SNMMI continues to work closely with the USP to disseminate information. Come back to this webpage for the latest updates from the USP or visit www.usp.org/compounding.

June 1, 2020 Update

The United States Pharmacopeial Convention (USP) has issued the following update:

In accordance with the Rules and Procedures of the 2015–2020 Council of Experts, the Chemical Medicines Monographs 4 (CHM4) Expert Committee is reinstating the official date of General Chapter <825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging, following the resolution of an appeal related to the chapter. The new official date for General Chapter <825> is December 1, 2020. It may be downloaded here.

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The Society of Nuclear Medicine and Molecular Imaging continues to work closely with the USP to disseminate information. Come back to this webpage for the latest updates from the USP.

 

March 12, 2020 Update

The United States Pharmacopeial Convention (USP) has issued the following update:

After thoughtful deliberation and evaluation, the USP Appeals Panel has issued final decisions on the appeals to revisions to General Chapters <795> Pharmaceutical Compounding – Nonsterile Preparation, <797> Pharmaceutical Compounding – Sterile Preparations, and new chapter <825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging, which were published on June 1, 2019.

The final decisions are as follows:

  • The Appeals Panel has granted the appeals to General Chapters <795> and <797> and is remanding the chapters to the Compounding Expert Committee (CMP EC) with the recommendation for further engagement on the issues raised in the appeals.
  • The Appeals Panel has denied the appeal to General Chapter <825> and is encouraging the appellant to submit the narrower request presented at the hearing before the Panel to the Chemical Medicines Monographs 4 Expert Committee (CHM4 EC) as a request for revision.

The impact of these decisions on the appealed chapters is as follows:

  • The currently official versions of <795> (last revised in 2014) and <797> (last revised in 2008) remain official as a result of the remand. Recognizing the public health impact of these standards, USP is committed to further stakeholder engagement through forums, roundtables, and other avenues to gather more input on the issues raised in the appeals. USP and the CMP EC are committed to moving forward in an open, transparent, and balanced manner as soon as practicable to enable the chapters to be finalized and implemented in a timely manner.
  • Due to the denial of the appeal to <825>, the CHM4 EC may reinstate the official date of this new chapter. Based on USP’s Bylaws, the Expert Committee must provide at least another six-month implementation period for this chapter. The CHM4 EC will announce an official date once it is determined. General Chapter <825> will be informational unless otherwise required by a regulatory body.

For more information, please visit the USP Compounding Appeals webpage.

USP shared the final appeals decisions with the appellants earlier today. We encourage you to share the information in this email with your constituents and any other relevant stakeholders. We appreciate your continued engagement and support. If you would like to discuss further, please do not hesitate to reach out to Ravi Ravichandran at  rr@usp.org to schedule a meeting. If you have further questions, please email GC825SL@usp.org.  

 

We remain committed to supporting the quality of and access to compounded preparations.

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The Society of Nuclear Medicine and Molecular Imaging continues to work closely with the USP to disseminate information. Come back to this webpage for the latest updates from the USP.

 

October 4, 2019 Update

The United States Pharmacopeial Convention (USP) is postponing the official dates of several recently revised chapters until further notice.

USP’s Bylaws provide that the date by which conformance with a standard is required shall be postponed while an appeal is pending. They further provide that if a standard is upheld, the date by which conformance is required shall be reestablished so that the period allowed for implementation is not less than that provided for upon original publication of the standard.

In practice, the above provisions mean the following with respect to the compounding chapters currently under appeal:

  • Chapters <795>, <797>, and <825> will be postponed until further notice.
  • None of these chapters will become official on the originally anticipated date of December 1, 2019.
  • Regardless of the outcome of the appeals process, USP would not reestablish an official date for chapters <795>, <797>, or <825> without granting another six-month implementation period, at a minimum.
  • USP cannot predict or project a future official date for any of these chapters at this time, as the appeals process remains actively in progress. 


The Story

On June 1, the U.S. Pharmacopeia (USP) published General Chapter <825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging. This General Chapter provides 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.

Immediately following the inception of <797>, there was widespread recognition within the Nuclear Medicine and Nuclear Pharmacy communities that radiopharmaceuticals were underserved by the founding chapter and specific standards based on the unique characteristics of radiopharmaceuticals were needed. This concern was addressed by the USP by inclusion of some standards for compounded sterile radiopharmaceuticals in the subsequent revisions of <797>, but many felt that this was still inadequate. In 2016 SNMMI developed a White Paper entitled “USP Public Standards for Compounded Sterile Radiopharmaceuticals: Recommendations from SNMMI” which recommended that USP create a separate General Chapter for Radiopharmaceutical Preparation, Compounding, and Dispensing. Subsequently USP held a stakeholders workshop on radiopharmaceutical compounding and thereafter agreed to create this new General Chapter <825> dedicated to radiopharmaceuticals.

The chapter will become official on December 1, 2020, and of that date, affected users are expected to meet its requirements.  Ensuring compliance with the requirements is the responsibility of regulators such as the U.S. Food and Drug Administration, states agencies including boards of pharmacy, and accreditation organizations. USP has no role in enforcement.

USP has updated their website with many resources and a FAQ page which can be accessed below. 

Why It's Important

USP 825 is important for members as it incorporates the specific needs of nuclear pharmacies and nuclear medicine departments in hospitals and clinics and provides the patient safety protection intended by USP.

The new guidance devotes whole sections to the importance of keeping an appropriate environment during the preparation of radiopharmaceuticals, including clean room regimes, hygiene, cleaning equipment, labeling, and air particulate matter monitoring.

Additionally, 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.

It is essential members review and compare the practices and procedures in place in their facility against what is included in the new USP chapter. Items like facility design, competency of staff, and infection control practices are critical areas that might need attention and review.

What SNMMI Is Doing

SNMMI is carefully reviewing the General Chapter. As previously reported, SNMMI submitted comments on the draft chapter in November 2018. Many of SNMMI’s recommendations are included in the newly published chapter. You can read SNMMI’s cover letter here. You can read the detailed line by line submission here.