ACMUI Sub-Committee Report on Ge-68/Ga-68 Generator Licensing Guidance, Final Report, 8/25/16 

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Nuclear Regulatory Commission (NRC) 

Advisory Committee on the Medical Use of Isotopes (ACMUI) 

Sub-Committee on

Germanium-68/Gallium-68 Generator Licensing Guidance 

Sub-Committee Members: 

Mr. Frank Costello 

Dr. Sue Langhorst 

Dr. Darlene Metter 

Dr. Christopher Palestro 

Dr. Pat Zanzonico (Chair)

Final Report: August 25, 2016 

Introduction 

The Unites States Food and Drug Administration (FDA) recently approved a gallium-68 (Ga-68) 

radiopharmaceutical, Ga-68-DOTATATE, for diagnostic imaging by positron emission tomography 

(PET) of somatostatin receptor-positive tumors. In contrast to most positron-emitting radioisotopes, 

Ga-68 can be produced by a radionuclide generator, the germanium-68/gallium-68 (Ge-68/Ga-68) 

generator, rather than a cyclotron. The Nuclear Regulatory Commission (NRC) in conjunction with 

Agreement-State representatives has drafted guidance to provide applicants with an acceptable 

means of satisfying the regulatory requirements for a license for the use of a Ge-68/Ga-68 generator 

for producing Ga-68 to be used in the preparation of Ga-68-labeled radiopharmaceuticals. The 

NRC Advisory Committee on the Medical Use of Isotopes (ACMUI) subsequently convened a SubCommittee to review and comment on this Licensing Guidance; this document represents the SubCommittee’s report on this Guidance. In this report, relevant sections of 10 CFR35 are included in 

an Appendix. 

Background

Neuroendocrine tumors (NETs) present a difficult diagnostic challenge in clinical oncology. For 

example, by conventional methods it currently takes on average seven years for definitive diagnosis 

of and delivery of appropriate therapy to a NET. The FDA recently approved NetspotTM1

, a sterile, 

single-dose kit for preparation of Ga-68-DOTATATE (or DOTA-octreotate) injection for 

intravenous use. Ga-68-DOTATATE is the first approved radiopharmaceutical among a new class 

of agents for diagnostic imaging of NETs2

. It consists of the positron-emitting radioisotope Ga-68 

 

1

 NetspotTM Package Insert. NETSPOT (kit for the preparation of gallium Ga68 dotatate injection) for 

intravenous use, Reference ID: 3939719. Manufactured by Gipharma Srl (Saluggia (Vc), Italy), Distributed 

by Advanced Accelerator Applications USA, Inc (New York, NY), June 2016. 

2

 Breeman WAP, De Blois E, Sze Chan H, Konijnenberg M, Kwekkeboom DJ, Krenning EP. 68Ga-labeled DOTApeptides and 68Ga-labeled radiopharmaceuticals for positron emission tomography: Current status of research, clinical 

applications, and future perspectives. Sem Nucl Med 41: 314–321, 2011. 
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labeled, via the DOTA3 chelator, to the somatostatin receptor (SSR)-binding peptide octreotate. 

The important diagnostic advantages of such agents are illustrated in Figure 14

, juxtaposing images 

of indium-111 (In-111)-DTPA5-octreotide (In-111-octreotide)6 (left panel) and Ga-68-DOTATOC 

(or (DOTA0

-Phe1-Tyr3)octreotide)7,8 (right panel). Until the approval of NetspotTM and Ga-68-

DOTATATE, In-111-octreotide was the only available radiopharmaceutical for diagnostic imaging 

of NETs. Ga-68-labeled SSR-binding agents compared to In-111-octreotide imaging clearly 

provide superior sensitivity and superior spatial and contrast resolution. Further, Ga-68-DOTATOC 

and-DOTATATE not only provide more favorable radiation dosimetry (with effective doses of 2.3 

mSv versus 11 mSv, respectively, for Ga-68 and In-111) but are also more convenient for patients 

than In-111-octreotide, allowing same-day imaging rather than adding a second visit for imaging at 

24 hours after radiopharmaceutical injection. The introduction of Ga-68-DOTATATE will thus 

result in far more reliable and more convenient diagnosis and more timely treatment of NETs. 

 

3

 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 4

 Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, Kovacs P, Von Guggenberg 

E, Bale R, Virgolini IJ. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: Comparison with 

somatostatin receptor scintigraphy and CT. J Nucl Med 48: 508-518, 2007. 5

 diethylenetriaminepentaacetic acid 

6

 Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging. Sem Nucl Med 32: 84–91, 2002 7

 DOTATOC is a structural analog of DOTATATE with a slightly lower binding affinity for the SSR. 8

 Bushnell DL, O'Dorisio TM, O'Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, Baulieu, JL, Borson-Chazot F, 

Anthony L, Benson AB, Oberg K, Grossman AB, Connolly M, Bouterfa H, Li Y, Kacena KA, Lafrance N, Pauwels 

SA). 90Y-Edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncology 28: 1652–1659, 2010. 
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Ga-68 is a short-lived (physical half-life: 68 minutes), positron-emitting radiometal which can be 

produced in a cyclotron or, more commonly, in the Ge-68/Ga-68 generator, similar to the familiar 

molybdenum-99/technetium-99m (Mo-99/Tc-99m) generator. The parent radionuclide, Ge-68, is 

relatively long-lived (physical half-life: 271 days) and therefore this generator can, in principle, 

provide Ga-68 for an extended period of time in excess of 1 year; in practice, however, the shelf-life 

of such generators is currently specified as 1 year from the date of calibration9

. Further, through 

chelation chemistry, Ga-68 can be used to radiolabel a wide variety of antibodies and antibody 

fragments as well as peptides and thus can provide PET radiopharmaceuticals with broad 

applications beyond NETs10. The potential impact of the Ge-68/Ga-68 generator in molecular 

imaging therefore is significant and the timely dissemination of practical regulatory guidance for the 

licensing and safe use of these generators is therefore needed to ensure physician and patient access 

to these new and promising diagnostic radiopharmaceuticals. This led to the development of the 

NRC’s draft Ge-68/Ga-68 Generator Licensing Guidance; the ACMUI review of this Guidance is 

the subject of this Report. 

As with any radionuclide generator such as conventional molybdentum-99/technetium-99m (Mo99/Tc-99m) and strontium-82/rubidium-82 (Sr-82/Rb-82) generators, which are regulated under 10 

CFR 35.20011, the parent radionuclide in the Ge-68/Ga-68 generators, Ge-68, can potentially 

breakthrough when eluting the Ga-68 from the generator. Such breakthrough and the resulting Ge68 contamination of the Ga-68-labeled radiopharmaceutical prepared using the eluate can result in 

avoidable radiation doses to patients receiving the Ge-68-contaminated Ga-68-labeled 

radiopharmaceutical. 10 CFR 35.204 provides permissible concentration limits for parent 

radionuclides for Mo-99/Tc-99m and Sr-82/Rb-82 generators to limit such exposures, but does not 

provide such a concentration limit for Ge-68/Ga-68 generators. As a result, according to the 

License Guidance the use of Ga-68 eluted from a Ge-68 generator to prepare Ga-68 

radiopharmaceuticals for imaging and localization studies must be regulated under 10 CFR 35.1000, 

"Other Medical Uses of Byproduct Material or Radiation from Byproduct Material" rather than 10 

CFR 35.200, “Use of Unsealed Byproduct Material for Imaging and Localization Studies for which 

a Written Directive is Not Required.” It should be emphasized that the additional radiation dose to 

patients resulting from Ge-68 breakthrough when eluting a Ge-68/Ga-68 generator is extremely 

low, as demonstrated by the following analysis. According to Sunderland et al12, Ge-68 

breakthrough is ~0.5 nCi Ge-68/mCi Ga-68. For quantitative elution of 50-mCi generator (i.e, 

elution of 50 mCi of Ga-68), the maximum breakthrough would be 25 nCi = 0.025 μCi Ge-68. 

According to Velikyan et al13, the gender-averaged effective dose for intravenously injected Ge-68 

 

9

 GalliaPharm Pharmaceutical GMP Grade 68Ge/68Ga-Generator: Instructions for Use, Revision 1.4. Eckert 

& Ziegler Radiopharma GmbH, Berlin, Germany, May 27, 2016.

10 Rosch F. 68Ge/68Ga generators and 68Ga radiopharmaceutical chemistry on their way into a new century. J Postgrad 

Med Edu Res 47: 18-25, 2013. 

11 The sections of the Code of Federal Regulations (CFR) cited in this Report are included as an Appendix. 

12 Sunderland J, Dick D, Schultz M, Gordon Watkins G, Sensoy L. Quantitative assessment of Ge068 

breakthrough from a commercial titanium-dioxide based Ge-68/Ga-68 generator. J Nucl Med 54 (Suppl 2): 

1186, 2013. 

13 Velikyan I, Antoni G, Jens Sörensen J, Sergio Estrada S. Organ biodistribution of germanium-68 in rat in 

the presence and absence of [68Ga]Ga-DOTA-TOC for the extrapolation to the human organ and whole-body 

radiation dosimetry. Am J Nucl Med Mol Imaging 3: 154-165, 2013. 
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is 13 μSv/MBq = 0.048 mrem/μCi, yielding a total effective dose of 0.025 μCi • 0.048 mrem/μCi = 

0.0012 mrem. Even if one conservatively assumed a 100-fold greater Ge-68 breakthrough than that 

reported by Sunderland et al., the additional effective dose to the patient would be 0.12 mrem. In 

comparison, the maximum permissible dose to the general public, 100 millirem/year, is 

approximately 10,000-fold greater. The actual Ge-68 activity in the Ga-68 radiopharmaceutical 

preparation would be reduced further by the radiochemical procedure (including the use of guard 

columns to “trap” Ge-68 in the eluate) used for the preparation of the radiopharmaceutical. As 

noted, therefore, the additional radiation dose to a patient from Ge-68 breakthrough would be 

trivial. 

The current breakthrough limit, 0.001%14, listed in the Ge-68/Ga-68 generator specifications is 

perhaps most useful in the context of tracking generator performance, rather than for the evaluation 

of hazard to the patient associated with Ge-68 breakthrough. While it is true, of course, that Ge-68 

breakthrough amounts exceeding the limit would contribute a higher radiation dose to the patient 

than those lower than the specified limit, the foregoing estimation of that dose makes it clear that 

even breakthrough at a relatively large excess above the limit would be inconsequential in terms of 

a possible adverse health effect on the patient. Further, even in the presence of Ge-68 in the eluate 

in amounts exceeding the breakthrough limit, higher activities of Ge-68 in the Ga-68 

radiopharmaceutical preparation itself would likely not result. The aliquot of the Ga-68 eluate that 

is used for breakthrough determination is obtained prior to the generator elution passing through the 

protective guard column and is thereby collected in a manner which yields a breakthrough result 

which actually reflects the current performance. However, the guard column through which the 

eluate passes reduces the amount of Ge-68 present by 80% and thus the actual amount of Ge-68 

administered to the patient as a radiocontaminant in a Ga-68 radiopharmaceutical would be far less 

than the measured Ge-68 breakthrough would suggest. 

Changes to Guidance Considered by the Sub-committee and its 

Recommendations 

General Comments 

Title 

No change is recommended. 

Table of Contents

The Table of Contents should be revised to be consistent with the changes recommended in the 

Specific Comments below. 

Purpose 

No explicit purpose of the Guidance is specified as such (i.e., as the “Purpose”). It is recommended 

that the section entitled, “Licensing Guidance,” be re-named, “Purpose,” and re-located to the 

beginning of the Guidance (i.e., immediately following the Table of Contents). Inclusion of an 

explicit statement such as the following would be particularly helpful, “This Guidance provides 

applicants with an acceptable means of satisfying the requirements for a license for the use of a 

 

14 GalliaPharm Pharmaceutical GMP Grade 68Ge/68Ga-Generator: Instructions for Use, Revision 1.4, Eckert 

& Ziegler Radiopharma GmbH, Berlin, Germany, May 27, 2016. 
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column based Ge-68/Ga-68 generator for producing Ga-68 to be used in the preparation of Ga-68 

radiopharmaceuticals.” 

10 CFR 35.200 versus 10 CFR 35.1000 Use of Ge-68/Ga-68 Generators 

The most problematic aspect of the Licensing Guidance, in the opinion of the ACMUI Subcommittee, is related to clarifying in the guidance that the regulation of Ge-68/Ga-68 generators 

used for production of Ga-68 radiopharmaceuticals is under 10 CFR 35.1000 and that the medical 

use of the Ga-68 radiopharmaceuticals remains under 10 CFR 35.200. Specifically, the Subcommittee is concerned that the scope of the current Licensing Guidance, which appears to be 

restricted to Section 35.200 and 35.1000 licensees, is too narrow because it does not explicitly apply 

to commercial nuclear pharmacies, since such entities are regulated under Part 32 (specifically CFR 

32.72) rather than Part 35. The Sub-committee therefore recommends clarification of what, exactly, 

is regulated under 10 CFR 35.200 and 10 CFR 35.1000, respectively. It is only the Ge-68/Ga-68 

generators, it appears, which are regulated under 10 CFR 35.1000, while Ga-68 

radiopharmaceuticals are regulated under 10 CFR 35.200. It should therefore be stated that 

regulation of Ga-68 radiopharmaceuticals under 10 CFR 35.200 applies to patient dosages obtained 

from appropriately trained authorized users (AUs) or authorized nuclear pharmacists (ANPs) within 

a medical facility as well as from commercial nuclear pharmacies. Accordingly, the Sub-committee 

recommends revision of the passage in lines 73-84 on page 2 of the Licensing Guidance, including 

the section entitled, “Commercial Nuclear Pharmacy Use under 10 CFR 30.33,” as follows. 

Use of Ga-68 Radiopharmaceuticals

Please note that licensees that use unit dosages of Ga-68 

radiopharmaceuticals for medical imaging and localization studies will 

be regulated under 10 CFR 35.200 and authorized users (AUs) must 

comply with the requirements of 10 CFR 35.290. The licensee may use 

a Ga-68 radiopharmaceutical that is prepared from the elution of a Ge68/Ga-68 generator for medical use for imaging and localization studies 

that is either: 

1) Obtained in a manner described in 10 CFR 35.200 (c) or (d); 

2) Obtained from a manufacturer or preparer licensed under 10 

CFR 32.72 or equivalent Agreement State requirements and has 

made commitments as described in this guidance; or, 

3) Prepared by an authorized nuclear pharmacist (ANP); a 

physician who is an AU who meets the requirements of this 

license guidance and the requirements specified in 10 CFR 

35.290, or 10 CFR 35.390 and 10 CFR 35.290(c)(1)(ii)(G); or 

an individual under the supervision, as specified in 10 CFR 

35.27, of the ANP or the physician who is an AU and have 

made commitments as described in this guidance. 
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Licensees that use cyclotron-produced Ga-68 radiopharmaceuticals for 

medical imaging and localization studies will be regulated under 10 

CFR 35.200 and AUs must meet 10 CFR 35.290. 

The foregoing recommendations thus generalize and clarify the Licensing Guidance, making it 

applicable both to commercial nuclear pharmacies and to medical facilities. Ga-68 can be used to 

radiolabel a wide variety of antibodies and antibody fragments as well as peptides and thus provide 

broadly applicable PET radiopharmaceuticals. The potential impact of the Ge-68/Ga-68 generator 

on molecular imaging is therefore significant and would potentially be delayed and otherwise 

undermined without these clarifications. 

Specific Comments 

Pg 2 Lines 54-61 This passage should be revised as follows. 

Use of Ge-68/Ga-68 Generators 

Recently, the FDA approved a gallium-68 (Ga-68) 

radiopharmaceutical for diagnostic imaging of somatostatin 

receptor (SSR)-positive neuroendocrine tumors. Ga-68 is a 

positron emitter which allows Ga-68 radiopharmaceuticals 

to be imaged using positron emission tomography (PET) in 

a manner similar to fluorine-18 (F-18) 

radiopharmaceuticals. Ga-68 produced in a cyclotron, like 

F-18, may be used to produce Ga-68 radiopharmaceuticals 

for use under 10 CFR 35.200. However, unlike F-18, Ga68 can also be produced from the elution of a Ge-68/Ga-68 

generator to prepare Ga-68 radiopharmaceuticals. As such, 

the Ge-68/Ga-68 generator eluate generally cannot be used 

directly in patients for imaging, but only as a precursor for 

the preparation of Ga-68-labeled radiopharmaceuticals. 

Pg 2 Line 69 The word, “present,” should be changed to, “specified.” 

Pg 2 Lines 69-70 The phrase, “..., the use of Ga-68 eluted from a Ge-68 generator...,” 

should be changed to, “...the use of a Ge-68 generator...” 

Pg 3 Lines 96 The word, “applicable,” should be inserted between the words, “the” and 

“general.” 

Pg 3 Lines 98-111 This entire section, entitled, “General,” has been re-located to the section 

now entitled, “Use of Ga-68 Radiopharmaceuticals,” and therefore should 

be removed from this location in the Guidance. Note that the phrase, 

“Except for quantities that require a written directive under 10 CFR 

35.40(b),...,” in Line 101 has been eliminated altogether, since Ga-68 

will not be used therapeutically and therefore its use will not require a 

written directive. 
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Pg 4 Line 133 The term, “(ANPs)” should be changed to, “authorized nuclear 

pharmacists (ANPs).” 

Pg 4 Line 142 The phrase, “...or an ANP,” should be appended to the end of this line. 

 The statement, “Identify each ANP and provide documentation of their 

training and experience in accordance with 10 CFR 35.55,” should be 

inserted as a separate paragraph immediately after Line 142. 

Pg 4 Lines 144-145 This statement should be revised as follows, “Identify each AU and 

provide documentation of their training and experience in the use of Ge68/Ga-68 generators for preparation of Ga-68 radiopharmaceuticals for 

imaging and localization studies. 

Pg 4 Lines 147-148 This statement should be revised as follows, “The physician should be 

considered qualified for use of the Ge-68/Ga-68 generators to prepare Ga68 radiopharmaceuticals if the licensee demonstrates that the individual 

meets the following.” 

Pp 4-5 Lines 156-204 This passage should be revised as follows. 

4) Meets the criteria under 10 CFR 35.290, “Training 

for imaging and localization studies;” 

AND 

5) Has completed the following training in the use of a 

Ge-68/Ga-68 generator for producing Ga-68 

radiopharmaceuticals for 35.200 use: 

a. elution and quality control procedures needed to 

determine Ga-68 activity and Ge-68 breakthrough 

levels appropriate for the preparation of 

radiopharmaceuticals for imaging and localization 

studies; 

b. measuring and testing the eluate for radionuclidic 

purity; and 

c. safety procedures for the use of the Ge-68/Ga-68 

generator. 

 Note that the foregoing revision elimination the enumeration of the actual 

training and experience requirements originally included in the Licensing 

Guidance. Even in the unlikely event that a medical facility only used 

Ga-68 radiopharmaceuticals, explicitly referencing the training and 

experience requirements pursuant to 35.200 would be unambiguous. 

Pg 5 Lines 208-209 This passage should be revised as follows. 
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Training for individuals others than AUs and ANPs 

The applicant shall commit to provide training in the 

licensee’s procedures to all individuals involved in Ge68/Ga-68 generator use for the production of Ga-68 

radiopharmaceuticals for 35.200 use, commensurate with 

the individual’s duties to be performed. This training must 

be provided to all individuals eluting the generator or 

preparing, or measuring the Ga-68 unit dose. 

Pg 5 Lines 211-214 No breakthrough limit for Ge-68/Ga-68 generators has been specified in 

10 CFR 35.204, so what constitutes “appropriate” breakthrough levels 

remains unspecified. If these are the limits specified by the generator 

manufacturer (as stated subsequently in the Guidance), that should be 

stated here as well. 

Pg 6 Line 229 The phrase, “...are used for patients...,” should be changed to, “...are to 

be used for patients...” 

Pg 6 Line 243 What, exactly, is meant by “locations” - different institutions, different 

building within the same institutions, different rooms within the same 

building, or different areas in the same room? 

Pg 7 Lines 279-280 This sentence should be revised as follows, “Survey all areas of licensed 

material use, including the generator storage and kit preparation areas, for 

contamination using a survey instrument each day of use.” 

Pg 7 Lines 280-282 The Guidance should include instructions/recommendations in the event 

that surveys of the Ge-68/Ga-68 generator indicate that it is leaking. 

Pg 7 Lines 285-291 This passage should be revised as follows. 

This guidance may be revised as additional experience is 

gained regarding the use of a Ge-68/Ga-68 generator for 

preparation of Ga-68 radiopharmaceuticals for 35.200 use. 

An applicant initially applying for authorization for use of 

Ge-68/Ga-68 generator under this 35.1000 use may request 

to incorporate into its license a change process similar to 10 

CFR 35.26. Such a change process can allow some future 

changes without the need to amend the license to radiation 

safety programs provided that the change process requires 

the following conditions to be met for revisions to the 

radiation safety program: 
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Pg 7 Lines 293-295 This passage should be revised as follows, “2. the revision is based upon 

NRC’s current guidance for use a Ge-68/Ga-68 generator under 35.1000 

posted on the NRC Medical Uses Licensee Toolkit;...” 

Pg 8 Lines 311-313 This passage should be revised as follows. 

Assay each patient dosage in the dose calibrator (or 

instrument) before administering it (10 CFR 35.63). 

Pg 8 Line 316 The phrase, “...small activity of Ge-68...,” should be changed to, “...a 

small amount of Ge-68 activity...” 

Pg 8 Lines 343-344 This commitment on the part of the Applicant will require a fuller 

explanation once the NRC has finalized this exemption and all of the 

applicable conditions. 

Pg 9 Line 361 The term, “authorization 8”, refers to the information in the table in line 

118 on page 3. That table should be specifically referenced and use the 

term, “Authorization 8”. 

 

Respectfully submitted, August 25 2016, 

Sub-Committee on Germanium-68/Gallium-68 Generator Licensing Guidance, 

Advisory Committee on the Medical Use of Isotopes (ACMUI), 

Nuclear Regulatory Commission (NRC) 

The ACMUI unanimously approved this report during its public teleconference meeting on 

August 10, 2016.
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Appendix: Cited Sections of 10 CFR 32 and 35 

§ 32.72 Manufacture, preparation, or transfer for commercial distribution of radioactive 

drugs containing byproduct material for medical use under part 35 

(a) An application for a specific license to manufacture, prepare, or transfer for commercial 

distribution radioactive drugs containing byproduct material for use by persons authorized pursuant 

to part 35 of this chapter will be approved if: 

(1) The applicant satisfies the general requirements specified in 10 CFR 30.33; 

(2) The applicant submits evidence that the applicant is at least one of the following: 

(i) Registered with the U.S. Food and Drug Administration (FDA) as the owner or operator of a 

drug establishment that engages in the manufacture, preparation, propagation, compounding, or 

processing of a drug under 21 CFR 207.20(a); 

(ii) Registered or licensed with a state agency as a drug manufacturer; 

(iii) Licensed as a pharmacy by a State Board of Pharmacy; 

(iv) Operating as a nuclear pharmacy within a Federal medical institution; or 

(v) A Positron Emission Tomography (PET) drug production facility registered with a State agency. 

(3) The applicant submits information on the radionuclide; the chemical and physical form; the 

maximum activity per vial, syringe, generator, or other container of the radioactive drug; and the 

shielding provided by the packaging to show it is appropriate for the safe handling and storage of 

the radioactive drugs by medical use licensees; and 

(4) The applicant satisfies the following labeling requirements: 

(i) A label is affixed to each transport radiation shield, whether it is constructed of lead, glass, 

plastic, or other material, of a radioactive drug to be transferred for commercial distribution. The 

label must include the radiation symbol and the words "CAUTION, RADIOACTIVE MATERIAL" 

or "DANGER, RADIOACTIVE MATERIAL"; the name of the radioactive drug or its abbreviation; 

and the quantity of radioactivity at a specified date and time. For radioactive drugs with a half life 

greater than 100 days, the time may be omitted. 

(ii) A label is affixed to each syringe, vial, or other container used to hold a radioactive drug to be 

transferred for commercial distribution. The label must include the radiation symbol and the words 

"CAUTION, RADIOACTIVE MATERIAL" or "DANGER, RADIOACTIVE MATERIAL" and an 

identifier that ensures that the syringe, vial, or other container can be correlated with the 

information on the transport radiation shield label. 

(b) A licensee described by paragraph (a)(2)(iii) or (iv) of this section: 
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(1) May prepare radioactive drugs for medical use, as defined in 10 CFR 35.2, provided that the 

radioactive drug is prepared by either an authorized nuclear pharmacist, as specified in paragraph 

(b)(2) and (b)(4) of this section, or an individual under the supervision of an authorized nuclear 

pharmacist as specified in 10 CFR 35.27. 

(2) May allow a pharmacist to work as an authorized nuclear pharmacist if: 

(i) This individual qualifies as an authorized nuclear pharmacist as defined in 10 CFR 35.2, 

(ii) This individual meets the requirements specified in § 35.55(b) and 35.59 of this chapter, and the 

licensee has received an approved license amendment identifying this individual as an authorized 

nuclear pharmacist; or 

(iii) This individual is designated as an authorized nuclear pharmacist in accordance with paragraph 

(b)(4) of this section. 

(3) The actions authorized in paragraphs (b)(1) and (b)(2) of this section are permitted in spite of 

more restrictive language in license conditions. 

(4) May designate a pharmacist (as defined in § 35.2 of this chapter) as an authorized nuclear 

pharmacist if: 

(i) The individual was a nuclear pharmacist preparing only radioactive drugs containing acceleratorproduced radioactive material, and 

(ii) The individual practiced at a pharmacy at a Government agency or Federally recognized Indian 

Tribe before November 30, 2007 or at all other pharmacies before August 8, 2009, or an earlier date 

as noticed by the NRC. 

(5) Shall provide to the Commission: 

(i) A copy of each individual's certification by a specialty board whose certification process has 

been recognized by the Commission or an Agreement State as specified in § 35.55(a) of this chapter 

with the written attestation signed by a preceptor as required by § 35.55(b)(2) of this chapter; or 

(ii) The Commission or Agreement State license, or 

(iii) Commission master materials licensee permit, or 

(iv) The permit issued by a licensee or Commission master materials permittee of broad scope or 

the authorization from a commercial nuclear pharmacy authorized to list its own authorized nuclear 

pharmacist, or 

(v) Documentation that only accelerator-produced radioactive materials were used in the practice of 

nuclear pharmacy at a Government agency or Federally recognized Indian Tribe before November 
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30, 2007 or at all other locations of use before August 8, 2009, or an earlier date as noticed by the 

NRC; and 

(vi) A copy of the State pharmacy licensure or registration, no later than 30 days after the date that 

the licensee allows, under paragraphs (b)(2)(i) and (b)(2)(iii) of this section, the individual to work 

as an authorized nuclear pharmacist. 

(c) A licensee shall possess and use instrumentation to measure the radioactivity of radioactive 

drugs. The licensee shall have procedures for use of the instrumentation. The licensee shall 

measure, by direct measurement or by combination of measurements and calculations, the amount 

of radioactivity in dosages of alpha-, beta-, or photon-emitting radioactive drugs prior to transfer for 

commercial distribution. In addition, the licensee shall: 

(1) Perform tests before initial use, periodically, and following repair, on each instrument for 

accuracy, linearity, and geometry dependence, as appropriate for the use of the instrument; and 

make adjustments when necessary; and 

(2) Check each instrument for constancy and proper operation at the beginning of each day of use. 

(d) Nothing in this section relieves the licensee from complying with applicable FDA, other 

Federal, and State requirements governing radioactive drugs. 

[59 FR 61780, Dec. 2, 1994; 59 FR 65244, Dec. 19, 1994, as amended at 60 FR 324, Jan. 4, 1995; 

67 FR 20370, Apr. 24, 2002; 67 FR 62872, Oct. 9, 2002; 67 FR 77652, Dec. 19, 2002; 71 FR 

15007, Mar. 27, 2006; 72 FR 45150, Aug. 13, 2007; 72 FR 55929 Oct. 1, 2007; 77 FR 43695, Jul. 

25, 2012] 
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§ 35.12 Application for license, amendment, or renewal. 

(a) An application must be signed by the applicant's or licensee's management. 

(b) An application for a license for medical use of byproduct material as described in §§ 35.100, 

35.200, 35.300, 35.400, 35.500, 35.600, and 35.1000 must be made by-- 

(1) Filing an original and one copy of NRC Form 313, "Application for Material License," that 

includes the facility diagram, equipment, and training and experience qualifications of the Radiation 

Safety Officer, authorized user(s), authorized medical physicist(s), and authorized nuclear 

pharmacist(s); and 

(2) Submitting procedures required by §§ 35.610, 35.642, 35.643, and 35.645, as applicable. 

(c) A request for a license amendment or renewal must be made by-- 

(1) Submitting an original and one copy of either-- 

(i) NRC Form 313, "Application for Material License"; or 

(ii) A letter requesting the amendment or renewal; and 

(2) Submitting procedures required by §§ 35.610, 35.642, 35.643, and 35.645, as applicable. 

(d) In addition to the requirements in paragraphs (b) and (c) of this section, an application for a 

license or amendment for medical use of byproduct material as described in § 35.1000 must also 

include information regarding any radiation safety aspects of the medical use of the material that is 

not addressed in Subparts A through C of this part. 

(1) The applicant shall also provide specific information on-- 

(i) Radiation safety precautions and instructions; 

(ii) Methodology for measurement of dosages or doses to be administered to patients or human 

research subjects; and 

(iii) Calibration, maintenance, and repair of instruments and equipment necessary for radiation 

safety. 

(2) The applicant or licensee shall also provide any other information requested by the Commission 

in its review of the application. 

(e) An applicant that satisfies the requirements specified in § 33.13 of this chapter may apply for a 

Type A specific license of broad scope. 

[67 FR 20370, Apr. 24, 2002; 67 FR 62872, Oct. 9, 2002] 
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§ 35.63 Determination of dosages of unsealed byproduct material for medical use. 

(a) A licensee shall determine and record the activity of each dosage before medical use. 

(b) For a unit dosage, this determination must be made by— 

(1) Direct measurement of radioactivity; or 

(2) A decay correction, based on the activity or activity concentration determined by— 

(i) A manufacturer or preparer licensed under § 32.72 of this chapter or equivalent Agreement State 

requirements; or 

(ii) An NRC or Agreement State licensee for use in research in accordance with a Radioactive Drug 

Research Committee-approved protocol or an Investigational New Drug (IND) protocol accepted by 

FDA; or 

(iii) A PET radioactive drug producer licensed under § 30.32(j) of this chapter or equivalent 

Agreement State requirements. 

(c) For other than unit dosages, this determination must be made by— 

(1) Direct measurement of radioactivity; 

(2) Combination of measurement of radioactivity and mathematical calculations; or 

(3) Combination of volumetric measurements and mathematical calculations, based on the 

measurement made by: 

(i) A manufacturer or preparer licensed under § 32.72 of this chapter or equivalent Agreement State 

requirements; or 

(ii) A PET radioactive drug producer licensed under § 30.32(j) of this chapter or equivalent 

Agreement State requirements. 

(d) Unless otherwise directed by the authorized user, a licensee may not use a dosage if the dosage 

does not fall within the prescribed dosage range or if the dosage differs from the prescribed dosage 

by more than 20 percent. 

(e) A licensee shall retain a record of the dosage determination required by this section in 

accordance with § 35.2063. 

[72 FR 55931, Oct. 1, 2007] 
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§ 35.200 Use of unsealed byproduct material for imaging and localization studies for which a 

written directive is not required. 

Except for quantities that require a written directive under § 35.40(b), a licensee may use any 

unsealed byproduct material prepared for medical use for imaging and localization studies that is— 

(a) Obtained from: 

(1) A manufacturer or preparer licensed under § 32.72 of this chapter or equivalent Agreement State 

requirements; or 

(2) A PET radioactive drug producer licensed under § 30.32(j) of this chapter or equivalent 

Agreement State requirements; or 

(b) Excluding production of PET radionuclides, prepared by: 

(1) An authorized nuclear pharmacist; 

(2) A physician who is an authorized user and who meets the requirements specified in § 35.290, or 

35.390 and 35.290(c)(1)(ii)(G); or 

(3) An individual under the supervision, as specified in § 35.27, of the authorized nuclear 

pharmacist in paragraph (b)(1) of this section or the physician who is an authorized user in 

paragraph (b)(2) of this section; 

(c) Obtained from and prepared by an NRC or Agreement State licensee for use in research in 

accordance with a Radioactive Drug Research Committee-approved protocol or an Investigational 

New Drug (IND) protocol accepted by FDA; or 

(d) Prepared by the licensee for use in research in accordance with a Radioactive Drug Research 

Committee-approved application or an Investigational New Drug (IND) protocol accepted by FDA. 

[67 FR 20370, Apr. 24, 2002, as amended at 68 FR 19324, Apr. 21, 2003; 69 FR 55738, Sep. 16, 

2004; 70 FR 16363, Mar. 30, 2005; 71 FR 15009, Mar. 27, 2006; 72 FR 55932 Oct. 1, 2007] 
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§ 35.290 Training for imaging and localization studies. 

Except as provided in § 35.57, the licensee shall require an authorized user of unsealed byproduct 

material for the uses authorized under § 35.200 to be a physician who— 

(a) Is certified by a medical specialty board whose certification process has been recognized by the 

Commission or an Agreement State and who meets the requirements in paragraph (c)(2) of this 

section. (The names of board certifications which have been recognized by the Commission or an 

Agreement State will be posted on the NRC's Web page.) To have its certification process 

recognized, a specialty board shall require all candidates for certification to: 

(1) Complete 700 hours of training and experience in basic radionuclide handling techniques and 

radiation safety applicable to the medical use of unsealed byproduct material for imaging and 

localization studies as described in paragraphs (c)(1)(i) through (c)(1)(ii)(G) of this section; and 

(2) Pass an examination, administered by diplomates of the specialty board, which assesses 

knowledge and competence in radiation safety, radionuclide handling, and quality control; or 

(b) Is an authorized user under § 35.390 and meets the requirements in § 35.290(c)(1)(ii)(G), or 

equivalent Agreement State requirements; or 

(c)(1) Has completed 700 hours of training and experience, including a minimum of 80 hours of 

classroom and laboratory training, in basic radionuclide handling techniques applicable to the 

medical use of unsealed byproduct material for imaging and localization studies. The training and 

experience must include, at a minimum- 

(i) Classroom and laboratory training in the following areas— 

(A) Radiation physics and instrumentation; 

(B) Radiation protection; 

(C) Mathematics pertaining to the use and measurement of radioactivity; 

(D) Chemistry of byproduct material for medical use; 

(E) Radiation biology; and 

(ii) Work experience, under the supervision of an authorized user who meets the requirements in §§ 

35.57, 35.290, or 35.390 and 35.290(c)(1)(ii)(G), or equivalent Agreement State requirements, 

involving— 

(A) Ordering, receiving, and unpacking radioactive materials safely and performing the related 

radiation surveys; 
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(B) Performing quality control procedures on instruments used to determine the activity of dosages 

and performing checks for proper operation of survey meters; 

(C) Calculating, measuring, and safely preparing patient or human research subject dosages; 

(D) Using administrative controls to prevent a medical event involving the use of unsealed 

byproduct material; 

(E) Using procedures to safely contain spilled radioactive material and using proper 

decontamination procedures; 

(F) Administering dosages of radioactive drugs to patients or human research subjects; and 

(G) Eluting generator systems appropriate for preparation of radioactive drugs for imaging and 

localization studies, measuring and testing the eluate for radionuclidic purity, and processing the 

eluate with reagent kits to prepare labeled radioactive drugs; and 

(2) Has obtained written attestation, signed by a preceptor authorized user who meets the 

requirements in §§ 35.57, 35.290, or 35.390 and 35.290(c)(1)(ii)(G), or equivalent Agreement State 

requirements, that the individual has satisfactorily completed the requirements in paragraph (a)(1) 

or (c)(1) of this section and has achieved a level of competency sufficient to function independently 

as an authorized user for the medical uses authorized under §§ 35.100 and 35.200. 

[67 FR 20370, Apr. 24, 2002, as amended at 68 FR 19324, Apr. 21, 2003; 69 FR 55738, Sep. 16, 

2004; 70 FR 16364, Mar. 30, 2005; 71 FR 15009, Mar. 27, 2006; 72 FR 45151, Aug. 13, 2007; 74 

FR 33905, Jul. 14, 2009] 
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§ 35.1000 Other medical uses of byproduct material or radiation from byproduct material. 

A licensee may use byproduct material or a radiation source approved for medical use which is not 

specifically addressed in subparts D through H of this part if-- 

(a) The applicant or licensee has submitted the information required by § 35.12(b) through (d); and 

(b) The applicant or licensee has received written approval from the Commission in a license or 

license amendment and uses the material in accordance with the regulations and specific conditions 

the Commission considers necessary for the medical use of the material.