radiogenix® system overview · 2019-03-14 · •two isomers react in the same way with components...

RadioGenix® System Overview

The RadioGenix® System moves source material and reagents using:

• 5 mL syringe pumps (x2)

• 6-way rotating valves (x3)

• 4-way rotating syringe valves (x2)

• PEEK1 tubing

1 Polyether ether ketone

Copyright 2019. Confidential Property of NorthStar Medical Radioisotopes, LLCv19Sept2018

RadioGenix® System Overview

Primary Separation Cartridge (PSC)

• Cartridge containing ABEC1 resin

• Separates Tc-99m pertechnetate from Mo-99 solution

• Conditioned using reagents to capture and then release Tc-99m pertechnetate

1 ABEC – aqueous biphasic extraction chromatography


• ABEC™-2000, an aqueous biphasic extraction chromatography resin consisting of monomethylated polyethylene glycol (PEG)-2000 covalently bound to a polystyrene support, for its ability to remove pertechnetate

• Developed jointly at Argonne National Laboratory and Northern Illinois University

• Rogers et. Al. 1996. “Aqueous Biphasic Systems as a Novel Environmentally-Benign Separations Technology for Metal Ion Removal"

• The relative “salting-out” ability was reported to depend on ionic charge, hydration radius, and specific interactions between the anion salt and PEG.

75

Aqueous Biphasic Extraction Chromatography (ABEC)

• NorthStar Medical Radioisotopes, LLC RadioGenix® Molybdenum-99/Technetium-99m Generator System Licensing Guidance for Medical Use Licensees, Medical Use Permittees, and Commercial Nuclear Pharmacies

• Existing fission generated Tc-99m falls under 10 CFR 35.200 licensing and 10 CFR 30.33 training

• RGX is licensed under 35.1000 and 10 CFR 30.33• The unique features that differentiate the RGX from a conventional

fission Mo-99/Tc-99m generator results in the need for additional commitments not required for conventional fission Mo-99/Tc-99m generator

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NRC Emerging Technologies and 10 CFR 35.1000

• Only for use by trained personnel

• Authorized Individual

• Certified Trainer

• RSO Training (Radiation safety and emergency procedures)

• System Administer

• Documents:

• RadioGenix PI; NorthStar Medical Radioisotopes, LLC Beloit, WI 90Q03078 Rev 04 (03/2018)

• Illustrated directions in the RGX Operator Guide 94S05058

• Short videos

• Available after training77

Training

Elution Protocol --RFID controls

KOH

H2

O

2

NaOAc

• Peroxide cleaning• Prep PSC for

source load• PSC source load

(multiple)• Prep PSC for

elution• PSC elution• Tc-99m ready• Transfer source• Peroxide cleaning

Reagent Assembly

ToDiscarded Material

Container

P

S

C

Saline

Mo

Tc

T

P

C


RadioGenix® System Elution Overview• Tc-99m Product Cartridge (TPC)

• Alumina column to prevent Mo-99 breakthrough

• 0.22 micron filter to help ensure sterility

> Vented spike to fill sterile vial

• Tungsten Elution Shield

> Shield TPC / vial during removal

> Shield vial during use

AluminaColumn

SterilityFilter

VentedSpike


Port Cap/Swab Cap

ProductVial

Tc-99mProduct

Cartridge(TPC)

USP Saline

Syringe

HydrogenPeroxide Wipe

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Steps for eluting

Radiogenix PI; NorthStar Medical Radioisotopes, LLC Beloit, WI 90Q03078 Rev 04 (03/2018) and illustrated directions in the RGX Operator Guide 94S05058

•Mo-99 Breakthrough

•Aluminum ion Test

•Determination of pH

81

Eluate quality control


82

Kit Preparation

• 30 mCi/mL to 1153 mCi/mL in approximately 5 mL of


RadioGenix® System Initialization Screen

Copyright 2019. Confidential Property of NorthStar Medical Radioisotopes, LLC

RadioGenix® System Software

7 user protocols• Produce Tc-99m • Change Reagent Kit – 10 elutions or

1 week• Sterilize System – weekly• Initialize System – after power up• Remove Source – 14 days• Add Source – 14 days• Exchange Discarded Material

Container – 4 to 16 weeks

v19Sept2018 Copyright 2019. Confidential Property of NorthStar Medical Radioisotopes, LLC

Mo-99 Source Vessel

• Mo-99 Source Kit

• Mo-99 and Tc-99m in 5M potassium molybdate solution

> Source Vessel expiration is 14 days post calibration

• Consumable kit containing components required to connect source to system

• Source expires 14 days post calibration

• Shipped to and from pharmacy in Type A package


Source Vessel

Consumables

Source Vessel

ReusableSource Vessel

Tools

v19Sept2018

Add Source Vessel Kit

Components

Remove Source Vessel Kit Components

Add / Change Reagents Protocol

Reagent kit contains:

• Primary separation cartridge (PSC) with RFID

• Reagent assembly with RFID>Hydrogen peroxide>Potassium hydroxide>Sodium acetate

• Swab caps for cleaning reagent ports

• All component connections sterile

Primary Separation Cartridge (PSC)

Reagent Assembly

Peroxide Wipes


RFID

Sterilize System Protocol

Sterilization kit contains:

• Purge Container

• Air filter

• Blank PSC with RFID

• Sterilization vial

• Blank TPC with RFID

• Sterile Water, USP bag

• Product port cap

• Tube with spike

• Swab caps

BlankTPC

Product PortCap

Tube w/Spike

BlankPSC

AirFilter

Vial

PurgeContainer

Sterile Water, USP

Swab Caps

Peroxide Wipes


Discarded Material Container

• Hydrophilic polymer to absorb fluids from the RadioGenix® System

• Contains trace amounts of source material

• Max capacity of 3.5 L

> System tracks usage and prompts user to exchange DMC

• Used for 4-16 weeks

• Decayed in place for 4-16 weeks

• Can be shipped back to NorthStar as solid Type A Package


TubeDiscarded Material Container

LuerCap

v19Sept2018

89


90

RGX Field Maintenance


• Monthly check-local NorthStar Field Service Engineer • The RGX system expiration is 1-year from date of installation

• NorthStar must perform annual preventative maintenance and recertify the RGX

• The ozone generator expiration is 6-months from installation • NorthStar must replace the ozone generator every 6-months

• Source vessels must be returned to NorthStar• Disposal of waste may be returned to NorthStar

• Elution records are recorded in a QC application report• Exports to NorthStar• First 5,000 elutions or 2-years

• Fluid path bioburden at interim time points and at expiry for 10 sites over 1-year

• Report all locations of occlusions, clog or deposit build up, and leaks for the 10 sites

• Report any elution yields or volumes which are out of tolerance from software estimate for 10 sites 91

FDA Required Surveillance

• Two isomers react in the same way with components of kits

• Early reports of labeling and imaging adversely affected with high ratio of 99 to 99m

• Accepted that ratios > 4:1 or (<25% 99mTc) will have an affect on labeling BUD

• During production, 99/99m ratio depends on the length of the irradiation (<7-days)

• 99/99m ratio is about 14:1 (1.8% to 7% 99mTc)

• Further delays before end of irradiation and 1st elution

• Affected by elution efficiency

• 90% elution efficiency the ratio can be reduced from 5% to 25% in two elutions 92

99Tc/99mTc ratio or 99mTc/99Tc percent

Moore PW. Technetium 99 in generator systems. JNM 1984

• Photon-induced transmutation of enriched molybdenum-100: 100Mo(γ,n)99Mo

• First production tested by NorthStar at RPI in 2008; demonstrated at mCi scale (Harvey 2015)

• Commercial scale capable of producing a SA of Mo99 ~10 Ci/g

• Target material-Stable isotope Mo100

• Low level Class A waste only

• Licensed as an accelerator by WI (Agreement State); no direct NRC role 93

Future Plan is to Produce Mo-99 Via Accelerator

• Domestic supply of non-uranium Mo-99

• Minimal processing & Small RAM waste

• Eliminate expensive processing; subsequent environmental hazards with disposal of other fission products

• Users can influence the radionuclidic content of the eluate by not adhering to the operating instructions

• Manufacturer included design features which minimize the chance of user error

• Divided responsibility that is perfect for the structure of the centralized nuclear pharmacy with skilled staff to handle the alternate separation techniques provided there is cost savings

94

1. Production of molybdenum 99 by neutron bombardment: A. Was never used in commercial generators from

1968 to 1977B. Produces a 1000x higher specific activity than

fission produced molybdenumC. Was abandon in the 70’s for fission produced

molybdenum D. Has higher capital cost and produces more

radioactive waste 95

Assessment Questions

2. The licensee must operate the RadioGenix® Molybdenum-99/Technetium-99m Generator under which NRC category?

A. 10 CFR 35.12B. 10 CFR 35.200C. 10 CFR 35.600D. 10 CFR 35.1000

96


3. The RGX PI limits kit preparation volume to 3 mLs and for certain kits (e.g. exametazime) this volume is limited to 1 mL because:

A. Excess volume of the high specific concentration might result in decomposition from radiolysis

B. Residual 1.5M sodium acetate used to neutralize the separation cartridge also reduces the technetium 99m

C. Residual 3% hydrogen peroxide used to clean the lines might oxidize the reducing agents in the kit

D. Residual 5M potassium hydroxide used as the molybdate solvent might cause precipitants in the kit

97


Annual Meeting & ExpositionSeattle, Washington | March 22-25

98

Annual Meeting & ExpositionSeattle, Washington | March 22-25

What’s New in the Wonderful World of 68Ge / 68Ga Generators?

Neil A. Petry, MS, RPh, BCNP

Associate Professor, RadiologyFaculty, Medical Physics ProgramDirector, Radiopharmacy ServicesDuke University Medical Center

Durham, North [email protected]

• Financial Relationships

• None

100

Disclosures

• At the completion of this knowledge-based presentation, participants will be able to:

1. Identify and explain differences among available 68Ge / 68Ga generators including use restrictions, elution processes, quality control, eluent specifications and maintenance requirements.

2. Recognize differences when comparing available 68Ge / 68Ga generators in terms of eluents used, elution volumes, elution rates, elution processes and useful shelf-life.

3. Explain the requirements for performing the 68Ge breakthrough test and describe a suitable test method.

4. Identify the required 68Ge breakthrough test limits and describe an action plan to be implemented when a test result exceeds this limit.

101

Learning Objectives

1. The following commercially available 68Ge / 68Ga generator(s) have been accepted by the FDA for use in the routine preparation of 68Ga-DOTATATE (NETSPOT®).

A. GalliaPharm® (Eckert & Ziegler) only

B. Galli Eo™ (IRE Elit) only

C. GalliaPharm ® (Eckert & Ziegler) and Galli Eo™ (IRE Elit)

D. Galli Eo™ (IRE Elit) and iTG Ga-68 Generator (ITM)

102


2. This 68Ge / 68Ga generator is eluted with sterile ultrapure 0.1M HCl, in a 5 mL volume, @ 2 mL / min with a peristaltic pump, and has a shelf-life of 12 months or 400 elutions.

3.

2. GalliaPharm® (Eckert & Ziegler)

3. Galli Eo™ (IRE Elit)

4. iTG Ga-68 Generator (ITM)

5. ITG Ga-68 Generator (RadioMedix)

103


104

What’s Not So New About 68Ge / 68Ga Generators?

• Reviewed difficulties / inconveniences associated with production / use of positron emitters

• Described potentially valuable source of short-lived positron emitter in Ge-Ga68 decay chain

• Investigated methods for Ge68 production and rapid separation of Ga68 short-live daughter

• Ga68-EDTA was suggested for brain tumor imaging since Cu64-EDTA localized reasonably well

• Properties of gallium are such that numerous opportunities for chemical variation exist

• Ge68 remains relatively expensive because of low production rate

• Expense more than offset by convenience and useful life of Ge68 as a source of positrons• Efficient operation with 2 mCi Ge68 would provide several Ga68 doses (250 µCi) per day for considerable time

• Cost per patient dose becomes negligible

• Nature has not provided many gamma-emitting parent-daughter relationships to work with

• Properties of Ge-Ga68 are optimum, unique and useful when short-lived tracers are required

• Note: Ga68 separation by liquid-liquid (acetylacetone/cyclohexane) extraction too complex and not ALARA! 105

SUMMARY

106

First Duke Ga-68 Generator?

10 µCi 10/5/683 ml EDTA

Greene MW and Tucker WD, Int J Appl Rad Isotopes. 12:62, 1961

• Advantages over Gleason solvent extraction milking method – satisfied desired criteria of improved “cow”

• Rapid, operation eliminates need for fast manipulation by inexperienced personnel, no mechanical loss or contamination of product

• Yield of Ga68 and its high radiopurity should be constant from milking to milking

• Alumina is retained in generator in essentially dry condition, no liquid to spill accidentally, with consequent loss of Ge68

• Generator can be handled quite roughly without danger of breakage or spillage

107


Fig. 1. A 10-minute positron scintiphototaken with Ga68-EDTA. This frontal view

shows a large midline meningioma.• Ga68-EDTA positron scintiphotos taken on more than 25 patients

• Patient shown had a craniotomy 1 year before examination, subtotal resection of left midline meningioma

• Frontal image shows large midline recurrence, this time predominantly on right side, surgery confirmed

• Marker sources at ear canals are visible at lower right and left

• Outline of head visible because of uptake of Ga68-EDTA in skin and diploe (spongy cancellous bone)

108


• This technique of localizing brain lesions may be applicable on a large scale as a screening procedure

• Radiation dose to patient is minimal, examination time is short and, except for intravenous injection, no discomfort to patient is produced

• With use of positron cow, Ga68-EDTA is readily available and is inexpensive, because hundreds of doses of the isotope can be obtained before the parent isotope has decayed

• Since Ga68 has such a short half-life, an examination can be repeated or other isotope studies can be done the following day if desired, and only minimal precautions are necessary in handling the isotope

• Ga68-EDTA positron scintiphotos were compared to photoscans with Hg203-Neohydrin (renal agent)

• Interpretation of Ga68-EDTA positron scintiphotos more difficult than Hg203-Neohydrin photoscans

SUMMARY

109

What’s Not So New World of 68Ge / 68Ga Generators?

Nuclear Medicine Pioneer 1920–2005

Nuclear Medicine Pioneer1924– ?

J Nuclear Medicine 5:485-488, 1964

- Convenient / economical source of Ga68-EDTA for PET brain imaging - Ge68 (280 days) decay provides supply of Ga68 a β+ emitter (68 min)- “Cow” makes use of activated alumina (Al203) ion-exchange properties- Cow “milked” of Ga68 daughter in a simple / rapid column “elution” process- Add EDTA “eluent” at column top and collect “eluate” at bottom- Ge68 strongly retained by alumina; Ge68 contamination extremely low- Reliable separation of Ga68-EDTA obtained; little possibility of Ge68 contamination - Obtaining sterile isotonic solution for IV injection rapid / simple

- 1 mCi Ge68 yields 350 μCi of Ga68 for injection after collection / processing- Decay equilibrium re-established 2 hrs; near maximum amount of Ga68 can be

obtained from column every 2-3 hrs- When “cow” is used several times per week, cost per dose becomes very low- Cost prorated over several months, isotope / shipping charges are saved

- Ga68-EDTA when used with positron scintillation camera, has given a good record of brain tumor localization

- To date > 100 patients have been examined, only small number of false positives and few known missed tumors

- Radiation dose to patient is very low compared to other isotopes- For 250 μCi dosage, whole body radiation dose is < 7 mRad, renal dose is < 50 mRad

110

68Ga-EDTA Brain Scan -- Anger Positron Camera

Anger HO, Gottschalk A: Localization of brain tumors with the positron scintillation camera. J Nucl Med 1963;4:326

Fig. 5: A 68Ga-EDTA brain scan acquired with the “Anger positron camera” circa 1962 showing the tomographic capability. The brain tumor is in best focus in the left image, taken at about the level of the temporal horn.

“To date more than 100 patients have been examined with only a small number of false positives and few known missed tumors.”

• Need for new improved PET scanners and related technologies

• No reliable source of generators with desired properties / qualities

• Inadequate generator designs yielding high 68Ga3+ activities• Needed for versatile radiochemistry to easily prepare wide variety of agents for diverse

clinical imaging procedures

• Agents available through existing technology gained only minor clinical relevance

• Parallel / rapid development of new classes of radiopharmaceuticals• 99mTc agents - prepared with eluates from high quality 99Mo / 99mTc generator

• Sodium Pertechnetate Tc 99m brain scans (Harper et al, UChicago, 1964)

• Presentation / publication of potential clinical utility of 68Ga slightly predated same for 99mTc

• 18F agents - prepared via expanding availability of medical cyclotrons• Fludeoxyglucose F 18 brain and whole body PET (Alavi et al, UPenn, 1976)

111

Why did development of 68Ga imaging agents seemingly go into hibernation in late 1960’s?

➢1960 – Powell Richards - Brookhaven National Laboratory

➢1961 – Harper / Lathrop - Argonne Research Hospital• Tc-99m based scintillation imaging investigations

➢1961 – Nuclear-Chicago Co. – Pho-Gamma• First commercial “Anger Camera” installed

➢1964 – Harper – Bad Gastein, Germany Meeting• Reported on 3 years of clinical studies with Tc-99m

• Tc-99m quickly becomes dominate imaging radionuclide

➢1965 – Nuclear Consultant Corporation

• Sells first commercial 99Mo/ 99mTc generator system

• NCC →Mallinckrodt →Tyco Healthcare → Covidien → Mallinckrodt → Curium

➢2018 – 99Mo/99mTc generators are still used routinely for preparing > 80% of all SPECT diagnostic imaging agents

➢ RadioGenix System – new technology – next presentation 112

Development of Technetium-99m

Circa 1958

Practical 99Mo/99mTc radionuclide generator system revolutionized nuclear medicine

• Interesting history . . . here’s a great place to start . . .

113

What brought 68Ga imaging out of the seemingly long period of hibernation?

Applied Radiation and Isotopes 76 (2013) 24-30

• Numerous publications 1970s & 1980s described use of inorganic matrixes / organic resins, selectively adsorbing 68Ge and releasing 68Ga within weak (0.1–1.0 N) or strong (>1 N) HCl concentrations, respectively

• Challenge was to design radiochemical separation systems to provide cationic 68Ga eluate species available for versatile radiolabeling chemistry

• Ga3+ exists as cationic species in HCl solutions pH between 0 and 2 approximately, (i.e., 0.01–1.0 N HCl)

• Me4O2-type matrixes (Me = Sn, Ti, Zr, Ce, etc.) appeared to be adequate, effectively adsorbing 68Ge4+

• Alternatively, organic resins have been developed eluting 68Ga3+ in stronger HCl solutions

114

Hibernating 68Ga Medical Applications - New Chemistry


• Pioneering achievement of radiochemists in Obninsk, Russian Federation, lead to new type of 68Ge / 68Ga generator

• Generator eluates based on hydrochloric acid provided ‘‘cationic’’ 68Ga3+

instead of ‘‘inert’’ 68Ga-complexes

• Opened new pathways of Me3+based radiopharmaceutical chemistry

• Generators became commercially available in first years of 21st century

115

Generator Eluates Delivering 68Ga3+ Cation (1)

Fig. 7. Electrophoresis of a 0.1N HCl 68Ga generator eluate (EZAG Obninsk generator; EZAG = Eckert & Ziegler Strahlen-und Medizintechnik AG) demonstrating the presence of ‘‘cationic’’ 68Ga. (parameters: 0.1N HCl, Whatman paper strip, l=19 cm, t=5 min,191V, 210mA, 40W).


• As commercial ‘‘ionic’’ generators entered clinical environments, questions regarding radiation safety, legal requirements and radiolabeling of medical tracers became more and more relevant

• Problem 1 - In principle, long 68Ge physical half-life should allow at least 1 year of usage

• Generator shelf-life, however, did not necessarily parallel long physical half-life due to potentially labile qualities of generators over time

• Decreasing 68Ga elution yields

• Increasing 68Ge breakthrough

• Radiochemical challenge

• Reduction and/or removal of 68Ge breakthrough from eluates116




• Problem 2 - Generator eluates did not have sufficient chemical and radionuclidic purity

• Non-radioactive metals compete with 68Ga3+ for coordinative labelling of radiopharmaceutical precursors

• 68Zn2+ -- generated on generator column as 68Ga decay product

• Fe3+ -- general and common chemical impurity

• 68Ge4+ -- breakthrough

• Removal of 68Ge from eluate, another important radiochemical challenge

117




• Problem 3 - New generation generators utilize HCl solutions for 68Ga3+ elution

• Relatively high H+ concentration may protonate functional groups of ligands

• Bifunctional ligands needed for radiolabeling with 68Ga3+

• Minimizing pH and volume of 68Ga3+ eluted prior to radiolabeling to facilitate syntheses yields

118



• Three approaches to address one or more of the problems

• Two processes include chemical separation strategies and may be called “post-processing‘‘

• Third, simple fractionation to isolate fractions with highest 68Ga [activity]

119

Post-Processing / Fractionation of 68Ga Generator Eluates


Fig. 8. Post-processing technologies for commercial 68Ge/68Ga radionuclide generators. (1) Direct generator elution through cation-exchange cartridge, (2) desorption of purified 68Ga using HCl/acetone or HCl/ethanol mixtures, (3)generator elution into HCl reservoir, (4)subsequently elution through anion-exchange cartridge, (5) desorption of purified 68Ga using water, (6) identification of eluate fraction representing at least 2/3 of the 68Ga activity, use without further purification.

• Many dramatic improvements since development of first generation 68Ge/68Ga generator systems in 1960’s

• Available commercial generators either TiO2- or SnO2-based or use organic resin

• 68Ga eluate yields range from ~ 70% - 80% for fresh generators, with more or less pronounced decrease over time

• 68Ge breakthrough levels of ~ 0.01–0.001% or even better for fresh generators, with increasing percentages over longer periods of generator usage

• Fortunately, need for post-processing (chemical separation, fractionation, other) continues to decrease

• Many 68Ga radiopharmaceuticals are being synthesized routinely and safely

• First 68Ga-based radiopharmaceutical, NETSPOT (kit for preparation of gallium Ga 68 dotatate injection) approved by FDA (June 1, 2016)

120

68Ge/68Ga Generators - Current State and Outlook


• Almost all technology / chemistry developments belong to late 20th century decades and last 15 years

• Definite room for further development to address several aspects of generator design and performance, radiolabeling chemistry and clinical applications

• Design and performance• Solid phase ion exchange chromatographic generators

• Improved resin material to decrease release of 68Ge over time of generator usage

• Sophisticated nano-particle/nano-composite systems• Zr IV and Ce IV based (Chakravarty et al., 2010, 2011)

• Guarantee effective adsorption of 68Ge, effective release of 68Ga, chemical stability and radiation resistance

• Further integration of elutions into online, fast, efficient automated post-processing units

• Avoid 68Ge transfer into 68Ga radiopharmaceuticals

• GMP-certified / licensed commercial generators to satisfy challenging regulatory requirements 121

Future Developments – 68Ga Generators


• New ligands / bifunctional ligands• Coordinate specifically with 68Ga3+

• Discriminate against Fe3+ and Zn2+

• Allow complex formation under a broader pH range

• Allow instant labelling at convenient temperatures

• Provide high thermodynamic and kinetic Ga3+-ligand-complex stability

• Discriminate between Ga3+ and Fe3+ and other competing metals

• New generations of ligands• Access to new monomeric derivatives

• One bifunctional chelate conjugated to one molecular targeting vector

• Also to di-, tri- and multi-meric analogues

• One central chelate core will become almost a biologically inert unit, linked to one or several active targeting moieties

122

Future Developments – Chelators / New Chemistry


• Diagnostic radiopharmaceuticals• New clinical applications will depend on classes of

peptidic / non-peptidic targeting vectors available

• Imaging will hopefully address not only tumors, but a variety of clinical indications similar to those for 99mTc based radiopharmaceuticals

• Example brain, heart, lung, etc.

• New instant 68Ga “kit” systems• Somewhat analogous to “instant” 99mTc kits

• NETSPOT® (68Ga-DOTATATE) – AAA (NDA, June 2016)

• Illumet™ (68Ga-PSMA-11) – Telix (IND, P3)

• THG-001 (68Ga-THP-PSMA) – Theragnostics (IND, P2)

• NeoB (68Ga-NeoBOMB1) – AAA (IND, P1)

• Others sure to follow

123

Future Developments – New Tracers / Kits


• Diagnosis and monitoring• Availability of state-of-the-art GMP 68Ge/68Ga generators

along with FDA approved 68Ga “kits” driving new PET/CT imaging volumes

• Making nuclear pharmacy / nuclear medicine exciting again!

• Many 68Ga agents under development and on track for FDA approval in short term

• Currently, extraordinary demand for limited worldwide supply of GMP 68Ge/68Ga generators

• Some future demand, of necessity, will be met by development of cyclotron produced 68Ga at medical and other centers already producing PET drugs

• In next decade, 68Ga diagnostics may approach a clinical molecular imaging impact closer to that for 99mTc, 18F and radioiodine based tracers

124

Future Developments – 68Ga PET/CT Indications


• New targeted patient treatments• All of these exciting recent developments will finally

contribute to more intense clinical development and expansion of theranostics in nuclear pharmacy / nuclear medicine practice

• One unique feature 68Ga is that 68Ga-PET/CT imaging is directly linked to new important treatment options

• For some classes of Ga3+ bifunctional ligands, there will be options to synthesize therapeutics analogues with trivalent radiometals such as 90Y, 177Lu, 213Bi etc.

• Perfect example of the “theranostic” concept

• Therapy radiopharmaceuticals• Lutathera (177Lu-DOTATATE) – AAA (NDA, January 2018)

• PSMA-617 (177Lu-PSMA-617) – Endocyte (IND, P2/3)

• PSMA-R2 (177Lu-PSMA-R2) – AAA (IND, P1)

• Many others in “theranostics” pipeline

125

Future Developments – Theranostics


126

What review article best provides a broad prospective of 68Ga-radiopharmaceutical development?

127

Commercial 68Ge/68Ga Generators - Circa 2015

Velikyan I: 68Ga-Based Radiopharmaceuticals: Production and Application Relationship, Molecules 2015

• Best clinical generator options • Determined by availability/user

• Chromatographic separation

• Provide several advantages• Long shelf-life of ~1 year

• Stable column matrixes

• Cationic 68Ga3+ chemical form

• Allow versatile and direct labeling chemistry

• Reproducible and robust performance

• Minor differences• Molarity of HCl eluent

• Metal cation content

• 68Ge breakthrough

• External Vs internal eluent

• Major differences• Regulatory status

128

Commercial 68Ge / 68Ga Generators - 2019

Manufacturer EZAG IRE iTG

Column Matrix TiO2 TiO2 Silica gel (dodecyl gallate modified)

Column Borosilicate Glass (Pharma Grade) PEEK PEEK

Eluent Sterile ultrapure 0.1 mol/L HCl(External)

Sterile 0.1 M HCl(Internal)

Sterile 0.05 M HCl(External)

Elution Volume 5 mL 1.1 mL 4 mL

Elution Yield > 60 % of nominal activity > 67% at release Not < 80%

Elution Rate/Time 2.0 mL/min (peristaltic pump) 3 min (vacuum vial) 1-5 mL/min (peristaltic pump)

Activity Calibrations 20, 30, 40, 50 mCi 20-50 mCi 8-54 mCi

Shelf-life 12 months or 400 elutions 450 elutions per 1 year 12 months or 250 elutions

Shielding 28 mm (Pb equivalent) 50 mm (Pb equivalent) 36-50 mm (Pb equivalent)

Weight 14 Kg 16.5 kg 16 Kg

GMP Yes Yes Yes

Drug Master File Type II DMF #28741 (10/13/2014) Type II DMF #31715 (3/6/2017) None

129

68Ge/68Ga Generators – Specifications (Generator)

Test Parameter EZAG IRE iTG

Appearance Clear colorless solution Clear colorless solution Clear colorless solution

pH ≤ 0.5 – 2.0 ≤ 2 ≤ 2

Identity Physical T1/2 62-74 minutes 62-74 minutes 67.71 minutes

Gamma-raySpectrometry

Principal gamma photons 0.511 MeV and 1.077 MeV



Radiochemical Purity > 95% free 68Ga(III) ≥ 95% 68Ga(III) ≥ 95% 68Ga(III)

Chemical Purity Fe and Zn< 10 μg / GBq

Al, Cu, Fe, Ga, Ni, Pb, Zn< 10 μg / GBq

Cu, Fe, Ga, Nb, Ni, Pb, Zn≤ 10 μg/GBq

Microbiological Sterile Sterile Eluate sterile @ release

Bacterial Endotoxin < 30 EU / mL ≤ 175 EU / mL ≤ 20 EU / mL

68Ge Breakthrough Not more than 0.001 % < 0.001% ≤ 0.005% total radioactivity

130

68Ge/68Ga Generators – Specifications (Eluant)

131

GalliaPharm® Generator – Conditioning / Maintenance

• Conditioning – first elution new generator• Introduce 10 mL sterile ultrapure 0.1 M HCl @ ≤ 2.0 mL/minute

• Eluting at a faster rate may reduce life of generator

• Elute manually or with peristaltic pump

• Verify eluent is flowing properly• Leaks: stop, tighten connections, clean up, check for radioactivity contamination

• Unusual high resistance: discontinue elution, do not force eluent into generator

• 68Ga3+ fully elutes in 5 mL, however, 10 mL elution fully removes accumulated 68Ge, Zn and Fe

• Recommendations:• Determine 68Ga3+ elution peak by collecting 0.5 mL eluate fractions

• Test eluate for 68Ge breakthrough after first elution by suitable method

• Breakthrough should be ≤ 0.001 %

• Maintenance – generator last eluted ≥ 3 days prior• 68Ge, Zn, Fe impurities accumulate

• Recondition with 10 mL elution as above

• Recommendation: elute once at least 7 - 24 hours prior to eluting for radiolabeling

Galli Eo™ Generator – Conditioning / Use / Maintenance

• Conditioning – 1st elutions new generator

• Six (6) consecutive 1.1 mL discarded elutions within 24 hours or back-to-back (over ~ 30 min)• Suggestion – use tared 10 mL evacuated vials and reweigh to confirm delivered volume

• Visually verify eluent begins to flowing properly

• Air leaks → no flow, tighten connections, use new evacuate vial

• Fractionated bolus typical, over at least 3 min (4-5 min may be more optimal)

• Post-conditioning – 1st 4 days or 1st week of use

• Eluates suitable for use if prior elution performed ≤ 24 hrs

•

• Routine Use – post-conditioning period

• Eluates suitable for use if prior elution performed ≤ 72 hrs•

• Maintenance – if no elutions ≥ 1 month

• Three (3) consecutive discarded elutions

• First eluate intended for radiolabeling with in next 24 hrs 132

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68Ge/68Ga Generator – Location?

Shielded Hot Cell Shielded Laminar Air Flow Hood

• Specific to this generator system

• Future Ge-68/Ga-68 generators will be addressed in revised licensing guidance

• All sections of guidance apply to both medical licensee and commercial nuclear pharmacy licensee use of this generator unless otherwise specified

• Does not apply to licensees/applicants receiving unit or bulk Ga-68 radiopharmaceutical dosages

• Licensees / applicants will be regulated under 10 CFR 35.200 and, as such, authorized users (AU) must meet the requirements in 10 CFR 35.290

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68Ge/68Ga Generator – RAM Licensing

https://www.nrc.gov/docs/ML1707/ML17075A488.pdf

• 10 CFR 35.1000 Use• FDA approved Ga-68 DOTATATE for diagnostic PET imaging of NETs (June 2016)

• Ga-68 can be eluted from Ge-68/Ga-68 generators (or produced by cyclotron)

• Ge-68 breakthrough is possible when eluting Ga-68 generators

• Ge-68 contamination has potential to deliver higher radiation exposures to patients

• Ga-68 generators are similar Mo-99/Tc-99m and Sr-82/Rb-82 generators

• Tc-99m and Rb-82 generators are regulated under 10 CFR 35.200

• Permissible Mo-99 and Sr-82 concentrations are provided in 10 CFR 35.204 • Limits potential unnecessary radiation exposures to patients

• No such concentration limit was specified for Ge-68/Ga-68 generators

• Therefore, use of a Ge-68/Ga-68 generator to prepare Ga-68 radiopharmaceuticals for imaging and localization studies is regulated under10 CFR 35.1000

• "Other Medical Uses of Byproduct Material or Radiation from Byproduct Material.“

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68Ge/68Ga Generator – RAM Licensing (2)


• Commercial Nuclear Pharmacy Use under 10 CFR 30.33

• Ga-68 radiopharmaceuticals may be prepared at commercial nuclear pharmacies and then provided to medical licensees for their use

• Potential for Ge-68 breakthrough in generator eluates exists, thus NRC will require appropriate commitments from applicants prior to granting authorization to possess and use these generators to produce Ga-68 radiopharmaceuticals

• In accordance with 10 CFR 30.33, “General requirements for issuance of specific licenses,” a commercial nuclear pharmacy will have to apply for a license or amend their license in order to be authorized to possess and use Ge-68/Ga-68 generators

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68Ge/68Ga Generator – RAM Licensing (3)


• An applicant requesting authorization for a 68Ge/68Ga generator shall commit to:• Providing instructions and/or training on the manufacturer’s procedures to all individuals involved in Ge-68/Ga-68 generator use, commensurate with the individual’s duties to be performed;

• Not to opening, breaching, or physically modifying the Eckert and Ziegler GalliaPharmTM generator in any way;

• Following the manufacturer’s procedures, including: generator set-up; generator elution; drug preparation; Ge-68 breakthrough testing; and final disposition;

• To eluting the generator in accordance with the manufacturer’s stated frequency and procedures to minimize the concentration of Ge-68 in the eluate; Not using an expired generator for preparation of materials that will be administered to patients or human research subjects; Only using a generator that has a clearly marked expiration date;

• After installation, eluting the generator and properly disposing of the eluate prior to the first use of eluate for testing or human use;

• Developing and implementing written procedures for the determination of breakthrough that will detect whether the eluate exceeds the manufacturer’s 0.001 percent breakthrough limit, i.e., the presence of Ge-68 in excess of a ratio of 0.01 μCi Ge-68 per 1 mCi Ga-68;

• Not knowingly administer to a patient or human research subject any material containing Ga-68 which is determined to exceed the manufacturer’s 0.001 percent breakthrough limit;

• If the generator has not been eluted within 48 hours, then discarding the first eluate prior to use (e.g., if the generator is used Friday and the next elution is not until Monday morning then the first eluate shall be discarded);

• Measuring the breakthrough of the generator at least once every 7 calendar days when in use;

• Removing a generator from use if the measured Ge-68 breakthrough exceeds the manufacturer’s stated breakthrough limit;

• Not returning a generator to service until the breakthrough has been measured again in a new elution and determined to be below the manufacturer’s stated breakthrough limit.

• Maintaining a record of the breakthrough tests for at least 3 years. These tests should include the ratio of the measured activity of Ge-68 per Ga-68 corrected for the time of elution, time and date of the elution, time and date of the measurement, and the name of he individual who made the measurement;

• Developing and implementing written emergency procedures for leaking or damaged generators;

• Notifying by telephone the NRC Operations Center (301-816-5100) and the manufacturer/distributor of the generator within 7 calendar days after discovery of an eluate (excluding eluates from flushing the generator in accordance with manufacturer procedures) that exceeded the manufacturer’s stated breakthrough limits of Ge-68;

• Include in the report to the NRC Operations center the manufacturer, model number, and serial number (or lot number) of the generator; the results of the measurement; the date of the measurement; whether dosages were administered to patients or human research subjects; when the manufacturer/distributor was notified; and the action taken;

• Reporting, in writing, within 30 days of a failed breakthrough calculation in accordance with the rules for medical events, and reportable events as applicable;

• Sending a written report to the appropriate NRC Regional Office within 30 days after discovery of an eluate (excluding eluates from flushing the generator in accordance with manufacturer procedures) that exceeded the manufacturer’s stated breakthrough limits of Ge-68. Include in the written report the action taken by the licensee; the patient dose assessment; the methodology used to make this dose assessment if the eluate was administered to patients or human research subjects; probable cause and assessment of failure in the licensee's equipment, procedures or training that contributed to the excessive readings if an error occurred in the licensee's breakthrough determination, and the information in the telephone report made as described above;

• Wipe testing all areas of licensed material use, including the generator storage and kit preparation areas, for contamination each day of use; and

• Wipe testing the generator casing quarterly for expired or unused generators in storage for more than 3 months. 137

68Ge/68Ga Generator – Licensing Commitments

Read the fine print carefully!


• Applicant requesting authorization for a Ga-68 generator shall commit to:• Following manufacturer’s procedures, including: generator set-up; generator elution; drug preparation; Ge-68

breakthrough testing; and final disposition

• Eluting generator in accordance with manufacturer’s stated frequency and procedures to minimize concentration of Ge-68 in eluate

• Developing / implementing written procedures for determination of breakthrough to detect whether eluate exceeds manufacturer’s 0.001 % breakthrough limit

• i.e., Ge-68 in excess of a ratio of 0.01 μCi Ge-68 per 1 mCi Ga-68

• Not knowingly administer to a patient / human research subject any material containing Ga-68 which is determined to exceed manufacturer’s 0.001 % breakthrough limit

• Measuring breakthrough of generator at least once every 7 calendar days when in use

• Removing a generator from use if measured Ge-68 breakthrough exceeds manufacturer’s stated breakthrough limit

• Not returning a generator to service until breakthrough has been again measured in a new elution and results determine Ge-68 content is below manufacturer’s stated breakthrough limit

• Maintaining a record of breakthrough tests for at least 3 years, data should include: ratio of measured activity of Ge-68 per Ga-68 corrected for time of elution, time and date of elution, time and date of measurement, and name of individual who made measurement

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68Ge Breakthrough Test – Commitments


• Verify dose calibrator setting with 68Ge/68Ga NIST traceable source

• Elute generator per manufacturer’s instructions into 10 mL vial

• Calibrate eluted Ga-68 with dose calibrator on verified setting, record activity and date / time of elution

• Allow minimum 36-48 hours for decay of eluted Ga-68 activity

• Accurately measure 1.0 mL of eluate, transfer to counting tube

• Place counting tube in auto gamma counter along with NIST traceable 68Ge/68Ga source and acquire counting data

• Use Excel spread sheet to calculate Ge-68 breakthrough • Enter: Time/date elution, time/date counting, sample counts, standard

counts, Ga-68 mCi date/time of elution, elution volume

• Calculates: decay time, corrected sample counts, corrected standard counts, Ge-68 µCi/mL, total Ge-68 µCi eluted, percent Ge-68 breakthrough

• Verify weekly test results are satisfactory• Must not exceed 0.001 % Ge-68 breakthrough limit

• If exceeded, follow license commitments

139

68Ge Breakthrough Test – Suitable Method

Wallac Wizard 3” 1480 Auto Gamma Counter; P-E

CRC-25R; Capintec

• According to 10 CFR 30.35 applicants must have a Decommissioning Funding Plan (DFP)• Exemption to DFP requirement (10 CFR Part 30 ) under certain circumstances

• Only when requested for generators and only if a legally binding agreement was in place for licensee to return generators to manufacturer / distributor when generators were no longer used

• Licensees must continue to provide FA in amounts described in exemption memorandum

• Licensees possessing 1 or 2 (50 to 100 mCi) must provide for financial assurance for decommissioning in the amount of $225,000.00

• Licensees possessing > 2 generators (>100 mCi) must provide for financial assurance for decommissioning in the amount of $1,125,000.00

• Legally binding agreement should contain terms that include:

• Commitment generator recipient shall return generator to manufacturer or distributor;

• Commitment that generator manufacturer or distributor shall accept receipt of returned generator;

• Conditions of manufacturer or distributor’s receipt of generator are included in agreement, these conditions are reasonable, do not appear unduly burdensome, and do not appear to make return of generator unreasonably onerous or impossible;

• Manufacturer or distributor is authorized to possess the radioactive material;

• Parties to agreement are recipient(s) of generators and the manufacturer or distributor(s) of the generators;

• Agreement is signed by persons authorized to enter into legally binding agreements on behalf of the recipient(s) and manufacturer or distributor(s); and

• Agreement is dated140

68Ge/68Ga Generator – Financial Assurance (FA) Exemption


• Wonderful world of 68Ge / 68Ga generators is rapidly changing / improving• Stimulated by FDA 68Ga-DOTATATE (NETSPOT®) / 177Lu-DOTATATE (Lutathera®) approvals

• Several new 68Ga-based radiopharmaceuticals in early-late stage development

• Several new 177Lu-based radiopharmaceuticals in early-late stage development

• Supply of 68Ge / 68Ga generators is not meeting rapidly expanding demand

• Two GMP / DMF generators (EZAG / IRE) are available, cost is increasing

• Room for improved supply and new technology generates

• Some demand will be met using cyclotron produced 68Ga3+

• Regulation / licensing of 68Ge / 68Ga generators remains challenging / costly

• Regardless, development of radiopharmaceutical theranostics is making nuclear pharmacy and nuclear medicine practice great again!

• The future of radiopharmaceutical theranostics is scintillating!!141

Closing remarks / conclusions

1. The following commercially available 68Ge / 68Ga generator(s) have been accepted by FDA for use in the routine preparation of 68Ga-DOTATATE (NETSPOT®).

A. GalliaPharm® (Eckert & Ziegler) only

B. Galli Eo™ (IRE Elit) only

C. GalliaPharm ® (Eckert & Ziegler) and Galli Eo™ (IRE Elit)

D. Galli Eo™ (IRE Elit) and iTG Ga-68 Generator (ITM)

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2. This 68Ge / 68Ga generator is eluted with sterile ultrapure 0.1M HCl, in a 5 mL volume, @ 2 mL / min with a peristaltic pump, and has a shelf-life of 12 months or 400 elutions.

A.

A. GalliaPharm® (Eckert & Ziegler)

B. Galli Eo™ (IRE Elit)

C. iTG Ga-68 Generator (ITM)

D. GalliMedix ™ (RadioMedix)

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Thank You for Your Attention!