The RadioGenix™ System(technetium Tc99m generator)

Edmond J. Fennell, R.Ph. MBA

• Target Audience:

• ACPE#:

• Activity Type:

Target Audience: Pharmacists

ACPE#: 0202-0000-18-078-L04-P

Activity Type: Knowledge-based

• Target Audience:

• ACPE#:

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DisclosuresStockholder – NorthStar Medical Radioisotopes, LLC – stock optionsStockholder – Triad Isotopes, Inc. – Various classes of stockConsultant - NorthStar Medical Radioisotopes, LLC

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

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Learning Objectives1. General theory and operation of the platform2. Key quality related features and components3. Key isotope related features and components4. Current and potential isotope pairs for use with the

system

• Target Audience:

• ACPE#:

• Activity Type:

1. Assessment Question1. What type of separation method is used with the

system? A. Liquid-liquid extractionB. Gaseous extractionC. Extraction chromatographyD. Pressurized liquid extraction

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• ACPE#:

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2. Assessment Question1. Which is NOT a key component of the system

A. Primary separation cartridgeB. Product cartridgeC. Network connectionD. CPU/Protocol

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• ACPE#:

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3. Assessment Question1. What quality related feature sterilizes the fluid pathway

A. Source vesselB. RFID SystemC. Liquid ozonation systemD. Product syringe

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• ACPE#:

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4. Assessment Question1. Which isotope pair is being developed for targeted

radiotherapy?A. 99Mo/99mTCB. 225Ac/213BiC. 188W/188ReD. 68Ge/68Ga

RadioGenix™ Isotope Separation System A CPU driven isotope separation system using extraction chromatography

Versatile platform technology which maintains a basic configuration

Four isotope pair specific components

Stock isotope solution (Mother/Daughter isotope pair)

Exchange media (Primary Separation Column)

Reagents (column prep, buffers, strip solution)

Computer Protocol

Portable Digital Data Records

Shielding adjusted to match the radiation exposure hazard

Ozone Generation unit for periodic fluid pathway sterilization

Key Benefits of the RadioGenix™ System Broad Application for multiple isotope pairs

Versatile design

Fairly uniform operation

Isotope pair storage separate from main support apparatus

Reliable performance

Low volume eluates

Automated, transmittable data record of each elution

Quality assurance features

Original Instrument Concept

Generic Multicolumn

Selectivity Inversion

Generator

E. P. Horwitz and A. H. Bond

PG Research Foundation

Extraction Chromatography

MobilePhase

InertSupport

StationaryPhase

Surface of Porous Bead

System Construction

Photo Archives, NorthStar Medical Radioisotopes, LLC

System Comparison

System ComparisonParent & Daughter Solution

Parent Solution

StripSolution

Highly Purified Daughter Solution

Resin Selective

for Daughter (PSC)

Resin Selective

for Parents (GC)

Shielding

E. P. Horwitz and A. H. Bond

Saline Solution

Shielding

99mTcO4-

in Saline Solution

99MoO42-

on Alumina

Evacuated Vial

Generic Multicolumn Selectivity Inversion Generator

Key Components of the RGX1. Computer/protocol

2. Source vessel

3. Reagents

4. Primary separation Cartridge (PSC)

5. Rotary valve

6. Syringe pumps for source material & final product

7. Product cartridge (combination of Guard Column (GC) and 0.22µ filter)

8. Ozone generator

9. RFID system

Isotope Specific Components Parent/Daughter isotope solution

Resin highly selective for daughter isotope

Reagents

Elution protocol

Shielding material

Quality Related Components & Features

RFID Technology

Password protected access

Single use product cartridge, includes guard column and 22µ filter

Automated filter integrity (bubble) test for product cartridge

Automated digital batch record

Remote diagnostics capabilities

Required periodic sterilization of fluid pathways using automated process and internal ozone generator

Current and Potential Future Medical Isotopes Current Mo-99/Tc-99m

Potential Future Candidates Ac-225/Bi-213

W-188/Re-188

Ge-68/Ga-68

System Summary Versatile separation technology platform

Suitable for numerous isotope pairs

Numerous automated safety features

Isotope Specific Key components

CPU to operate the system and deliver separation and elution instructions

Isotope pair solution

Reagents

Separation Resin

Appropriate Shielding

Mo-99/Tc-99m System Overview

Sources of 99Molybdenum

Non-HEU Processes

System Comparison

Generic Multicolumn Selectivity Inversion Generator

99MoO42-

& 99TcO4-

SolutionSolution

99MoO42-

in Solution

Strip Solution

ABEC® Resin Selectivefor 99mTc

(PSC)

Resin Selective

for 99Mo (GC)

Tungsten Shielding

E. P. Horowitz and A. H. Bond

Saline Solution

Shielding

99mTcO4-

in Saline Solution

99MoO42-

on Alumina

Evacuated Vial

99mTcO4-

in Saline Solution

System ComparisonRadioGenix™ System

Domestically sourced 99Mo

Low Specific Activity, Non-HEU 99Mo

Eluate of Na99mTcO4 ,USP

~75 Minute Elution Time

Single activity size

RFID tech & active system diagnostics

Single use moly guard & Sterility Filter

Capital Equipment & Consumables

Weekly fluid pathway sterilization

Current Dry Column System Foreign sourced 99Mo

High specific activity HEU and/or LEU 99Mo

Eluate of Na99mTcO4 , USP

~2-3 Minute elution time

Wide selection of activity sizes

Passive moly cartridge integrity system

Multi-use 0.22 Filter

Consumables

No fluid pathway sterilization capability

Mo-99/Tc99m Specific Aspects Isotopes: Mo-99/Tc99m

Reagents: KOH, H2O2, C2H3NaO2, SWFI, 0.9% Saline

Resin: ABEC® (Eichrome Technologies, Inc.)

Protocol (system instructions)

Shielding: Lead, Tungsten and Depleted Uranium

Time to finished product: 75 minutes

Time to re-initiated an elution: 90 minutes

Chemistry Components99Mo and 99mTc in 5.0M KOH

Extraction Chromatography using ABEC® Resin

Extractant is polyethylene glycol, PEG

5M KOH (pre-condition PSC), C2H3NaO2

0.9% NaCl

Alumina resin

99mTc Sodium Pertechnetate, USP

Primary Separation Cartridge (PSC)

Strip Sol’n

Guard Cartridge (GC)

Eluate

Isotope Sol’n

Conditioning Sol’ns

Chemistry

Surface of Porous Bead

MobilePhase, Saline

Inert Support, Polystyrene

StationaryPhase, PEG

Polyethylene Glycol

TRISKEM

Elution Protocol

Timing

99mTc Ready in ~75 min.

Ready for re-elution in 90 min.

Each fluid is moved in 5ml increments

Sequence of Events

• Rinse lines with H202

• Precondition PSC with 5M KOH*

• Source solution passed through PSC (5ml x 7)*

• PSC rinsed with 5M KOH*

• PSC rinsed with Na acetate*

• Rinse with 0.9% NaCl to elute 99mTc

Low specific activity 99Mo/99mTc mixture is separated and concentrated resulting in high specific activity 99mTc in approximately 5ml

Tc-99m Final Product 99mTc Sodium Pertechnetate, USP

Sterile

Pyrogen Free

Activity concentration useful for preparing kits, ~ 5ml Volume

Equivalent to eluate from HEU and LEU 99Mo/99mTc generators

Potential System UpgradesNear Term

Fewer reagents

Faster elution times

More thorough and streamlined integration with pharmacy software

Long Term

Variety of activity sizes

Fractional elution

Increased life cycle for consumables

Higher volume reagent cassettes

Enterprise performance metrics

225Actinium/213Bismuth System Overview

225ActiniumSupply is currently Limited

At least 6 different methods to create 225Ac

NorthStar is pursuing 225Actinium by high energy proton induced spallation of 232Thorium.

Working with ANL, FERMI and CNL

projectile (p, n, π, ...)

Forschungszentrum Jülichin der Helmholtz-Gemeinschaft

FRANK GOLDENBAUMTHE PHYSICS OF SPALLATION PROCESSES ---

EXPERIMENT AND THEORY

target

233Uranium Decay Chain

E. P. Horwitz and A. H. Bond

System Comparison

Silicone Tubing Frit Quartz Wool

Fig. (3). Schematics of the ITU Standard 225Ac/213Bi Radionuclide Generator.

Frit

Perfluoroalkoxy Tubing

AG-MP 50 Resin

Polypropylene Fittings

Inlet Outlet

E. P. Horwitz and A. H. Bond

Production of Ultrapure Bismuth-213 for Use in Therapeutic Nuclear

Medicine

255Ac/213Bi Specific Aspects Isotopes: 225Ac/213Bi in 0.1M HCl

Reagents: 0.75 M NaCl in 0.5M (NaH)OAc Buffer a pH 4.0

Resin: UTEVA® (DAAP on Amberchrome®-CG-71)

Software protocol specific for this separation process

Shielding: Lucite*

Time to finished product: XX minutes*

Time to re-initiated an elution: XX minutes*

Chemistry225Ac and 213Bi in 0.1M HCl

Extraction Chromatography using UTEVA® Resin

Extractant is DAAP

0.75M NaCl in 0.5M (Na,H)OAc Buffer, pH 4.0

AGAMP-50 cation exchange resin

213Bi in NaCl/(Na,H)OAc at pH 4.0

Primary Separation Cartridge (PSC)

Strip Sol’n

Guard Cartridge (GC)

Eluate

Isotope Sol’n

Chemistry

Surface of Porous Bead

Mobile Phase,0.75 M NaCl in 0.5 (Na,H)OAc

Inert Support,Amberchrome-CG71

Stationary Phase,DAAP

DAAP

225Ac/213Bi Elution Protocol Pass 225Ac/213Bi solution through primary separation column

Collect daughter depleted solution of 225Ac in system transfer vessel

Rinse UTEVA column (PSC) with 0.75M NaCl in 0.5M (Na,H)OAc Buffer, pH 4.0

Eluate passes through AGMP-50 (GC) cation exchange resin to capture contaminants 225Ac and 225Ra

Collect high purity 213Bi elute

Return daughter depleted solution of 225Ac to source vessel

Re-elution possible at 2 Hrs. (83% yield) to 3 Hrs. (93% yield).

213Bi Final Product

213Bi in isotonic, buffered solution

Low volume eluate

Ready for conjugation with various compounds for TAT

Conclusion Versatile separation platform technology

Broad application to numerous isotope pairs

Utilizes extraction chromatography

Small volume eluates

Fairly uniform operation

Key system components are: Computer/protocol

Source Vessel

Reagents

Primary Separation Column (PSC)

Product Cartridge (includes Guard Column (GC) and 0.22µ filter)

Ozone Generator

RFID system

Conclusion Continued Key quality components are

RFID Technology

Portable digital data records

Single use guard column

Automated filter integrity (bubble) test

Isotope pair stored separately from support apparatus

Weekly required fluid pathway sterilization

Current and potential future medical isotopes 99Mo/99mTc

225Ac/213Bi

188W/188Re

68Ge/68Ga

• Target Audience:

• ACPE#:

• Activity Type:

1. Assessment Question1. What type of separation method is used with the

system? A. Liquid-liquid extractionB. Gaseous extractionC. Extraction chromatographyD. Pressurized liquid extraction

• Target Audience:

• ACPE#:

• Activity Type:

2. Assessment Question1. Which is NOT a key component of the system

A. Primary separation cartridgeB. Product cartridgeC. Network connectionD. CPU/Protocol

• Target Audience:

• ACPE#:

• Activity Type:

3. Assessment Question1. What quality related feature sterilizes the fluid pathway

A. Source vesselB. RFID SystemC. Liquid ozonation systemD. Product syringe

• Target Audience:

• ACPE#:

• Activity Type:

4. Assessment Question1. Which isotope pair is being developed for targeted

radiotherapy? A. 99Mo/99mTcB. 225Ac/213BiC. 188W/188ReD. 68Ge/68Ga