13.1 INTRODUCTION

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PART IV

Practical Aspects of

Radiopharmaceutical

Production and Use

Chapter 13

Automated Synthesis Modules for PET Radiochemistry

Laura Bruton and Peter J.H. Scott

Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA

13.1 INTRODUCTION

The recent approval of several radiopharmaceuticals for positron emission tomography (PET) imaging by the United States Food and Drug Administration (FDA ) and other

regulatory agencies around the world has led to increases in annual PET scan numbers[1]. For example, millions of PET scans are now conducted in the US every year[2]

increased demand for access to short-lived PET radiopharmaceuticals has created a corresponding need for more ecient means for their production. For some radiochemistry facilities, this requires the production of very large batches of one radiopharmaceu-

tical for distribution (see, for example,[3]), while other facilities need to produce multiple dierent research radiopharmaceuticals using a single synthesis module (for recent examples, see[4–7]). The eld of radiochemistry is thus constantly evolving to meet the

needs for increased starting amounts of radioactivity, and in the last couple of decades it has seen a move from manual radiochemistry to the use of automated synthesis mod-

ules (for reviews of new developments, see[8, 9]) supported by sophisticated software programs[10]. These modules are enclosed in hot cells and controlled by a computer

Handbook of Radiopharmaceuticals: Methodology and Applications, Second Edition. Edited by Michael R. Kilbourn and Peter J.H. Scott. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

and the

from the outside, either using a preprogrammed synthesis sequence (timelist) that is

executed manually or totally under computer control. The modules are congured for

the synthesis and the hot cell is sealed in advance of delivery of radioactivity, thus signif-

icantly decreasing worker exposure. Radiochemistry synthesis modules need to be able

to deliver doses at a fast pace while maintaining compliance with radiation safety requirements, especially when handling the very large amounts of radioactivity that some facil-

ities use today[3]. The daily synthesis and delivery of PET radiopharmaceuticals create

challenges for such systems, including short preparation times, compliance with pharma-

ceutical quality procedures, reproducibility, and reliability. Through the years, radiochemistry synthesis modules have changed with the increasing pressure of these standards.

Compared to the early days of manually operated and hard-wired systems, modern computer-controlled radiopharmaceutical synthesis modules are more advanced in terms

of automation, eciency, and radiochemical yields, as well as the ability to meet the

increased demands of FDA-mandated current Good Manufacturing Practice (cGMP). This chapter provides an overview of radiopharmaceutical synthesis modules from the home-

made systems used in early PET centers when the rst edition of this book was published (2002) through to the new modules used today and concludes with thoughts on future directions for the eld.

13.2 EARLY RADIOCHEMISTRY SYNTHESIS MODULES

Figure 13.1 A tradi-

tional homemade radiochemistry module. Source: Reprinted with permission from Welch

etal. 1983[11],

The early radiopharmaceutical synthesis modules (for example, Figure13.1) were hardwired systems where valves, uid movements through lines, gas ows, and temperature

438 Handbook of Radiopharmaceuticals

changes (heating and cooling) were controlled by manually activated electrical switches

that were located externally to lead shielding placed around the module[11]. If physical

movement of items was required, this could be done using the manipulator arms of a

hot cell. As automation was introduced in the 1980s, the components of the synthesis

apparatus began to be controlled using programmable logic controllers and, eventually, small computers; a unique intermediary application was the use of a computer-controlled robot to interact with, and control, an array of work stations that accomplished the

individual steps of a complex radiochemical synthesis (Figure13.2)[12].

By 1990, automated modules were increasingly common in many PET facilities. This

was mainly due to the manufacturing and reimbursement approval for [

cose ([

F]FDG), which was granted in the USA by the FDA and the Centers for Medicare

F]udeoxyglu-

and Medicaid (CMS), respectively. As FDG was the most important PET radiopharmaceu- tical that needed to be synthesized, there was a move to automate this process (see[13]). Many PET facilities acquired a Coincidence FDG synthesizer (Figure13.3), which had been commercially released in late 1998; that module was later acquired by General Electric (GE) and rebranded as the TRACERlab MX

[14]. The module introduced an impor-

FDG

tant new concept: the use of sterile, disposable, pre-assembled synthesis pathways and reagents (termed kits) dedicated to single radiopharmaceutical syntheses, such as

[

F]FDG. In the following years, GE and a number of third-party companies including Advanced Biochemicals (ABX) and Rotem Industries oered (and continue to oer) kits for making dierent radiopharmaceuticals on the TRACERlab MX

[

F]NaF, [18F]F-L-DOPA, [18F]uoroethyltyrosine, and [18F]uorthymidine. While the syn-

, including [18F]FDG,

FDG

thesis module is somewhat dated at this point, because of its very large install base, it

continues to be utilized extensively worldwide, and new reports of use of the TRACERlab MX

for the syntheses of radiopharmaceuticals such as [18F]uoromisonidazole[15],

FDG

Figure 13.2 An

early radiochemistry module run using a computercontrolled robot. Source: Reprinted with permission

from Brodack etal. 1988[12], copy-

right Elsevier.

Chapter 13: Automated Synthesis Modules for PET Radiochemistry 439

Figure 13.3 Early

TRACERlab MX

FDG

cassette-based synthesis module. Source: Image courtesy of GE.

[18F]uoromethylcholine[16], [18F]PSMA-1007[17, 18], and [18F]uoroestradiol[19] continue to be published. Most recently, with the increasing popularity of PET studies using gallium-68[20, 21], use of the TRACERlab MX module for synthesizing

Ga-labelled

tracers has also been disclosed[22].

13.3 MODERN CASSETTE-BASED MODULES

The design and development of synthesis modules have continued to evolve, leading

to the improved and more versatile modules that are in use today. For example, in the late 2000s, it became mandatory to prepare PET radiopharmaceuticals for clinical use according to cGMP. Building on lessons learned with early cassette-based systems such as the TRACERlab MX

control, use of information from sensors in pre-run diagnostics, post-run trouble-

shooting, trend analysis, and process documentation were introduced. For example, GE rened the TRACERlab MX into the FASTlab and, more recently, FASTlab 2 (Figure13.4a); other modules that have evolved from the TRACERlab MX include the NEPTIS (Figure13.4b) and the Trasis AllinOne (Figure13.4c) platforms. Cassette-based module systems were also introduced by Siemens (Explora), IBA (Synthera), and Scintomics (GRP Series). Similar to the TRACERlab MX, this new generation of synthesis modules was primarily developed for the preparation of [ PET radiopharmaceutical. To improve the control and use of the cassettes used with

these modules, they are frequently labeled with a barcode that, when read by the com-

puter, relays information as to which synthesis program should be executed. The use

of single-use cassettes is attractive from a cGMP perspective because it eliminates the

need for cleaning validation studies[23] and reduces errors during setup and operation. The use of these precongured sterile cassettes also enables quick transitions between

and incorporating cGMP principles, new features such as real-time

FDG

F]FDG, as it remains the most widely used

440 Handbook of Radiopharmaceuticals

(a) (b) (c)

Figure 13.4 Cassette-based synthesis modules. (a) GE FASTlab 2. Source: Image courtesy of GE Health-

care. (b) NEPTIS Perform. Source: Image courtesy of Optimized Radiochemical Applications (ORA). (c) Trasis AllinOne. Source: Image courtesy of Trasis.

syntheses. A common theme with all of these new synthesis modules is that they have been designed to address the challenges of a modern radiochemistry laboratory. Con-

scious of the space limitations many facilities have, manufacturers have designed many of

these new modules in a compact size that allows two (or more) units to t inside a single mini-cell. Moreover, cassettes have been developed for these new modules that include reagents and cartridges for multiple syntheses of a radiopharmaceutical (e.g. FDG),

enabling repeated batches to be prepared without the need to open a hot cell between

syntheses[24]. In addition to [

F]FDG, cassettes for these modules are also commercially

available for the production of other commonly used radiopharmaceuticals. Alternatively,

many of the systems can be adapted to prepare other radiotracers through the use of customizable cassettes, most often for the preparation of

F-labeled radiopharmaceu-

ticals[4, 5]; custom cassettes have also been developed for products labeled with other radionuclides, such as gallium-68[25].

13.4 FULLY AUTOMATED FIXED-

TUBING MODULES

The development of new PET radiopharmaceuticals is a very active area of research. Whereas cassette-based modules have become the industry standard for routine daily production of established PET radiopharmaceuticals such as [

F]FDG, they are not always suitable for the synthesis of new PET radiopharmaceuticals. For example, the majority of the modules have limited temperature and pressure tolerances due to the ttings, valves, and materials used to manufacture the cassettes. The systems are usually designed for

liquid-phase chemistry (

phase chemistry (e.g.

Ga and 18F ion reactions) and often not compatible with gas-

C). In addition, many modules have only one reaction vessel, which prohibits the synthesis of probes that need multi-reactor protocols (e.g. tracers prepared using radio-click chemistry; see[26]); however, newer systems such as the GE FASTlab 2 and Trasis AllinOne have two reaction vessels, which potentially allow the automation of

Chapter 13: Automated Synthesis Modules for PET Radiochemistry 441

more complex chemistry. For the most part, though, cassette-based systems are somewhat limited in how much they can be recongured for novel radiochemistry, and new chemistry tends to be developed on fully automated xed-tubing modules such as the GE TRACERlab FX series (Figure13.5a), iPhase MultiSyn systems (Figure13.5b), Synthra radiopharmaceutical synthesizers (Figure13.5c), and Eckert & Ziegler Modular-Labs (Figure13.5d). There are systems available for conducting liquid-phase chemistry with

[

F]uoride (e.g.[6, 27, 28]) as well as gas-phase chemistry with [11C]CO2 or [11C]CH4[7].

Recent reports have also demonstrated compatibility with

Ga[29].

The new fully automated synthesis modules (Figure13.5) have gradually replaced the

early homemade remote systems (Figures13.1 and13.2). These synthesis modules con-

tain multiple interconnected parts, including modules for receiving radioactivity from a cyclotron (or generator); the synthesis component, which typically contains one or more reaction vessels and a heater; a vacuum pump for evaporating solvents; a semi-preparative high-performance liquid chromatography (HPLC) purication system; and a module

for the reformulation of the puried radiopharmaceutical into a solution suitable for

Figure 13.5 Fully

automated xed-

tubing modules. (a) GE TRACERlab. Source: Image courtesy of GE. (b) iPhase F-18 FlexLab. Source: Image courtesy of iPhase Technologies. (c) PET radiosynthesizer. Source: Image courtesy of Synthra GMBH. (d) ModularLab. Source: Image courtesy of Eckert & Ziegler.

(a) (b)

442 Handbook of Radiopharmaceuticals

intravenous injection. These xed-tubing machines are housed in hot cells and controlled

by a computer from outside, with a preprogrammed computerized timelist executed

manually or under full computer control. A radiotracer-specic program (Figure13.6) controls every step of the synthesis, from setting the parameters of the reaction (e.g. time, temperature) to the addition of reagents and solvents, purication, reformulation, and delivery of the nal product to a sterile vial. During the synthesis, information from

numerous components and detectors is sent to the interactive computer, allowing radiochemists to see data such as temperature and pressure measurements in real time, as

well as track, trend, and troubleshoot syntheses after completion.

These synthesis modules are often provided by vendors with programs for preparing

standard radiolabeling precursors (e.g. [

C]MeI, [11C]MeOTf) as well as established radiotracers, and such radiosyntheses are often accomplished using the basic conguration of the module. However, we and others have also shown that such modules can be easily recongured for dierent applications, including gas-phase reactions[30] and loop chemistry[31, 32]. The basic module conguration is typically designed for the production of radiopharmaceuticals requiring HPLC purication but can be modied to incorporate purication by Sep-Pak cartridge (e.g. [

F]NaF, [11C]carfetanil, etc.) or a reformulation step when using non-injectable HPLC mobile phases. By way of example, in 2011, our group reported the synthesis of 7

F-labeled radiotracers and 12 11C-labeled radiotracers

using the TRACERlab FX platform[6, 7].

After a synthesis is completed, the module has to be cleaned and disinfected before

the next radiosynthesis. This is done by resetting the module to its basic conguration,

cleaning with sterile water, disinfecting with ethanol, and drying with acetone; the pro-

cess takes approximately 20 minutes. The time needed for cleaning and reset of the modules, and possibly a cleaning validation[23], should be planned for, especially in a smaller lab setting. The need to open hot cells between syntheses to clean and recongure modules also potentially increases radioactivity exposure to sta. Moreover, although these systems can be recongured for dierent tracers, to maintain reproducible production conditions (and compliance with cGMP), constant reconguration is not always ideal. The need for more exible automation that matches the increasing demand for

the development of radiopharmaceuticals has led to the development of the new hybrid

modules and microuidic systems discussed next.

13.5 HYBRID MODULES

To overcome the limited nature of the cassette-based systems and the impact of recon-

guring xed-tubing modules on a routine basis, hybrid modules have been developed.

These modules aim to combine the simplicity of cassette-based systems with the ability

to handle high pressures and temperatures. For example, the Soe Biosciences ELIXYS FLEX/CHEM (Figure13.7) oers a three-reactor design suitable for both synthesis

development and routine production and is capable of accommodating complex multi-

pot radiochemistry[33–35]. The cassettes for this module include the uidic paths and

various reagent vial sizes, which enables a large number of probes to be produced within

Chapter 13: Automated Synthesis Modules for PET Radiochemistry 443

iso.

EtOH

NaCI

V8 V9

HPLC

Pump

V31

Helium

V30

off

VENT.

0.2 μm

Strata

V16

NH2

V15

VENT.

Eluent

V22

V17

WASTE

0.2 μm

V21

HELIUM PRESSURE

V19

AIR PRESSURE

0.2 μm0.2 μm

V26

Load

WASTE

VENT.

0.2 μm

Pre-

cursor

Eluent

Inject

HILIC

UV Lamp

RDYTEMP.1

down

V24

V23

V18

stop

start

COOLING AIR

PRESSURE

V25

WASTE

off

STIRRERS

EXHAUST

Fluid

V1 V3V2 V4 V5 V6

GammaDep.

V12

V14

V20

18F SEPARATION

CARTRIDGE

V10

Auto Zero

UV Detector

NEEDLE

V13

V11

444 Handbook of Radiopharmaceuticals

FROM

TARGET

TRANS-

HEATER

FORMER

POWER

VACUUM

PUMP

off

Figure 13.6 Computer program for running a TRACERlab synthesis module. Source: Image courtesy of GE

Healthcare.

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