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(a)
56.6 cm
(b)
Reagent and
gas-handling robot
Dispoable cassettes
Reactors
Figure 13.7 ELIXYS
hybrid synthesizer.
Source: (a) Lazari,
M., Quinn, K.M.,
Claggett, S.B. et
al., [33]. Under a
creative Commons
License (https://
creativecommons.
org/licenses/by/
2.0/).
(c)
37.3 cm
63.2 cm
the same module. The only changes between syntheses are the reagents, program, and
purication cartridges, as well as a small number of connections between the cassettes.
The ELIXYS module also provides access to the reaction vessel, giving the radiochemist
the ability to take intermediate measurements while eliminating the need for large num-
bers of valves: the decreased number of ttings and valves increases module reliability.
These features enable the production and development of multiple syntheses in a single
system and hot cell, thus requiring less space in smaller lab settings.
The ELIXYS FLEX/CHEM allows for automation without operator intervention up to
the nal purication step, as this module does not support integrated HPLC purication
and formulation; this can, however, be automated by incorporating a separate ELIXYS
PURE/FORM module. Cleaning of this latter system is necessary unless disposable cassettes are used as intended. In a recent report, Collins’ etal. used ELIXYS FLEX/CHEM to
produce 24 dierent
18
F-labeled radiopharmaceuticals and prosthetic groups, showcasing
the utility of the hybrid synthesis module in the eld[4]. A hybrid system such as ELIXYS
therefore has great utility for laboratories that perhaps just have space and/or funding
for a single synthesis module but want to be able to conduct both routine production of
established radiopharmaceuticals and development of new radiotracers.
Chapter 13: Automated Synthesis Modules for PET Radiochemistry 445
13.6 MICROFLUIDIC SYSTEMS
(a)
Many of the traditional radiochemistry synthesis modules described in this chapter use a
single uid bus architecture in conjunction with stopcock valve manifold(s), in which every
uid runs through parts of the central pathway, and many have been designed for the
express purpose of manufacturing [
a more exible radiopharmaceutical synthesis platform that is compatible with dierent
levels of radioactivity (single dose-on-demand production or multidose batches) as well
as a variety of radionuclides and/or radiopharmaceuticals, and that can t into the space
connes of a typical radiochemistry laboratory with only one or two hot cells. In addition
to the xed-tubing modules described in this chapter, signicant work has also been
undertaken to develop microuidic approaches for radiopharmaceutical manufacturing
(for recent examples, see[36–84]), as well as purication/reformulation[85]. Microuidic
devices have been used to manufacture radiopharmaceuticals for clinical use[86–89],
but continuing challenges have limited their commercialization and transition into
widespread use[90]. The reasons for the slow uptake are numerous and depend on the
particular application, but include (i) cost, (ii) the lack of aordable components due to
dependence on specialized chips, and (iii) challenges with the macro-to-micro interface
(incompatibility between microuidic volumes [≤ 0.05 ml] and the typical “large-scale”
volumes used in cyclotrons and radiopharmaceutical dosing [≥ 10 ml]). Modules that
have been commercialized include the Advion NanoTek (Figure13.8a), used for both
PET radiochemistry[91, 92] and standard organic synthesis[93], as well as ABTs BG75
(Figure13.8b)[38]. Most recently, we have collaborated with GE to introduce ISAR[94].
The ISAR system (Figure13.8c) oers parallel uidics that overcomes the single uid bus
and associated challenges at the macro-to-micro interface by marrying standard volumes
and techniques and o-the-shelf components for radiopharmaceutical synthesis with the
established benets of a microreactor setup; this system oers a promising approach for
the automated production of radiopharmaceuticals in the future.
18
F]FDG. However, as stated earlier, there is a need for
(b) (c)
(a)
(c) (d)
Figure 13.8 (a) Advion NanoTek. Source: Reproduced from Palmieri etal. 2009 with permission from
Elsevier. (b) ABT BG75. Source: Reproduced from Awasthi etal. 2014 with permission from Elsevier. (c) ISAR. Source: Reproduced from Frank etal. 2019 under a Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0).
(b)
446 Handbook of Radiopharmaceuticals
13.7 SYNTHESIS MODULES FORUSE
WITHSOLID TARGETS
The increased use of longer-lived PET radionuclides has led to eorts to commercialize
methods for their production. Smaller amounts of such radionuclides can be prepared
on cyclotrons using liquid targets[95], but large-scale production requires the use of
solid targets[96]. Initial solid-target work involved the use of homemade systems,
and such systems continue to be reported[97–99], but moving solid targetry from the
research arena to a point where it can be used for daily routine production has necessi-
tated the development of dedicated commercially available solutions. These systems
usually include the solid targetry, a shuttle method to move the solid target to and from
the cyclotron, and a module for the chemistry steps needed to dissolve the solid target
and convert the radionuclide to a useable form for subsequent radiochemical syntheses,
in the same module or one of the other synthesis modules already described in this
chapter. For example, the ALCEO solid target system has been developed by Comecer
(Figure13.9), while IBA introduced Nirta, and ARTMS also oers a solid target system.
Both the ALCEO and Nirta systems require electrodeposition steps to manufacture the
(a)
Electrodeposition of
the
enriched
Dissolution of
Shuttle storage
Electrochemical cell
Shuttle delivery pipe
(b) (d)
Irradiation
Cooling
PTS
64
irradiated
target
(c)EDS PRF
Ni
64
Cu product capillary
Final preparation
Reservoirs
Ion exchange
Purication
TA DDEO
Figure 13.9
Modular setup of
the ALCEO system.
The shuttle is transported between
the EDS (a) and PTS
(b) via a delivery
pipe; the EDS (a)
and PRF (c) are
connected by capillaries to enable
the circulating uid
transport; and the
nal product is
transferred from
the PRF (c) through
capillaries to the
Taddeo module (d)
for nal processing.
Source: Reproduced from Fiedler
etal. 2018 with permission from John
Wiley and Sons.
Chapter 13: Automated Synthesis Modules for PET Radiochemistry 447
actual target, while ARTMS targets are commercially available. These solid target systems have been developed for cyclotron production of
64
Cu, 68Ga, 86Y, 89Zr,
123
I, and
124
I,
etc., and reports on such systems discuss their installation and use in the eld[100, 101].
For example, the production of
64
Cu using ALCEO was described by Fiedler[100]. ALCEO is
composed of a number of dierent modules for electrodeposition, dissolution, transfer,
and storage of targets (EDS), an irradiation unit (PTS) connected to the cyclotron, a puri-
cation module (PRF) and a synthesis module (Taddeo). The enriched material is deposited on the target by the EDS and shuttled to the PTS on the cyclotron for irradiation.
Once irradiation has occurred, the EDS shuttles the target back to the laboratory and
dissolves the target. The radionuclide is then sent through capillary lines to the PRF for
purication and, nally, Comecer’s Taddeo synthesis module for radiochemistry. With the
rapid uptick in use of
growth in use of both
68
Ga radiopharmaceuticals for clinical studies recently, and steady
68
Ga and 89Zr use for immuno-PET (for recent reviews, see[102,
103]), the growth in use of these solid-target systems for production and handling of such
radioactive metal ions is expected to continue in the future.
13.8 AUTOMATED QUALITY CONTROL TESTING
In addition to advances and automation in synthesis modules, a similar push has been
made to automate quality control testing of PET radiopharmaceuticals[104–106]. In
order for a dose to be released for clinical use, it must pass a battery of quality con-
trol tests such as radiochemical and chemical purity (HPLC and TLC), residual solvent
levels gas chromatography (GC), visual inspection, pH, osmolarity, radionuclidic identity
(half-life), purity, sterile lter integrity, bacterial endotoxin levels, and sterility. These
tests generally use separate pieces of analytical equipment, which are expensive to pur-
chase and maintain. To reduce waste and reduce lab space requirements, a push for automation has led to the design of miniaturized systems such as the Tracer-QC (Figure13.10)
and QC1 that can incorporate all of these tests into a single unit. The concept is beyond
the scope of this chapter, as it is discussed at length in Chapter14.
13.9 CONCLUSIONS ANDFUTURE DIRECTIONS
Radiochemistry modules have come a long way from the early systems of the 1980s, with
a number of advanced systems now commercially available for dierent radionuclides
and a wide range of applications. The increased demand for PET radiopharmaceuticals
has led to the development of cassette-based modules that are compliant with cGMP and
capable of handling multiple curies of radioactivity, while a continuing need to develop
novel radiopharmaceuticals and/or new radiosynthesis methods has also led to the evolution of more exible xed-tube synthesis modules and systems for working with solid
targetry. For labs that have limited hot-cell space available, hybrid systems that use
cassettes capable of both routine cassette-based production and exibility have been
recently introduced. This is the current state of the art at the time of writing. However,
448 Handbook of Radiopharmaceuticals
Figure 13.10
Tracer-QC
automated QC
module. Source:
Image courtesy
of LabLogic and
Trac e - A b i lity,
Inc. Other manufacturers of
automated QC
equipment
include QC1.
there remains a desire to reduce the cost and scale of PET radiosyntheses through the
use of microuidics. To this end, the rst microuidic systems for radiosynthesis, reformulation, and automation of quality control have been commercialized since the rst
edition of the Handbook of Radiopharmaceuticals.
The next generation of PET radiochemistry equipment is beginning to be conceived,
with two new approaches emerging. The rst of these considers the need for rapid and
exible production of new components for automation of new radiochemistry and/or
synthesis of novel PET radiotracers, and capitalizes on recent developments in 3-dimensional (3D) printing technologies to translate optimized reaction conditions into synthesis
modules and components composed of 3D-printed, electronic, and robotic parts[107].
The second development imagines a future of cGMP PET radiopharmaceutical produc-
tion that is one of full automation, with little to no interaction by radiochemists. With
the increasing connection of PET equipment to the Internet of Things (for more thoughts
on PET radiochemistry and the Internet of Things, see[108]), it is possible that in the
future, the various systems described in this chapter could communicate with each other
to check inventory, order supplies, and ensure the suitability of the cyclotron, synthesis
modules, and quality control equipment for use. The synthesis could potentially be set up
the day before, and the entire process could be remote-activated so the dose was ready
when the radiochemists arrived. Notications of the synthesis could also be sent to the
radiochemists, keeping them up to date on its progress as well as warning them of any
Chapter 13: Automated Synthesis Modules for PET Radiochemistry 449
problems, and articial intelligence (AI) could be used to track, trend, and troubleshoot
the big data logged from every radiosynthesis to improve eciency and reduce the cost
of radiopharmaceutical manufacture in the future. The features to enable these advances
are becoming available on today’s equipment, and it will be exciting to see how the technology develops next.
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