Making a radiopharmaceutical that will be injected into the human body is a complex procedure.  Each step in the production process is carefully designed and measured to make sure the radiopharmaceutical - or tracer as they are more commonly known - can do the important job it is made to do:  help in diagnosing and managing the treatment of cancer and other diseases.

To ensure the manufacturing process is as easy, safe and efficient as possible, a new production system has been developed that reduces the level of manual handling of radioactive materials that scientists need to do when making a tracer.

The new two step reactor provides the scientists with two “pots” or reactors in which the synthesis of more complex, novel tracers can be carried out in an automated process.  In the end, this means that the cost of supply of the tracer is kept as low as possible, due to the efficiencies of automated manufacture, which is good for patients and doctors alike.

The two or dual step reactor, known as FlexLAB, has been undergoing testing at the laboratories at the Australian Nuclear Science and Technology Organisation (ANSTO) since December 2010.  It is a key goal in the research program of the CRC for Biomedical Imaging Development (CRCBID), which is developing novel radiopharmaceuticals for use as investigational medicinal products.

“Installing this system for testing at ANSTO is a big achievement for CRCBID,” says Dr Gerry Roe, CEO of CRCBID. “The system’s development resulted directly from CRCBID participants’ collective understanding that these newer tracers needed to be produced more efficiently, and with greater safety.”  Until now, these compounds were made either by joining two separate single reactor units together, or by including manual steps in the synthesis.

“The dual reactor lets the scientists perform easier separation and analysis of the compounds that are involved in making the tracer, using a technique known as high performance liquid chromatography (HPLC),” says Dr Ivan Greguric, Head of Research and Innovation, Life Sciences, at ANSTO.  “Having HPLC built in to the dual step reactor provides users with flexibility so that they can improve the chemistry, and open up opportunities for new areas of discovery in a wider range of medical need.”

With minor refinements, FlexLAB would also be suitable for good manufacturing practice (GMP) production of tracers in a commercial environment.

ANSTO team members, Dr Ivan Greguric, Maxine Grant, Naomi Wyatt and Dr Tien Pham  image courtesy ANSTO

The FlexLAB is the result of a cooperative effort of the commercial and research partners of CRCBID.  Liaising with Dr Thomas Bourdier and Dr Tien Pham, from ANSTO, Dr Peter Roselt from Peter MacCallum Cancer Centre, and Adam Corbett from Cyclotek, a detailed technical specification was produced by CRCBID systems engineer, David Prowse early in 2010. As a result of these consultations, equipment developers, Associate Professor Henri Tochon-Danguy and Stan Poniger of iPHASE Technology Pty Ltd, have been able to build a system that is providing safer and faster options for radiopharmaceutical production.

Researcher at ANSTO, Dr Tien Pham, says that the major benefit of an automated dual radiosynthesis reactor is that it provides more options for the design of the materials that make up potential radiotracers.

”Working with single reactors is limiting,” says Dr Pham.  “We could perform classic single step reactions, which are ideal as they are more likely to be more robust, but this avenue is not always an option. We could also perform multistep reactions using the same reactor, with purification being performed only at the very end of synthesis. But without purification between the two steps ... (it) leads to the production of an array of side products and essentially to a lower yield of your desired product. It also makes purification of the final reaction mixture more challenging.

“The third approach was to combine two single reactors together. However, this generally requires two of everything; it’s a very inefficient use of equipment and of the limited space in the hot cell. The FlexLAB is essentially two single reactors ... but with a much smaller footprint thanks to a more efficient design. With a FlexLAB available at ANSTO, multistep reactions could be more routine.”

 The FlexLAB in situ at ANSTO  image courtesy ANSTO

Researchers at Peter Mac have a keen interest in peptide radiolabelling for the development of tracers based on amino acids, and have been interested in accessing a dual reactor synthesis platform for some time.  Dr Peter Roselt says, “While such a platform is desirable for safe and reliable peptide radiolabelling, what excites us most about the FlexLAB is the ability to perform sophisticated HPLC purification on radiolabelled molecules arising from both reactors.

“As a result of further consultation with CRCBID partners and iPHASE Technologies, we are now looking to tailor this unit to meet some of the particular challenges peptide and protein labelling present.”

The FlexLAB prototype has been undergoing testing by ANSTO scientists Naomi Wyatt and Maxine Grant since December 2010, and they have been pleased to have the opportunity of working with the unit.  “I like the set up,” says Naomi Watt.  “We can do everything that we have done in the past, but now it is all in the one system.  And it is easy to clean.”  She also values the system’s capacity to enable the automated sequence to be stepped through.

  image courtesy ANSTO

“Its safety is also really important,” says Maxine Grant (pictured above).  “And it has been great to be able to do separate purification steps with an HPLC system, and then do the second reaction without the need for manual intervention.”

Mr Stan Poniger, Director of iPHASE Technologies, says that one of the biggest challenges in developing FlexLAB was the requirement for two full synthesizers that would only occupy the space of one.  “But we made it work. We’ve developed some custom-made parts resulting in a reliable, inert unit that is compact in form.”

Based on user feedback from the prototype FlexLAB, Mr Poniger says that refinements will be made to the system’s software.  “We’re also looking at how to make FlexLAB easier to manufacture, and improve the ergonomic layout of the components for routine use and also maintenance purposes.”

“To see the development of a new product resulting from this CRCBID project is particularly rewarding,” says Greg Santamaria, Director of Cyclotek (Aust) Pty Ltd. “It’s results-driven research at its best, due to our researchers engaging proactively in the development process.  We were able to generate a product because they needed to solve a chemistry synthesis problem in one of the novel tracers being developed in CRCBID. As a result, we’ve now got a product that can be reproduced and manufactured here in Australia.  The system is to be used for synthesis of three new tracers within our radiopharmaceutical research stream – the glutamine research, our alternate melanoma molecule, and the work being done on duramycin.”

Overseas development of PET tracers has advanced significantly in recent years, not only within the commercial sphere but also within hospital and research institutions.  Providing a single, compact unit for synthesising tracers will broaden the research scope even further, and is therefore a very valuable tool.

“There is evidence that international markets are moving to adopting dual step reactors such as this one,” says David Krenus, Managing Director of Cyclotek (Aust) Pty Ltd.  “We will be looking to promote this product overseas in the coming months.”