Apparatus and Experiments Towards Fully Automated Medical Isotope Production Using an Ion Beam Accelerator

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors describe a potentially automatic Zr-89 production technique, which should improve the efficiency of the current existing process. This proposal seems to be relatively cost effective and also safer as human presence will be not required.
The specifications to implement this process are also described in detail and seem technically sound to implement (and optimize).  
Overall, the manuscript is well written, the content is suitable for publication and it fits well within the journal's themes. Some minor corrections below:

line 19 - maybe 'immune-PET imaging' would be better for the unfamiliar reader.
line 27 - perhaps use 'refractory Ta substrate'.
line 45 - please define PET here instead of in line 47
line 48-49 - Eave, t1/2, beta+ and Emax are not properly formatted. Please employ sub- and superscripts accordingly.  
line 64 - this listing is quite long, consider using itemization. Generally speaking, the manuscript would benefit from shorter paragraphs and a better use of listings/enumerations where applicable. Even schematics could be helpful too.
line 102 - superscript missing.
It would really help to have some form of scale in one of the figures to give the reader a better sense of the dimensions.
line 267 - rather than an intensity interval it is perhaps more useful to provide the integrated current delivered.
line 304 - minutes
line 564 - please correct reference format

One observation and possible suggestion to the authors is to employ some more schematics/lists (or any form of graphic means as visual support) for the process description. 
Doing so would definitely make it easier for unfamiliar readers to follow and might help the manuscript to reach a wider audience. Finally, another suggestion is to state (more clearly) some figures of merit at different steps, e.g. cost/time etc. 

Author Response

Reviewer 1

Comment 1 (Line 19): Maybe 'immune-PET imaging' would be better for the unfamiliar reader.
Response 1: Thank you for the helpful suggestion. We have updated the text to use the term "immune-PET imaging" to improve clarity and accessibility for readers who may be less familiar with the terminology.

Comment 2 (Line 27): Perhaps use 'refractory Ta substrate'.
Response 2: We appreciate the reviewer’s suggestion. The text has been revised to refer to the material as a "refractory Ta substrate" to improve technical accuracy and clarity.

Comment 3: Please define PET here instead of in line 47.
Response 3: Thank you for the suggestion. We have moved the definition of positron emission tomography (PET) to its first mention in the manuscript to improve clarity and assist readers who may be less familiar with the abbreviation.

Comment 4 (Lines 48–49): Eave, t₁/₂, beta⁺ and Emax are not properly formatted. Please employ sub- and superscripts accordingly.
Response 4: Thank you for pointing this out. We have revised the formatting throughout the manuscript to ensure correct subscript and superscript notation for physical quantities such as half-life (t₁_/₂), average and maximum positron energies (Eₐᵥₑ, Eₘₐₓ), and β⁺ emission symbols, in line with standard conventions.

Comment 5 (Line 64): This listing is quite long, consider using itemization. Generally speaking, the manuscript would benefit from shorter paragraphs and a better use of listings/enumerations where applicable. Even schematics could be helpful too.
Response 5: Thank you for the suggestion. We have revised the section to present the considerations for developing target and dissolution systems in an itemised format, improving readability and clarity. Additionally, we have reviewed the manuscript to shorten paragraphs and incorporate listings where appropriate. We also added a schematic (Figure 1) to visually support the workflow as recommended.

Comment 6: It would really help to have some form of scale in one of the figures to give the reader a better sense of the dimensions.
Response 6: Thank you for your helpful comment. We have updated Figure 3 to include dimensions for the target holder in the irradiation position, as now reflected in the caption: “Figure 3. Left: Target holder in the irradiation position (with dimensions shown); right: Target holder in the dissolution position.”

Comment 7 (Line 267): Rather than an intensity interval it is perhaps more useful to provide the integrated current delivered.
Response 7: Thank you for the suggestion. We have revised the sentence to report the estimated integrated current delivered during the irradiation, rather than just the beam intensity range.

Comment 8 (Line 304): "Minutes"
Response 8: Thank you for catching this. We have corrected the formatting to ensure the word "minutes" appears appropriately.

Comment 9 (Line 564): Please correct reference format.
Response 9: Thank you for your comment. The reference format has been corrected as requested.

General Point: One observation and possible suggestion to the authors is to employ some more schematics/lists (or any form of graphic means as visual support) for the process description. Doing so would definitely make it easier for unfamiliar readers to follow and might help the manuscript to reach a wider audience. Finally, another suggestion is to state (more clearly) some figures of merit at different steps, e.g. cost/time etc.
Response: Thank you for your valuable suggestions. In response, we have added Figure 1, which provides a schematic representation of the production process with clear visual flow and timing information to support reader understanding. We believe this addition improves accessibility for a broader audience. Key time requirements for each step are now also indicated in the figure to provide relevant figures of merit, as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

An excellent piece of work. This type of innovation is exactly what is needed in isotope production.

Author Response

Comment: An excellent piece of work. This type of innovation is exactly what is needed in isotope production.
Response: We sincerely thank the reviewer for the encouraging feedback. We are pleased to know that our work is seen as a valuable contribution to innovation in isotope production.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

In your manuscript, you describe a fully remote controlled setup, with the potential to handle the complete procedure beginning with radionuclide production up to photochemical radiolabeling.

This comprises a very interesting project and you doing very well in describing the experimental setup and technical developments, but there a several points I would like to address to allow for a thorough assessment of your work.

1. The design and dimension of your apparatus are well described, however many important numbers regarding the functionality are missing: heating – what temperatures can you achieve? Cooling – what is the cooling power of your installation? Liquid handling – what liquids and in what volume can you use? Your custom-made glass beaker was called the core of the unit but only its casing is shown. Was this done on purpose? (That would be o.k., just say so.)
2. Automated process versus remote controlled process: Both is fine, but please specify which part of the process is done remotely and which is done automated (software controlled)?
3. Please revise your experimental section. You describe different chemical processes, but I cannot clearly follow, if those experiments were done using your module or if they were proof-of-principle experiments prior to your developments. How are the individual steps (irradiation, dissolution, separation labelling) connected? And did you do a complete test run of the whole process? Was a photo-labelling experiment done with your setup? This section is rather crucial for your work, as it has the potential to differentiate between a “good idea” and an auspicious development.
4. Your tests were only done at low beam currents. In your view, what are the prospects and challenges of scaling up to clinical radiotracer production?
5. For your all-in-one setup a significant amount of electronic equipment needs to be close to the radiation facility. Could this turn out to be a problem?
6. At least for the radiolabeling part, there are automated modules available already. Would you like to briefly comment on those in comparison to your work?

Author Response

Comment 1: The design and dimension of your apparatus are well described, however many important numbers regarding the functionality are missing: heating – what temperatures can you achieve? Cooling – what is the cooling power of your installation? Liquid handling – what liquids and in what volume can you use? Your custom-made glass beaker was called the core of the unit but only its casing is shown. Was this done on purpose? (That would be o.k., just say so.)
Response 1: We thank the reviewer for this detailed and constructive comment. In response, we have updated the manuscript to provide quantitative details and additional clarification:

1. Heating: If the comment refers to the target head, we note that the system can withstand temperatures well in excess of 200 °C, as already stated in the manuscript. If the comment refers to the vortex mixer, we have now added to Section 2.4 that the vortex mixer has been successfully operated at temperatures up to 95 °C with water, and that the heater can raise the temperature to approximately 140 °C for liquids that do not boil below this point and are compatible with quartz glass.
2. Cooling: The section on the target holder has been updated to include that we used a K1 chiller with a cooling capacity of 1750 W, which maintained a stable temperature of 5 °C during irradiation.
3. Liquid handling: The system was tested with aqueous solutions and dilute mineral acids. Peristaltic pumps were calibrated to handle up to 50 mL per cycle, ensuring precise liquid transfer and control. This information has been added to the relevant section describing liquid handling.
4. Glass beaker: The custom quartz beaker, which appeared as Figure 16 in the previous version of the manuscript, is now incorporated into Figure 9b alongside the casing for improved clarity. Please note that Figure 16 in the current version refers to a different figure.

Comment 2: Automated process versus remote controlled process: Both is fine, but please specify which part of the process is done remotely and which is done automated (software controlled)?
Response: Thank you for this helpful observation. In response, we have revised the manuscript to consistently describe the system as automated, reflecting that all processes are software-controlled locally rather than operated remotely.

Comment 3: Please revise your experimental section. You describe different chemical processes, but I cannot clearly follow if those experiments were done using your module or if they were proof-of-principle experiments prior to your developments. How are the individual steps (irradiation, dissolution, separation, labelling) connected? And did you do a complete test run of the whole process? Was a photolabelling experiment done with your setup? This section is rather crucial for your work, as it has the potential to differentiate between a “good idea” and an auspicious development.
Response 3: Thank you for this insightful and important comment. In response, we have revised the manuscript to clearly distinguish between proof-of-principle studies and integrated experiments performed using the developed automated system. Specifically:

• The chemical separation experiments (Zr/Y separation) were conducted using our automated chemical separation unit as described in Figure 7. These were performed using non-radioactive zirconium and yttrium surrogates due to temporary limitations in access to the accelerator facility. This enabled safe and effective optimisation of resin performance, flow rates, and chemical handling without radiological constraints.
• A clarifying sentence has been added to the methods section to confirm that the separation process was performed using the automated unit.
• The connection between the individual stages—irradiation, dissolution, separation, and labelling—is now explicitly described in the introduction, and a schematic representation of this modular integration is provided in Figure 1.
• While photolabelling was not carried out in this study, the vortex mixing and controlled heating components of the integrated photolabelling system were successfully validated using non-radioactive model systems. However, the photolabelling function itself, including UV-activated labelling, has not yet been experimentally validated and remains a subject for future work. This has been noted in the methods section.
• Additionally, we note in the Conclusion that in a follow-on project, the system has been further upgraded and successfully used to produce medical isotopes of copper and scandium. Complete test runs of the full process—from irradiation through to separation and final product—have been demonstrated for both isotopes. These upgrades and innovations will be reported in a future publication.
  We hope these additions and clarifications adequately address the reviewer’s concerns and help distinguish the current work as a robust and evolving development platform.

Comment 4: Your tests were only done at low beam currents. In your view, what are the prospects and limitations for scaling up?
Response 4: Thank you for this insightful comment. The beam currents used in this study were constrained by the specifications of the available vacuum window at the time of testing. However, a new vacuum window has since been commissioned, enabling irradiation at beam currents of up to 50 µA. Based on current yield estimates, this would facilitate the production of approximately 50 GBq/hour of ⁸⁹Zr, subject to internal permit limits. This level of output would be more than sufficient to support clinical radiotracer production. We appreciate the opportunity to highlight the scalability of the system and the proactive steps being taken to support clinical-level implementation.

Comment 5: For your all-in-one setup, a significant amount of electronic equipment needs to be close to the radiation facility. Could this turn out to be a problem?
Response 5: Thank you for raising this important point. We would like to clarify that the electronics used in our setup are simple, low-cost, and designed to be robust. Additionally, all electronic components are located within a hot cell and are not exposed to direct radiation from the primary ion beam. The system receives only low levels of secondary radiation—primarily from positron and gamma emissions—measured to be well below 1 mGy/hour. This is significantly lower than the tens of Gray typically associated with radiation-induced damage to electronics.
We appreciate the opportunity to clarify this aspect of the system design.

Comment 6: At least for the radiolabelling part, there are automated modules available already. Would you like to briefly comment on those in comparison to your work?
Response 6: Thank you for this important comment. In response, we have expanded the relevant section of the manuscript (Section 4.3) to briefly compare our system with previously reported automated photolabeling modules. Specifically, we now reference the work by Klingler et al., who developed a photolabeling module tailored specifically for ⁸⁹Zr-labeled antibodies. We clarify that while their system is highly effective for a dedicated purpose, our platform is distinct in its modular design, which integrates irradiation and dissolution (within the target holder), chemical separation, and photolabeling in dedicated but connected units. This modularity enables broader flexibility in adapting the system to other isotopes and labelling chemistries. We believe this distinction demonstrates the versatility and scalability of our platform beyond a single radiolabelling application.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for taking all my comments into consideration, and for the substantial work they did in improving the manuscript quality overall.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for revising your manuscript so thoroughly. 

I do not have any further comments or requests and recommend it for publication.