Production and Regulatory Issues for Theranostics

Abstract

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the recent introduction of approved therapeutics in neuroendocrine tumours and prostate cancer, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this review we explore the issues impacting on access and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that may impact on availability of theranostic treatments for patients.

Introduction

In recent years, theranostics has emerged as a transformative change in the landscape of personalized and precision medicine, offering the potential to revolutionize cancer diagnosis and treatment.^1,2 Theranostics in cancer therapy combines imaging of targets in-vivo with radiopharmaceuticals, and after confirmation of expression of the target, using a therapeutic radiopharmaceutical to deliver radiation specifically to the tumor^1,2. Combining therapeutic and diagnostic capabilities, theranostics allows for precise targeting of tumour cells and real-time monitoring of treatment response. The development of radionuclide theranostic agents has seen significant progress, with an increasing number of regulatory approvals and opportunities for new indications. However, challenges still exist in terms of access, availability, radionuclide production, distribution, waste management, and regulatory aspects.^1–13

The aim of this paper is to provide an in-depth analysis of radiopharmaceuticals associated with theranostics, focusing on issues relating to access and availability and implications for new treatments. We also discuss the available regulatory pathways for investigational drug studies and explore strategies for efficient nonclinical and clinical product development for theranostic pairs.

The growing interest in theranostics has led to advancements in imaging and therapy radiopharmaceuticals. However, disparities in access and availability remain, particularly in low- and middle-income countries.^{1–3, 14–17} Radionuclide production is a crucial aspect of theranostics, as it directly impacts the capacity and capability to meet the increasing demand.^1,18–19 Distribution and waste management are also essential components of theranostics, as they ensure the safe and efficient use of radiopharmaceuticals.^20–22 We will discuss the current distribution systems, waste management practices, and the regulatory aspects governing their implementation.

Lastly, we will explore the regulatory pathways for the production and patient use of theranostic agents. Understanding these pathways is essential for the successful development and commercialization of new theranostic drugs and technologies.^1,2 Our discussion will include an examination of regulatory challenges and potential strategies to streamline the process for future theranostic developments.

Standard production

Radiopharmaceuticals are medicinal products. Their production must be performed under carefully controlled conditions and their quality must be tested before administration to patients, using validated standard operating procedures. The last few years have seen important changes in the development and chemistry of radiopharmaceuticals that have been introduced in clinical practice. These changes have led to new delivery requirements and processes, mainly patient centric.⁴

The production of radiopharmaceuticals typically involves the incorporation of radionuclides with a targeting ligand, with radionuclides either produced by nuclear research reactors, linear accelerators or cyclotrons, generators, and chemical processing (Table 1). So far, more than 100 radiopharmaceuticals have been approved and received market authorisation in individual countries, and over 400 are in clinical development.^1–3,23

Table 1.

Radionuclides useful in nuclear medicine and their production routes

Main applications	PET	SPECT	Therapy
Medical radionuclides produced in reactors
Fission products		99Mo/99mTc, 133Xe	89Sr, 90Sr, 90Y, 106Ru, 131I, 131Te, 137Cs,
Neutron activation	(64Cu)	(24Na), (42K), 47Ca, (51Cr), 59Fe, 75Se, 81Rb, 99Mo, (125I), 153Sm	32P, 57Co, 58Co, 60Co, 67Cu, 90Y, 103Pd, 117mSn, 125I, 131I, 153Sm, 161Tb, 165Dy, 166Dy, 169Er, 177Lu, 186Re, 188Re, 188W, 192Ir, 213Bi, 228Th
Non-generator decay products		-	211Rn, 212Bi, 212Pb, 223Ra, 224Ra, 226Ra, 225Ac, 227Ac, 229Th, 232Th, 251Cf
Medical radionuclides produced with accelerators and distributed per cyclotron energy (size)
<6 MeV	(11C), [13N]d, 15O, [15O]d, [43Sc]d	-	-
<15 MeV	11C, 13N, 18F, 22Na, 43Sc, [43Sc]α, 64Cu, 68Ga, 77Br, 94mTc, (124I), 132La	(67Ga), (111In), 127Xe	[57Co]d, 135La
15–24 MeV	18F, [18F]d, 44Sc, 52Mn, 61Cu, 63Zn, [64Cu]d, 68Ga, 76Br, 86Y, [86Y]He, 89Zr, [89Zr]d, 124I	81Rb, [81Rb]He, [81Rb]α, 99mTc, (123I), 203Pb	(57Co), 103Pd, 114mIn, [125I]d, 225Ac, 77Br
25–54 MeV	62Zn, [64Cu]d, 68Ge, 72Se, [76Br]He, [82Sr]He, [82Sr]α, [86Y]d	44Ti, 67Ga, (99Mo), ([99Mo]α), 111In, ([111In]α), 123I, (127Xe), 201Tl	([32P]d), 47Sc, (57Co), (67Cu), [117mSn]α, (131Cs), 169Yb, 211At
55–75 MeV	(22Na), 82Sr	(127Xe)	67Cu, (103Pd), 117mSn,
>75 MeV	(82Sr)	-	(67Cu), (225Ac)
Medical radionuclides produced with linear accelerators (linacs, betatrons or Rhodotrons)
(γ,n) reaction basis		(99Mo)	47Sc, 67Cu, 212Pb, 225Ac
Deutons acceleration			177Lu, 225Ac
Alpha particles	(68Ge), (82Sr)	(99Mo)	47Sc, 67Cu, 117mSn, 211At
Medical radionuclides produced in generators
Generator daughter radionuclides	44Sc, 52mMn, 62Cu, 68Ga, 82Rb	81mKr, 99mTc, 113mIn, 115mIn	90Y, 166Ho, 188Re, 211At, 212Pb, 213Bi, 225Ac

• Radionuclides have been split into PET, SPECT and therapeutic subtypes, but if a radionuclide could belong to both categories, it appears only in the main application subgroup
• When a radionuclide appears twice, this means there are several production routes
• Brackets () are used to indicate an alternative route, not the standard or preferred route
• Square brackets [ ] indicate an alternative route that is not based on a proton beam. In this case, the brackets are followed by a code indicating the type of beam (d for deutons, He for Helium beam, and α for alpha beam)
• Radionuclides now mainly useful for in vitro diagnostic or limited to animal studies are provided under the SPECT heading (they are all gamma emitters) and appear between brackets
• Parent radionuclides used in generators are listed in the column corresponding to the application of the daughter nuclide

Source: Reference²³; www.medraysintell.com

In contrast with conventional pharmaceuticals, radiopharmaceuticals are produced on a relatively small scale. However, several aspects can be quite demanding for small-scale manufacturers. The major challenge is the half-life of the radionuclide, and the decay that will limit availability of the drug over time. This half-life directly impacts the distance to final customer and the geographic distribution and number of manufacturing sites. Other aspects include the operation and maintenance of processing facilities, compliance with current good manufacturing practices (GMP), effective quality assurance and quality control systems, radioactive material transport and distribution networks, and registration of the products with the relevant health authorities. Wide variations exist in the availability of radionuclides produced in reactors and in medical cyclotrons, and Good Manufacturing Practice (GMP) compliant production facilities, which can also lead to substantial differences in costs between commercial suppliers and ‘in-house’ producers.^{1–2, 11, 24}

Compared to conventional cancer therapies, both manufacturing (central or local) and logistics (delivery, application, and waste management) should be adapted to compensate for the shelf-lives of radiopharmaceuticals, mainly related to the radioactive half-lives of the radionuclides.^4,11,21

To bring benefits to patients in all countries and to overcome inequalities in access to healthcare, diagnostic and theranostics agents should be made available and accessible worldwide.^14,25 Reliable distribution networks capable of ensuring both secure and timely delivery of these agents must be established to meet the rapid increase in demand. In addition, the limited global supply of some radionuclides, which are often used for theranostic applications, also poses challenges.^1–3,14,25 Furthermore, the infrastructure available in some countries, particularly in middle- and low-income countries, may also limit the implementation of some strategies and/or requires modifications, such as the need for use of SPECT radiopharmaceuticals for the diagnostic portion of theranostics instead of PET in countries with a scarcity of PET scanners.¹⁴

Research Reactor Produced Radionuclides

Historically research reactors and their fission products were the first radionuclide production sources for medical applications. Starting in the 1940‟s, iodine-131 was introduced for human application, as one of the first medically used radioisotope/radiopharmaceutical, and a perfect theranostic radiopharmaceutical with extraordinary physiological and nuclear properties. Since then, many research reactors worldwide have been installed and produced crucial radionuclides for imaging and therapy, such as ⁹⁹Mo, ¹³¹I, and ¹⁷⁷Lu (Table 3) (Figure 1).^18,19,23

Table 3.

Medical cyclotron installations worldwide

	Cyclotrons Total		<25 MeV: very small to medium size cyclotrons		25 to 70 MeV: large size cyclotrons
	2019	est. 2023	2019	est. 2023	2019	est. 2023
Asia (total) Among which	687	~800	648	>750	39	>50
China	231	~320	224	>310	7	>10
Japan	202	~215	191	~200	11	>15
Russia	48	~55	45	~50	3	~5
Europe	302	~320	263	~280	39	>40
North America	319	~335	285	~300	34	~35
Central and South America	54	~60	51	<60	3	<5
Africa	25	~25	23	~25	2	3
Oceania	17	~18	19	~18	0	0
Total World	1,406	>1,550	1,289	>1,430	117	>140

Figures up to end of 2023 are extrapolated from actual Cyclotrons figures as of end of 2019 with complete references available for each individual cyclotron, from Goethals PE and Zimmermann R, MEDraysintell report “Cyclotrons used in Nuclear Medicine Report & Directory, Edition 2020”²⁷, updated by the authors to end of 2023, www.medraysintell.com (January 2024). Also, decommissioned cyclotrons during this 2020–2023 period have not all been identified.

Figure 1.

World map showing the distribution of research reactors used in the production of radionuclides. Large capacity reactors for radionuclide production are in Europe (Belgium, Netherlands), Australia and South Africa.

The production of the main medical radionuclides (⁹⁹Mo, ¹⁷⁷Lu, ¹³¹I) is based on the capacity of the 4 major large scale research reactors (size defined in terms of their capacity in producing radionuclides) and the 5 medium size reactors reported in Table 2. The definition for high capacity reactors is not related to the size of the unit, nor to the neutron flux, but to the availability and real use of these reactors over the year, while the definition of medium size reactors definition relates to the reactors which other priorities have been affected and cannot supply as large amounts all over the year, or that are used only as non-regular supply sources, or that have lower capacity compared to the reactors on which the industry can rely but still enough to compensate over short periods for large capacity reactors during shutdown periods. Altogether, one can estimate that this capacity is equivalent to 6 large scale reactors operating in parallel, a figure that could be increased to the equivalent of 9 large scale reactors capacity by adding all the smaller units that could become operational in this field but probably not earlier than 2035. New large reactors under construction (RA-10, HJR, Pallas, MBIR, PIK) are primarily intended to replace decommissioned or to be shut down reactors (such as RA-3, Osiris, HFR, Argus, etc). Current production capacity for ⁹⁹Mo for ^99mTc generators, and ¹³¹I, has been shown to be sufficient for global use, although recent supply chain issues due to COVID-19 have been challenging.^{15–17,23,25} The construction of research reactors is an expensive and lengthy process, hence the capacity of existing research reactors for radionuclide production is a constraint on production requirements for some radionuclides for theranostics. It is imperative however to underscore the importance of ^99mTc agents, particularly in low-income countries that do not have access to PET scanners. The continued availability of ^99mTc generators and the development of precursors suitable for ^99mTc for these companion diagnostics needs to be supported, including accessibility to ^99mTc-PSMA, ^99mTc-SSTR2 analogues and emerging agents for theranostic purposes.

Table 2.

Research reactors for radionuclide production

Research reactors	Operational	Under construction	Planned
Total reported	222	11	13
Reactors with potential of radionuclide production	79	6	9
Reactors with industrial production capacity (*)	30	5	8
Larger units (none of the listed reactors under construction or planned will be operational by 2032) (**)	Large capacity: 4 units Australia (Opal), Belgium (BR-2), Netherlands (HFR), South Africa (SAFARI-1)	5 units: Argentina (RA-10), France (HJR), Netherlands (Pallas), Russia (MBIR, PIK)	5 units: Belgium (Myrrha) Brazil (RMB), India (HFRR, TRR), South Africa (Safari-2),
	Medium capacity: 5 units Argentina (RA-3), Czech Republic (LVR-15), Germany (FRM II), Poland (MARIA), USA (MURR)		3 units: Korea (KJRR), UK (Arthur), USA (MURR NextGen)
Reactors dedicated to local use or local non-medical radionuclide production, or with limited capacities (***)	19 units: Algeria (Es-Salam), China (CARR, HFETR), Egypt (ETRR-2), Hungary (BRR), India (Dhruva, FBTR), Indonesia (RGS-GAS), Iran (TRR), Japan (JRR-3M), Republic of Korea (Hanaro), Pakistan (PARR-1), Romania (TRIGA II), Russia (BOR-60, IVV-2M, MIR-M1, SM-3, WWR-TS), Uzbekistan (WWR SM)	Several small capacity reactors could be adapted to the production of radionuclides, at least for local use.
Large capacity reactors presently in use for some radionuclide production, with high potential	2 units: USA, (ATR, HFIR)

^(*)reactors with thermal power >10 MW and neutron flux > 1e12 n/cm²-sec

^(**)all reactors under construction are in fact supposed to replace older units that will be decommissioned, and therefore only limited additional capacity.

^(***)Presently capacity from operational reactors in Russia, India and China will probably continue to be entirely dedicated to local use

Source: IAEA Research Reactor Database https://nucleus.iaea.org/rrdb/#/home¹⁸ and MEDraysintell Nuclear Medicine Report 2023 Part 1 https://medraysintell.com²³

To estimate the global ¹⁷⁷Lu production capacity of these reactors (which is the therapeutic radioisotope of currently approved theranostics for neuroendocrine tumours and prostate cancer), one can consider that one of these large units could irradiate 4 to 6 ampoules (targets) in 5 to 10 capsules (positions), each ampoule being loaded with 1 to 2g of ¹⁷⁶Yb. Taking into account maintenance periods and time for target loading, and availability of enriched target material, such reactors can be operational between 26 and 45 weeks a year, depending upon local technology. One week of irradiation could become average standard. The extraction yield after irradiation of 1g of ¹⁷⁶Yb can lead to between 20 and 40 Ci ¹⁷⁷Lu (end of irradiation, EOI). On this basis, a rough calculation of capacity for a single large size reactor would lead to an estimation of 34 (2023) to 68 kCi/year (2032), based on an average 5 capsules times 6 targets (twice as much in 2032) times 30 operational weeks/year times 25 Ci yield per gram and 1.5 g in average per ampoule. With 6 (2023) or 9 (2032) large scale reactor equivalents, the total worldwide irradiation capacity could potentially increase from 204 kCi/year to 612 kCi/year by 2032.

There is presently some difficulty in accessing ¹⁷⁶Yb, as this material is available only from a major Russian source and another North American company is beginning to produce quantities of ¹⁷⁶Yb. There is still a challenge for others such as ¹⁶⁰Gd for ¹⁶¹Tb production, and other emerging theranostics. This is a transient situation as several private companies and public institutions have initiated a program of large-scale production of this isotope, and even if some of them will not reach the completion of their program, larger additional amounts will be available by 2026 from these sources. The situation is similar to the access to ¹⁸O-enriched water for the production of ¹⁸F in the years 2000‟s which was solved within five years, leading to increased supply and reduced cost. An additional important point to take in account relates to the competition with other radionuclides, as the production of ¹⁶¹Tb needs the same equipment and the same irradiations slots as ¹⁷⁷Lu. There is also loss in activity related to shipping and distribution to countries distant from the site of production.

In the absence of investment in new large size research reactors and next to increasing the level of production capacity of small reactors, there are some variations and improvements possible in adapting the irradiation slots and changing the priorities, but in any case, even if these figures can be improved, they will hit very quickly a plateau. New non-reactor-based technologies need to be developed. Some of them already are financed, but this is not sufficient for new radionuclides. Alternative routes to produce ⁹⁹Mo (i.e., increasing access to ^99mTc) will be operational soon, while some interesting solutions can be further developed to increase access to ¹⁷⁷Lu.²⁶ If ¹⁶¹Tb will be needed in high capacity by 2032, development of new production routes for this radionuclide will need to be explored.

Cyclotron-produced radionuclides

Cyclotrons are typically used to produce diagnostic radionuclides that emit positrons and can be used for diagnostic indications in theranostics, although therapeutic radionuclides can also be produced with higher energy cyclotrons (Table 3). Investment in cyclotrons to produce diagnostic radionuclides has progressed globally, while therapeutic radionuclide production is expanding capacity to address the anticipated demand particularly for α-emitting therapeutic radionuclides (Table 3) (Figure 2). The location and operation of medical cyclotrons globally is distributed mainly in high income countries, which has impacts on the access and availability of these radionuclides (which are typically short-lived) in low- and middle-income countries.

Figure 2.

World map showing the worldwide distribution of cyclotrons used in the production of radionuclides.

The establishment of cyclotrons throughout the world has been primarily driven to date by requirements for short-lived PET radioisotopes (e.g. ¹⁸F, ¹¹C), and investment cost is dependent on the size of the cyclotron installed. The number of cyclotrons has also been dependent on the demand and half-life of PET radiopharmaceuticals produced.²⁷ The use of cyclotrons for production of long half-life imaging PET radionuclides (e.g. ⁶⁴Cu, ⁸⁹Zr, ¹²⁴I), or therapeutic radionuclides (e.g. ²²⁵Ac, ²¹¹At, ⁶⁷Cu) requires investment in high capacity cyclotrons with different sources or in electron accelerators (e.g. ²²⁵Ac, ⁶⁷Cu) as well as in supply chains suitable for distribution (Table 1). The availability of these radionuclides, especially α-emitters, will require careful planning for clinical trials and ultimately production capacity. Additionally, the nuclear reaction cross-sections (probability of a specific reaction occurring) to produce isotopes via charged particle reactions is typically several orders of magnitude lower than for neutron induced reactions, thus production of therapeutic radionuclides via particle accelerators is currently limited to a handful of specific cases (mainly alpha emitters).

New technologies to produce some therapeutic radionuclides, alternative to cyclotrons, such as linear accelerators or Rhodotrons are starting to be installed and could be operational before 2025 for radionuclides such as ⁹⁹Mo or ²²⁵Ac (Table 1).²⁸ These same facilities could be used for large scale production of ⁶⁷Cu.

Generator-produced radionuclides

Radionuclide generators are devices that allow for the isolation and purification of a short-lived nuclides from the decay of a longer-lived parent radionuclide – the ^99mTc/⁹⁹Mo generator perhaps being the most widely used and accepted. The daughter radionuclide is general a different element than the parent allowing for the collection of the destined nuclide by an elution method. The use of a generator allows for the local production (often in a radiopharmacy) of a radionuclide without the need for an in-house cyclotron or other accelerator. This is of particular importance when the desired nuclide has a relatively short radioactive half-life e.g., obtained ⁶⁸Ga from a ⁶⁸Ga/⁶⁸Ge generator. Generators can also be used for several therapeutic radionuclides, including ¹⁸⁸Re, ¹⁶⁶Ho, ²¹³Bi, ²¹¹At, ⁹⁰Y, ²²⁵Ac and ²¹²Pb (Table 1). While many of these generator produced radionuclides have been evaluated in the clinic as part of theranostic treatments, such as ¹⁸⁸Re with ¹⁸⁸W/¹⁸⁸Re generators, there is an increasing interest in the development of ²¹²Pb through ²²⁸Th/²²⁴Ra/²²⁰Rn/²¹²Pb generators. More than 15 companies are currently involved in ²¹²Pb-labeled drug development, and most of these companies are developing in parallel their own technology of ²¹²Pb generators.²⁹ Both ¹⁸⁸W and ²²⁸Th do not have issues with availability, which may also positively impact the cost of these therapeutic radionuclides, and provide competitive opportunities compared to ¹⁷⁷Lu and ²²⁵Ac. These generators have the advantage of local site availability and avoiding unreliable supply chains. These generators typically have capacity of a maximum of 3 to 6 doses a day. In the future, if these radionuclides are required for clinical use then larger scale generators will need to be developed and installed at central locations for production of therapeutic radiopharmaceuticals.

Clinical Production of Theranostic Radiopharmaceuticals

The development of radionuclides for imaging and therapy dates to the initial development of ¹³¹I for treatment of thyrotoxicosis and thyroid cancer in the 1940’s. Subsequent development and approval of radiopharmaceuticals for treatment of lymphoma, liver cancer and bone metastases established the role of nuclear medicine in patient care.^{1,2,7, 30,31} The more recent development and clinical use of ⁶⁸Ga-, / ¹⁷⁷Lu-DOTATATE for the diagnosis and treatment of neuroendocrine tumours has paved the way for novel, specific, safe and effective nuclear theranostics for the management of various cancers that express specific receptors. With the approval of ¹⁷⁷Lu-PSMA by the FDA and EMA the medical community anticipates a significant increase in clinical utilization of nuclear theranostics, recognising that approvals of these treatments in many countries is still awaited. Besides the marked increase in the clinical use of ¹⁷⁷Lu-PSMA for the treatment of metastatic prostate cancers, other therapies in brain, kidney, lung, colon and breast cancer are in early phase of development, both in the adult and paediatric populations.^1,2,31 The This surge in demand and utilization of nuclear theranostics will require appropriate and additional infrastructure and skilled health care professionals and represents both a challenge and opportunity for medical school and healthcare systems.^9,32–34

In most countries access to nuclear theranostics procedures is currently limited, essentially due to the fragility of supply chains, regulatory approvals, and the impact of costs.³ Even in countries with a strong track record in theranostics, the existing infrastructure, related to production/shipping and site capabilities, may be insufficient to meet the growing demand.

Projections of requirements for radionuclides necessary for imaging and therapy need to consider the existing and anticipated requirements for approved theranostic indications. The development of new theranostic radiopharmaceuticals is driven by commercial development by existing and new companies globally.^1,2,31 Radionuclide supply remains a key factor in implementation of theranostics, with cyclotron access being driven primarily by industry initiatives, and research reactors primarily by government programs due to cost and regulatory burden.

The projected amount of radionuclide required for typical theranostic patient doses is outlined in Table 4. The figures provided consider the losses due to radionuclide decay during processing and transport, as well as the typical yields of radiolabelling, and time to administration. Based on these calculations, the number of patients who could be treated with ¹⁷⁷Lu-theranostics (current global ¹⁷⁷Lu supply capacity approximately 200kCi/year) would be around 200,000 patients per year, worldwide. Projected numbers in the US for current approved indications for neuroendocrine cancer (¹⁷⁷Lu-DOTATATE) and prostate cancer (¹⁷⁷Lu-PSMA) are around 41,500 patients per year, which are likely to substantially increase as new indications are approved.³⁵ The global requirements for ¹⁷⁷Lu will necessitate increased production capacity, which is being addressed in the available research reactors (see prior section), but some limits will remain. In this context, and with increasing exploration of α-emitters (which typically require lower doses) for theranostic radiopharmaceutical trials, the development of production capacity that is not reactor based will be increasingly important. The production of ¹⁶¹Tb for novel theranostics may also impact on ¹⁷⁷Lu production due to both radionuclides requiring similar target enrichment, reactor access and will therefore require careful planning and implementation of production facilities.

Table 4.

Theranostic Radionuclide Production Requirements

Radionuclide	Source	Average activity-dose (pre-labelling)	EOI activity per dose	Number of doses per patient	Yearly needs to treat 100K patients
67Cu - t½: 2.6 d	Accelerator	200 mCi 7.4 GBq	600 mCi 23 GBq	2 to 6 – average 3	180 kCi 6.6 106 GBq
177Lu - t½: 6.7 d	Reactor	200 mCi 7.4 GBq	400 mCi 15 GBq	2 to 6 – average 3	120 kCi 4.4 106 GBq
211At - t½: 7.2 h	Accelerator	6 mCi 200 MBq	25 mCi 925 MBq	2 to 4 – average 3	7.5 kCi 2.8 105 GBq
212Pb - t½: 10.6 h	Industrial generator	5–6 mCi 200 MBq	18 mCi 666 MBq	2 to 4 – average 3	5.4 kCi 2.0 105 GBq
225Ac - t½: 9.92 d	Accelerator Generator	3 μCi/kg 100 kBq/kg	330 μCi 12 MBq	2 to 4 – average 3	100 Ci 3,700 GBq

• Average activity doses correspond to the average amount ordered for peptide radiolabelling. Not all activity will be injected into patients but this value takes into account decay losses during handling, losses due to synthesis yields and adaptation to the patient weight. Variation can apply if antibody or peptides are used as targeting therapeutic approaches. Figures correspond to 2023 average dose sold for marketed products, but higher doses could be used in the future with different theranostic approaches.
• The End of Irradiation (EOI) activity is an estimate of the amount needed to be produced to guarantee the average activity dose at calibration. It takes into account extraction from target yields, and losses due to decay during transportation
• Calculations are based on an average of 3 treatments per patient, noting that for some patients the number of treatments can be up to 6 or more depending on response.

Nuclear theranostics manufacturing, supply, distribution and access must provide equitable access and availability for patients across the globe. The production of approved radiopharmaceuticals for theranostic use is principally through commercial facilities and suppliers, and the development of new theranostic radiopharmaceuticals is also driven primarily by industry sponsored trials.^1,2 In-house (hospital-based) preparation of radiopharmaceuticals is an essential practice for nuclear medicine in many countries, and in some countries extends to theranostic radiopharmaceuticals for investigator-initiated trials, and clinical use. The importance of a suitable regulatory framework for patient access of radiopharmaceuticals has been recently addressed by the IAEA.³⁶ The need for in-house preparations is expected to increase when considering the rapid development of the field, both in terms of technical advances (e.g., new radionuclides, including short-lived radionuclides from generators, new technologies for automated production), and current and upcoming targeted therapies that will be part of precision medicine.

Development and Regulatory Issues for Theranostics

The development of new radiopharmaceuticals usually takes place in radiopharmacies, research centres or nuclear medicine laboratories linked to nuclear medicine sites for clinical trials. During the last decade, all major clinical breakthroughs in theranostics in Nuclear Medicine, exemplified by the success of radiolabelled somatostatin analogs and prostate cancer applications, have originated in academia and research radiopharmacies. After preclinical validation, and in some cases early phase clinical trials, these new radiopharmaceuticals frequently make their way to pharmaceutical and biotech companies which have extended clinical development into later stage clinical trials.

The number of dedicated clinical trials of theranostics continues to increase.^1,2,31 This development is driven by several factors, including: the perspective and potential of theranostic radiopharmaceuticals to significantly improve the quality of life and lifespan of cancer patients; the promising preliminary results attained with some of the radiopharmaceuticals tested clinically; the growing availability of multimodality/hybrid imaging technologies for better cancer detection and monitoring; and the increasing applications of nuclear oncology.

The development of radiopharmaceuticals needs extensive evaluation before clinical application, and have some differences compared to typical drugs.^1,2,36 To ensure the quality of these new products, chemical, radiochemical, and pharmaceutical parameters must be defined, implemented and verified. Preclinical tests are required to provide supportive evidence for the potential in vivo behavior in humans, and to bring innovative diagnostic and therapeutic radiopharmaceuticals into clinical evaluation in a safe and effective way. These tests include non-clinical pharmacology, radiation exposure and dosimetry, toxicological studies, pharmacokinetic modelling, and imaging studies. To transition into clinical trials, strategies for human use production of the radiopharmaceutical including scale up, stability quality control and sterility must be developed by academic centres or research partners. In some case, this may require extensive changes to the chemistry to be compliant with local and federal guidelines.³⁷

From a regulatory perspective, the development and approval of new theranostic radiopharmaceuticals will follow established guidelines in each country. Radiopharmaceutical production in commercial radiopharmacies is performed under Good Manufacturing Practice (GMP) guidelines. For hospital-based radiopharmacies, the radiopharmaceuticals should be manufactured by a trained radiopharmaceutical scientist (radiochemist or radiopharmacist) using appropriate standard operating procedures (SOP) under Good Laboratory Practice (GLP) adopted for continued process control and high-quality standards. Where applicable, radiopharmaceuticals should be prepared according to regulatory and monograph guidelines.^4,11,36–39 A risk-based approach to process validation should be completed prior to preparing radiopharmaceuticals for human use. Equipment used in the manufacturing and quality control testing of radiopharmaceuticals should be certified at installation and routine checks and calibration to ensure reliability in operation, and ongoing maintenance and use logs for critical equipment are also recommended. The staff involved in the production of theranostic radiopharmaceutical should be required to follow all the training and certifications for initial and professional qualification and continuing education.^9,32–34

Prior to marketing approval, national regulatory bodies must review the safety and efficacy of any proposed theranostic treatment or imaging agents. Novel agents can be administered to patients prior to marketing approval under the auspices of a clinical trial; however, full regulatory approval generally forms the basis for the initiation of widespread clinical use and the initiation of reimbursement systems by both government agencies and private insurers. A lack of co-ordination of approval processes between different regulatory agencies can delay availability of theranostics: for example, many countries do not recognize the approval decisions of other national agencies and independent national regulatory review is required prior to marketing approval, often leading to delays and/or additional administrative costs. There may also be different approval decisions made in countries owing to the application of different thresholds for clinical benefit and/or cost effectiveness.⁴⁰ The complexity of the processes leading to discovery, testing, production, approval, and marketing of clinical radiopharmaceuticals highlight the fact that drug development should generate data that must be impactful for scientific, regulation and funding basis. Single observational studies should therefore be replaced by prospective multicentre international trials, to generate more expeditiously evidence-based conclusions.^1,2 This can be undertaken with industry sponsored studies (eg VISION trial⁴¹), or through co-operative clinical group trials (eg TheraP trial⁴²) where engagement between academic clinical trial groups and companies can lead to highly impactful evidence leading to regulatory approval of theranostics.

Waste management for therapy patients and radionuclide pharmacies is a critical aspect of maintaining safety in the use of radiopharmaceuticals. The IAEA has provided guidelines and recommendations on handling and disposing of radioactive waste generated by therapy patients and radionuclide pharmacies.^20–22 These guidelines emphasize the importance of establishing waste management systems that minimize the current and future risk of radiation exposure to healthcare workers, patients, and the environment. Such systems should include the segregation, collection, storage, treatment, and disposal of radioactive waste in accordance with IAEA safety standards and local regulations. Proper training and education for personnel involved in waste management are essential to ensure the safe and effective implementation of these practices. Additionally, the IAEA emphasizes the need for continuous monitoring and improvement of waste management processes to adapt to evolving technologies and practices in the field of nuclear medicine.^{21,22,43–45}

To achieve effective waste management, it is crucial to establish a well-defined organizational structure and clear lines of responsibility within healthcare institutions and radionuclide pharmacies and government agencies. Furthermore, the development of comprehensive waste management plans, regular audits, and the implementation of corrective actions based on the audit findings are essential components of a robust waste management system. Collaboration between various stakeholders, including medical professionals, waste management experts, and regulatory authorities, is key to ensuring the continuous improvement of waste management practices. By adhering to IAEA guidelines and best practices, healthcare institutions and radionuclide pharmacies can contribute to the safe and responsible use of radiopharmaceuticals while minimizing the potential risks associated with radioactive waste.^21–22,44

Implementation of Theranostics Practice

There has been a series of guidelines published on the requirements for establishing centres for theranostics treatment.^8,34 Special attention is required for logistical and technical challenges, medical considerations including training of staff, radiation safety, collaboration with clinical partners, and appropriate treatment indications. Therefore, strategic planning of hospital or clinic investments taking into consideration the needs of infrastructure (including radioprotection rooms and radioactive waste storage solution), appropriate resources, skilled healthcare professionals (including medical staff, nurses, medical physicists and radiopharmacists) and equipment for radiopharmaceutical therapy should be ensured to cope with the expected exponential increase in the demand for theranostics procedures. Consideration of all these aspects was highlighted by the COVID-19 pandemic crisis.^15–17

Current guidelines and recommendations for theranostics do not always include advanced dosimetric calculations for registered radiopharmaceuticals treatments in clinical practice. Based on the dosimetry study during registration process, fixed radioactivity doses, with or without visual assessment of pretherapy scans, or activity doses based on body weight or body surface area and organ toxicity might be considered sufficient in clinical practice for the main clinical theranostic protocols.⁴⁶ However, it should be noted that recent publications show clinical benefits using internal dosimetry at least for several clinical applications that may lead to dosimetry-guided treatment protocols.^29,47,48 Additionally, it should be taken into consideration that the use of clinical dosimetry is a multistep procedure, and both PET and SPECT imaging are used for image acquisition to select patients suitable for therapy, and to allow calculation of normal organ and tumour dose.^34,48 Image analysis provides an accurate estimate of the absorbed dose delivered to one or more tumours or normal tissues, and to ensure that the radioactivity in the rest of the body is kept as low as reasonably achievable.⁴⁹ With the introduction of new isotopes for theranostic approaches, accurate measurements and calibration of dose calibrators and scanners is critical. While larger academic centres may have access to a calibrated high purity germanium detector for gamma ray analysis, these are not the norm at many smaller sites. Thus, dose calibrator cross calibration with sites with access to carefully calibrated detectors might ensure better measurement accuracy globally.

Conclusions

Theranostics is poised to have a major impact on cancer care, and development and availability of radionuclides and radiopharmaceuticals for imaging and therapy is critical to ensure equitable access for patients. Through innovative approaches to preclinical and clinical development, recognition of supply and regulatory issues, and collaborative efforts from academia and industry, theranostics will have an increasingly important role in cancer patient care.