radiopharmaceuticals

Abstract

The invention relates to an arrangement for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition, to anhydrous and aqueous radiopharmaceutical compositions and to methods for the preparation thereof.

Description

[0001] P138096PC00

[0002] Title: Radiopharmaceuticals

[0003] Field of the invention

[0004] The invention relates to the field of radiopharmaceutical compositions and to methods and arrangements for their preparation.

[0005] Background of the invention

[0006] Nuclear Medicine is widely utilized for the early diagnosis and treatment of a variety of chronic disorders. The therapeutic nuclear medicines industry is continuously growing owning to the incidence rates of cancer and cardiac illness, and traditional chemotherapy techniques are being substituted by more efficient therapeutic radiopharmaceuticals. It is well-known that ionizing radiation cause direct and indirect damage through reactive oxygen species produced by radiolysis of water and water radiolysis affect primarily the stability of the radiopharmaceutical preparation before its administration to the patients.

[0007] Although considerable attention has been devoted to the production and quality control of radiopharmaceuticals production under GMP rules, little attention has been paid to the development of methods to further increase the stability of radiopharmaceuticals. Radiolysis can produce highly reactive molecules which interact with the biological active radiopharmaceutical and, therefore, change the properties. As a result, the radiochemical purity is reduced and so is the therapeutic response (less effective).

[0008] Radiopharmaceuticals production, unlike conventional pharmaceuticals production, is still performed on a relatively small scale due to both the half-life and stability (based on the radiochemical purity) of most of the radiopharmaceuticals. In addition, ensuring cGMP compliance is a demanding task, in particular for a small scale manufacturer, which involves (1) the development of well qualified personnel; (2) the use of controlled materials and procedures, and availability of qualified equipment; (3) the production of the products in designated clean areas; (4) the implementation of validated processes and analytical methods; (5) the full documentation of the process and release of the final product by a qualified person and; (6) all the processes should be compatible with the requirements for both radiological and pharmaceutical safety.

[0009] WO 2023 / 152671 Al, US 11,904,027 and De Zanger et al. (Journal of Radioanalytical and Nuclear Chemistry-Articles, 2019321(1), 285-291. https: / / doi.org / 10.1007 / s10967-019-06573-y) describe the use of stabilizing agents against radiolytic degradation in aqueous radiopharmaceutical compositions.

[0010] US 2007 / 0248533 Al describes a freeze-drying process removing water from a radiopharmaceutical formulation, thereby eliminating the risk of radiolysis and enhancing the stability and shelf life of the product. However, several steps in preparing the radiopharmaceuticals for the freeze-drying process, including the introduction of a suitable stopper allowing for water evaporation during freeze-drying and transferring the vial from the hot cell to the freeze-drying equipment, compromises the sterility of the solution once it is removed from the production hot cell, violating GMP standards. In addition, inserting vials containing the radiopharmaceuticals into conventional freeze-drying equipment and further handling of the material will result in surpassing the annual allowable radiation dose limits for the personnel. These issues further impede the large-scale implementation of the methods.

[0011] Hence, there remains a need in the art for radiopharmaceutical products with high chemical and radiochemical stability, that can be produced at sufficiently large scale.

[0012] Summary of the invention

[0013] It is an object of the present invention to provide an arrangement and methods for preparation radiopharmaceutical compositions that overcome one or more of the above mentioned disadvantages.

[0014] The invention therefore provides an arrangement for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition, the arrangement comprising:

[0015] a preparation unit for preparation of a bulk volume of aqueous radiopharmaceutical composition using a radionuclide;

[0016] a dispensing unit for receiving the bulk volume of aqueous radiopharmaceutical composition and for dispensing a plurality of unit dosages of aqueous radiopharmaceutical composition into a plurality of containers; and

[0017] a dehydration unit for receiving a plurality of containers each containing a unit dosage of the aqueous radiopharmaceutical composition and for forming a plurality of unit dosages of anhydrous radiopharmaceutical composition from the plurality of unit dosages of the aqueous radiopharmaceutical composition in the plurality of containers by dehydration;

[0018] wherein the arrangement further comprises: a bulk transportation unit for transporting the aqueous radiopharmaceutical composition from the preparation unit to the dispensing unit; and

[0019] a container transportation unit for transporting a plurality of containers containing each a unit dosage of the aqueous radiopharmaceutical composition from the dispensing unit to the dehydration unit;

[0020] further wherein the preparation unit, the dispensing unit, and the dehydration unit are contained within a single sterile and radiation-shielded environment. In a further aspect, the invention provides a method of producing a plurality of unit dosage of an anhydrous radiopharmaceutical composition, the method comprising:

[0021] in a preparation unit, preparing a bulk volume of aqueous radiopharmaceutical composition using a radionuclide;

[0022] by a bulk transportation unit, transporting the bulk volume of aqueous radiopharmaceutical composition to a dispensing unit;

[0023] by the dispensing unit, dispensing unit dosages of the bulk volume of aqueous radiopharmaceutical composition into a plurality of containers;

[0024] by a container transportation unit, transporting the containers each containing a unit dosage of aqueous radiopharmaceutical composition from the dispensing unit to a dehydration unit;

[0025] by the dehydration unit, dehydrating the aqueous radiopharmaceutical composition in the containers to form unit dosages of anhydrous radiopharmaceutical composition in the containers;

[0026] wherein the preparation unit, the dispensing unit, and the dehydration unit are contained within a single sterile and radiation-shielded environment.

[0027] In a further aspect, the invention provides an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety and at least one stabilizing agent, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent.

[0028] In some embodiments, the composition comprises TRIS. In some embodiments, the composition does not comprises any further radical scavengers.

[0029] In some embodiments, the composition comprises ethanol or methionine as the sole stabilizing agent or a combination of ethanol and methionine as the sole stabilizing agents.

[0030] In a further aspect, the invention provides an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent and wherein the composition does not comprise a stabilizing agent. In some embodiments, the composition comprises TRIS. In some embodiments, the composition does not comprises any further radical scavengers.

[0031] In some embodiments, the composition comprises ethanol or methionine as the sole stabilizing agent or a combination of ethanol and methionine as the sole stabilizing agents.

[0032] In particular, the anhydrous radiopharmaceutical composition is in unit dosage form, comprising a therapeutically or diagnostically effective amount of said complex.

[0033] In a further aspect, the invention provides a method for preparing a plurality of unit dosages of an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, the method comprising:

[0034] radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, the method comprising:

[0035] (i) radiolabeling a targeting moiety with a radionuclide in aqueous solution to provide a bulk aqueous radiopharmaceutical composition comprising said complex; (ii) adding a buffer to the bulk aqueous radiopharmaceutical composition to increase the pH to or stabilize the pH at >6;

[0036] (iii) dispensing a plurality of unit dosages of the radiopharmaceutical composition into a plurality of containers; and

[0037] (iv) dehydrating, preferably lyophilizing, the plurality of unit dosages, optionally further comprising:

[0038] v) sealing the plurality of containers, and / or

[0039] vi) labelling the plurality of containers.

[0040] In preferred embodiments, said method is performed within a single sterile and radiation-shielded environment.

[0041] In some preferred embodiments, the buffer is a buffer comprising TRIS. In some preferred embodiments the buffer is added to the bulk aqueous radiopharmaceutical composition to increase the pH to or stabilize the pH at 7-9, more preferably at 7.4-8.5, more preferably at 7.8-8.5.

[0042] In a further aspect, the invention provides a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention, comprising:

[0043] a) preparing said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent, by: i. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent and optionally at least one stabilising agent, or ii. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent, and adding the optional at least one stabilising agent;

[0044] b) allowing preparation of said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent;

[0045] c) optionally diluting the mixture with an aqueous solution optionally comprising a bulking agent;

[0046] d) dispensing a plurality of unit dosages of the optionally diluted mixture, preferably of 10- 100 ml, into a plurality of containers;

[0047] e) dehydrating, preferably lyophilizing, the plurality of unit dosages, wherein said method is performed within a single sterile and radiation-shielded environment. In preferred embodiments, the method is performed using an arrangement according to the invention.

[0048] In a further aspect, the invention provides an aqueous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, and at least one stabilizing agent, wherein the at least one stabilizing agent comprises ethanol.

[0049] In some preferred embodiments, the aqueous radiopharmaceutical composition comprises TRIS. In some preferred embodiments, the aqueous radiopharmaceutical composition does not comprise a further radical scavenger.

[0050] In a further aspect, the invention provides a use of an arrangement according to the invention for preparing a plurality of anhydrous radiopharmaceutical compositions in unit dosage form according to the invention.

[0051] Brief description of the drawings

[0052] FIG 1: Radiochemical purity of Lu- 177- A.

[0053] FIG 2: A schematical depiction of a first example of an arrangement of the present disclosure.

[0054] FIG 3: A schematical depiction of a second example of an arrangement of the present disclosure.

[0055] FIG 4: Overview of % of RCP vs time for n=3 for177Lu-PSMA.

[0056] FIG 5: Overview of % of RCP vs time for n=3 for161Tb-PSMA. FIG 6: Overview of % of RCP vs time for n=3 for111In-PSMA.

[0057] Detailed description

[0058] As used herein, "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition the verb “to consist” may be replaced by “to consist essentially of’ meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.

[0059] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0060] The word “approximately” or “about” when used in association with a numerical value (e.g. approximately 10, about 10) preferably means that the value may be the given value (e.g. 10), plus or minus 5% of the value (e.g. 10, plus or minus 5%), preferably plus or minus 1% of the value.

[0061] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0062] As used herein, the term “subject” encompasses humans and animals, preferably mammals. Preferably, a subject is a mammal, more preferably a human.

[0063] The term "therapeutically effective amount," as used herein, refers to an amount of a compound or composition being administered sufficient to relieve one or more of the symptoms of the disease or condition being treated to some extent. This can be a reduction or alleviation of symptoms, reduction or alleviation of causes of the disease or condition or any other desired therapeutic effect.

[0064] As used herein, the term “prevention” refers to precluding or delaying the onset of a disease or condition and / or the appearance of clinical symptoms of the disease or condition in a subject that does not yet experience clinical symptoms of the disease.

[0065] As used herein, the term “treatment” refers to inhibiting a disease or condition, i.e., halting or reducing its development or at least one clinical symptom of the disease or disorder, and / or to relieving symptoms of the disease or condition. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0066] The terms “polypeptide” and “peptide” refer to compounds comprising amino acids joined via peptide bonds of any length and are used interchangeably.

[0067] Polypeptides and peptides may comprise both natural and non-natural amino acids.

[0068] The term “peptidomimetic” as used herein refers to a peptidedike molecule. Such peptidomimetics include chemically modified peptides and / or peptide-like molecules containing non-natural amino acids.

[0069] A used herein “non-natural amino acid” refers to any amino acids other than the proteinogenic amino acids that are naturally encoded in the genome of organisms. Such amino acids are also referred to as non-coded amino acids.

[0070] In amino acid sequences or variants thereof as defined herein amino acids are denoted by single-letter or three-letter symbols. These single-letter symbols and three-letter symbols are well known to the person skilled in the art and have the following meaning: A (Ala) is alanine, C (Cys) is cysteine, D (Asp) is aspartic acid, E (Glu) is glutamic acid, F (Phe) is phenylalanine, G (Gly) is glycine, H (His) is histidine, I (Ile) is isoleucine, K (Lys) is lysine, L (Leu) is leucine, M (Met) is methionine, N (Asn) is asparagine, P (Pro) is proline, Q (Gin) is glutamine, R (Arg) is arginine, S (Ser) is serine, T (Thr) is threonine, V (Val) is valine, W (Trp) is tryptophan, Y (Tyr) is tyrosine.

[0071] As used herein the term “plurality” indicates more than one. In preferred embodiments, a “plurality” refers to at least 5, at least 10, at least 20, preferably at least 100, such as between 100 and 400, e.g. 100, 200, 300 or 400.

[0072] As used herein, the term “unit dosage” refers to a physically discrete unit of a radiopharmaceutical composition that contains one predetermined quantity of the radiopharmaceutical. This quantity is preferably calculated to achieve a desired therapeutic or diagnostic effect. The unit dosage is intended to be administered to a patient in a single dose.

[0073] As used herein “bulk volume” refers to a volume containing the quantity of the radiopharmaceutical of more than one unit dosage, preferably the quantity of the radiopharmaceutical of a plurality of unit dosages.

[0074] As used herein, the term "sterile" refers to its common definition, indicating that an environment is free or substantially free of bacteria and other living microorganisms.

[0075] As used herein, the term “radiation-shielded”, which is also abbreviated as “shielded” herein, refers to an environment, component or product, such as a housing, container or vial, that contains a barrier, in particular of a material which absorbs the energy of the radiation, to prevent or at least reduce radiation outside the environment to a level safe for humans. Radiation shielding may consist of barriers containing for instance lead and / or concrete, but the material may depend on the type of radiation to be shielded. The material required for each type of radiation is well known in the art.

[0076] The present inventors have developed a technology that combines the use of stabilizing agents against radiolysis in radiopharmaceuticals and dehydration thereof. The present inventors have further developed methods that use dehydration of radiopharmaceuticals and / or controlling the pH thereof, which reduces dependence on stabilizers against radiolysis in radiopharmaceuticals and dehydration thereof. As demonstrated in the Examples herein, raising pH with TRIS after radionuclide labeling improves radiochemical purity (RCP) relative to maintaining pH ≈5. The novel methods and arrangements allow for radiolabeling of therapeutic and diagnostic formulations using a high radionuclide activity, which are chemically and radiochemically very stable during the preparation (radiolabeling) phase. In this way, radiopharmaceuticals can be prepared in production batches compatible with an industrial production scale to meet current global demand. In addition, the technology that has been developed is compliant with good manufacturing practices (GMP). The dehydration equipment is integrated into the preparation process of the radiopharmaceuticals. After the radiolabeling process, the resulting formulations can be immediately dispensed into lyophilization vials in the form of individual doses and the technology allows automatic insertion into dehydration equipment integrated into the dehydration unit. In addition, the methods and arrangement of the invention ensure quick and easy reconstitution of the radiopharmaceutical for patient injection.

[0077] Current manufacturers of radiopharmaceuticals registered in the U. S. A, and Europe report a production capacity of approximately 25,000 doses per year (around 100 doses per day) of Pluvicto, a PSMA-targeted radioligand therapy (RLT) for prostate cancer. However, due to radiolysis occurring during the radiolabeling process, each production batch is limited by a radioactivity threshold, allowing for instance for a maximum of 20 doses per radiolabeling vial. Radiolysis during synthesis thus presents a significant hurdle to scaling up production. A key advantage of the methods of the invention is enabling larger production batches that align with future market demands. This involves protecting tracer molecules from radiolysis effects during the entire process, from the radiolabeling phase up until the drying and water elimination phase of unit dosages.

[0078] Existing stability methods can guarantee the stability for up to 48-72 hours while the novel method can extend the stability to more to up to weeks. With the arrangement and methods of the present invention, ready-to-use therapeutic radiopharmaceuticals can be shipped over long distances while still keeping their radiochemical purity above 95%. This will reduce the need for setting up small facilities with the required full GMP infrastructures for local production

[0079] of radiopharmaceuticals. The product will be shipped in compact packages and, therefore, will be more cost-effective and reduce environmental impact of packaging.

[0080] The invention provides an integrated and scalable process and equipment to produce ready-to-use radiopharmaceuticals in anhydrous form, in particular in a dry-lyophilized form. The full integration of radiopharmaceutical production with the dehydration, e.g. freeze-drying, process, along with the customization of hot cell and dehydration, e.g. freeze-drying, equipment allow for the industrial applicability of the process to a ready-to-use radiopharmaceutical formulations.

[0081] A first aspect of the present disclosure provides an arrangement for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition. Integrated production implies that preferably the entire production process from separate starting materials to finalized composition takes places within the arrangement. Thus, starting materials enter the arrangement, and the end product being the anhydrous radiopharmaceutical composition can exit the arrangement.

[0082] Any arrangement disclosed herein may comprise one or more of the following units: a preparation unit, a dispensing unit, and a dehydration unit. Optionally, any arrangement may further comprise a reception unit, a pH controlling unit and / or a packaging unit. Different arrangements are thus envisioned with one, two, three, four, five or six of the units as described herein.

[0083] As a preferred option for any of the arrangements of the present disclosure, a single sterile and radiation-shielded environment is provided by the arrangement. This allows the preparation unit, the dispensing unit, and the dehydration unit to be contained within said single sterile and / or radiation-shielded environment. When different units are contained within a single sterile environment, sterility of material being transported between the units can be ensured. When different units are contained within a single radiation-shielded environment, leakage of radiation to the outside of the arrangement can be prevented or at least reduced, in particular when transporting radioactive material between different units of the arrangement. A radiation-shielded environment may also be referred to as a hot cell. The arrangement itself may thus be formed as a hot cell. Any individual unit may also be formed as a hot cell, wherein a connection between the units can be radiation-shielded.

[0084] In general, any unit disclosed herein, such as the preparation unit, dispensing unit, dehydration unit, reception unit, and packaging unit, describes the structural features required to perform one or more tasks attributed to the respective unit. Any unit may comprise a housing in which the structural features are housed. Adjacent units may be connected such that matter may be transported from one unit to another. For any of the described units, the structural features may be incorporated into a single housing, in any combination.

[0085] Any unit may comprise a viewing window allowing an operator to view inside the unit. Any unit may comprise one or more manipulators allowing an operator to manipulate matter inside the unit, as will be elaborated on further in the present disclosure. Any unit may comprise one or more sealable access port into the unit. Any access port may be configured to be sealed by a closure mechanism, such as a door, hatch, or similar apparatus. The closure mechanism can be operable between an open state, allowing access to the interior of the unit, and a closed state, wherein the access port is sealed. When the access port is in the closed state, essentially no matter and / or radiation can pass through it. In the open state, matter may be transferred through the access port, for example to allow the unit to be supplied with a starting material, or to retrieve one or more containers each with a unit dose of anhydrous radiopharmaceutical composition through the access port.

[0086] The preparation unit is arranged for preparation of a bulk volume of aqueous radiopharmaceutical composition using a radionuclide. The bulk volume is preferably held in a single bulk container after the bulk volume has been produced. The bulk volume, e.g. per single bulk container, is preferably between 10 ml and 200 ml, such as between 10 and 100 ml, between 20 and 80 ml, or between 25 and 50 ml, after being produced. Preparation may take place in a single bulk container, such as a flask. In preferred embodiments, the preparation unit is arranged for preparation of a bulk volume of aqueous radiopharmaceutical composition using a radionuclide, and further components of the bulk volume of the radiopharmaceutical composition that is prepared, preferably of an aqueous radiopharmaceutical composition according to the invention. Preferred examples of such components include but not limited to a targeting moiety and optionally a chelating agent, optionally linked together, one or more stabilizing agent, one or more bulking agents, buffer and / or water, which components are described herein below in more detail.

[0087] In general, for any preparation unit and any production method, it is envisioned that multiple, for example two or three or more, bulk volumes can be simultaneously prepared in the preparation unit. The multiple bulk volumes may have the same composition, or different compositions, for example based on the same radionuclide or a different radionuclide. Thus, any preparation unit may be arranged to accommodate multiple bulk containers. Bulk volumes being simultaneously prepared implies that the bulk volumes are present in the same preparation unit at the same time. After their preparation, the bulk volumes may then be individually transported to the dispensing unit, or the bulk volumes may be transported together. Multiple bulk volumes may for example be employed if the capacity of the dehydration unit exceeds the volume of a single bulk volume.

[0088] The preparation unit may comprise any number of preparation modules which can be used to perform one or more preparation steps of any method for the preparation of an anhydrous radiopharmaceutical composition of the present disclosure. As an example of a preparation module, a mixer may be used for mixing an aqueous solution comprising a radionuclide with an aqueous solution. As another example of a preparation module, a heater may be used for heating the mixture. As yet another example of a preparation module, a dilutor may be used for diluting the mixture with an aqueous solution optionally comprising a bulking agent. A microwave is yet another example of a preparation module. A dry bath is yet another example of a preparation module.

[0089] Any preparation module may be an automated module, or may require human interaction and / or input. For example, one or more manipulators may be comprised by the preparation unit, by which a human operator can operate one or more of the preparation modules. The manipulators may have an input located outside the sterile and / or radiation-shielded environment, and an output located inside the sterile and / or radiation-shielded environment. The input and the output are linked such that the operator’s actions at the input are transmitted to the output within the sterile and / or radiation-shielded environment, enabling manipulation of a preparation module without compromising the integrity of said environment. The link between the input and the output may be a direct mechanical link. Alternatively, the input and output may act as a master-slave control system, wherein the output is electronically controlled according to the manipulation of the input. Another example of a manipulator is a glove associated with a glove port. Any transportation unit may comprise one or more manipulators to allow an operator to perform the required transportation using the one or more manipulators.

[0090] The preparation unit can receive radionuclide to be used in the preparation of the bulk volume of aqueous radiopharmaceutical composition, and optionally further components thereof, from a reception unit, in particular via a radionuclide transportation unit. The radionuclide transportation unit may thus also optionally be used for transporting one or more of the optional further components required in the preparation of the bulk volume.

[0091] The dispensing unit is arranged for receiving the bulk volume or bulk volumes of aqueous radiopharmaceutical composition and for dispensing a plurality of unit dosages of aqueous radiopharmaceutical composition into a plurality of containers. Any dispensing unit may thus be arranged for receiving a plurality of containers, in particular empty containers. The empty containers can then be at least partially filled in the dispensing unit.

[0092] The amount of the final bulk volume may vary, depending on the specific radionuclide and targeting moiety and application thereof. Exemplary amounts and preferred amounts of bulk volume are between 10 and 1000 ml. The higher volumes are typically obtained after dilution and / or addition of a bulking agent. For instance, the bulk volume of aqueous radiopharmaceutical composition may be between 10 and 1000 ml, between 10 and 500 ml, between 10 and 200 ml, between 10 and 100 ml, between 20 and 80 ml, or between 25 and 50 ml. Furthermore, the bulk volume is for instance dispensed in a plurality of volumes of 100 µl to 5 ml, more preferably about 100 µl to 2 ml, more preferably in about 150-500 µl, such as about 250 µl. These dispensed volumes represent unit dosages.

[0093] The dispensing unit may be in fluid communication with the preparation unit, such that liquid aqueous radiopharmaceutical composition can be transferred from the preparation unit to the dispensing unit. For this transfer, in particular a bulk transportation unit as disclosed herein may be used. The dispensing unit may further be in fluid communication with the pH controlling unit, such that liquid aqueous radiopharmaceutical composition can be transferred from the pH controlling unit to the dispensing unit. For this transfer, in particular a bulk transportation unit as disclosed herein may be used.

[0094] The dispensing unit comprises a liquid dispenser with a dispensing outlet, typically in fluid communication with a conduit of a bulk transportation unit or of a pH controlling unit. By controlling the position of the dispensing outlet relative to the position of containers, selectively, unit doses of aqueous radiopharmaceutical composition can be dispensed into the containers.

[0095] The dispensing unit may be further arranged for placing a seal, such as a rubber stopper, onto containers – in particular after having dispensed the unit dose of aqueous radiopharmaceutical composition into the containers. The seal may be used for at least partially sealing an access opening of the container. The seal may allow for moisture to escape the inner volume of the container via the access opening, for example during a dehydration process.

[0096] In some preferred embodiments, the arrangement comprises a pH controlling unit for controlling the pH of the bulk aqueous radiopharmaceutical composition, wherein the pH controlling unit is contained within the single sterile and radiation-shielded environment. The pH controlling unit is arranged for controlling the pH of the bulk aqueous radiopharmaceutical composition, before it is dispensed into a plurality of dosage units. In particular, the pH controlling unit is arranged for increasing the pH of the bulk aqueous radiopharmaceutical composition, in particular to a pH >6, more preferably a pH > 7, more preferably a pH > 8, more preferably from 7-9, such as a pH of 7.4-8.5 or 7.8-8.5. The pH controlling unit may be arranged for adding a buffer to the bulk aqueous radiopharmaceutical composition. The pH controlling unit can receive the bulk aqueous radiopharmaceutical composition and a buffer for controlling pH. The pH controlling unit can further discharge a pH adjusted aqueous radiopharmaceutical composition. As used herein, the term “buffer” refers to a component, used to set and / or maintain pH of an aqueous solution. The buffer can be any buffer useful for controlling, in particular increasing, pH. It is preferably an aqueous buffer.

[0097] Examples of suitable buffers include a buffer, in particular an aqueous buffer, selected from the group consisting of a 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES), acetate, succinate,

[0098] Tris (hydroxymethyl) aminomethane (TRIS), 2-Morpholinoethanesulfonic acid (MES), glutamate, lactate, oxalate, or tartrate buffer. In some preferred embodiments, the buffer comprises TRIS or is a TRIS buffer.

[0099] The pH controlling unit is preferably located between the preparation unit and the dispensing unit. The pH controlling unit may be in fluid communication with the preparation unit, such that liquid aqueous radiopharmaceutical composition can be transferred from the preparation unit to the pH controlling unit. For this transfer, in particular a bulk transportation unit as disclosed herein may be used. The pH controlling unit may be in fluid communication with the dispensing unit, such that liquid aqueous radiopharmaceutical composition, in particular pH adjusted liquid aqueous radiopharmaceutical composition, can be transferred from the pH controlling unit to the dispensing unit. For these transfer, in particular one or more bulk transportation unit as disclosed herein may be used. In some preferred embodiments, the arrangement further comprises a conduit for transporting a bulk aqueous radiopharmaceutical composition from the preparation unit to the pH controlling unit, a conduit for transporting the aqueous radiopharmaceutical composition, in particular pH adjusted liquid aqueous radiopharmaceutical composition, from the pH controlling unit to the dispensing unit, and one or more fluid transportation units for transporting the aqueous radiopharmaceutical composition through these conduits.

[0100] The dehydration unit is arranged for receiving a plurality of containers each containing a unit dosage of the aqueous radiopharmaceutical composition. The dehydration unit is further arranged for forming a plurality of unit dosages of anhydrous radiopharmaceutical composition from the plurality of unit dosages of the aqueous radiopharmaceutical composition in the plurality of containers by dehydration. The dehydration unit can thus preferably simultaneously process multiple containers, for example more than 4, more than 10, more than 50, or even 100 or more, 200 or more, or up to 1000 containers, in batches.

[0101] Preferably, the dehydration unit is arranged for performing freeze-drying. Freeze-drying is also referred to as lyophilization. When the dehydration unit is arranged for performing freeze-drying, the dehydration unit comprises a chamber and a cooling unit for lowering the temperature inside the chamber, preferably to a temperature below 0 degrees C. The dehydration unit further comprises a vacuum system arranged to reduce the pressure within the chamber to a level sufficient to facilitate the sublimation of ice directly into water vapor. Additionally, the dehydration unit preferably comprises a condenser or cold trap designed to collect vaporized moisture by re-freezing it, thereby preventing it from returning to the radiopharmaceutical composition. The dehydration unit may also include a heating unit to heat the radiopharmaceutical composition inside the chamber.

[0102] Alternatively, the dehydration unit is arranged for vacuum drying. In such examples, the dehydration unit comprises a chamber for holding the containers. By lowering the pressure in the chamber, the boiling point of water decreases, allowing for dehydration at lower temperatures. A heater may be comprised by the dehydration unit to heat the containers to aid the dehydration process.

[0103] As a further alternative, the dehydration unit is arranged for spray drying. In such examples, the dehydration unit is arranged for forming fine droplets of the aqueous radiopharmaceutical composition, for example using an atomizer. By introducing the droplets into a chamber with a stream of heated inert gas, evaporation of water from the aqueous radiopharmaceutical composition is achieved.

[0104] As another alternative, the dehydration unit is arranged for heat drying. In such examples, the dehydration unit is arranged for heating the aqueous radiopharmaceutical composition.

[0105] It will thus be understood that the dehydration unit is generally arranged for rendering the aqueous radiopharmaceutical composition anhydrous, in any one or more manners described herein, in any combination thereof. Preferably, the dehydration unit allows for dehydration of the aqueous radiopharmaceutical composition while said composition is held as unit doses in containers.

[0106] The dehydration process may take place with a seal placed on the container, which seal may have been applied at the dispensing unit. The seal allows moisture to escape the inner volume of the container via the access opening. The seal may be a rubber stopper.

[0107] The reception unit is arranged for receiving radionuclide therein, for example through an access port.

[0108] The reception unit is further preferably arranged for receiving further components of the bulk volume of the radiopharmaceutical composition that is prepared, preferably of an aqueous radiopharmaceutical composition according to the invention, for example through an access port. Preferred examples of such components include but not limited to a targeting moiety and optionally a chelating agent, optionally linked together, one or more stabilizing agent, one or more bulking agents, buffer and / or water, which components are described herein below in more detail. An access port for receiving radionuclide may be the same or different from an access port for receiving one or more further components as described herein.

[0109] The reception unit thus typically comprises at least one access port as described herein. The reception unit is preferably contained within the single sterile and / or radiation-shielded environment of the arrangement by which the reception unit is comprised. From the reception unit, radionuclide may be transported to the preparation unit by a radionuclide transportation unit.

[0110] It is envisioned that the reception unit is comprised by the preparation unit. Thus, any functionality and feature attributed to the reception unit may be readily attributed to the preparation unit.

[0111] In the reception unit, radionuclide may be received which is held in a shielded container. Since the shielded container is preferably opened only once inside the reception unit, the reception unit may comprise a manipulator with which an operator can open the shielded container by operating an input of the manipulator from outside the reception unit. Alternatively, an automated opening unit may be comprised by the reception unit for opening the shielded container. For example, the automated opening unit may be arranged to engage with the shielded container to open the container allowing access to radionuclide inside the shielded container. The same or a further manipulator may be used to retrieve radionuclide from the shielded container, and the transport the radionuclide to the preparation unit. Said manipulator may form or be comprised by a radionuclide transportation unit.

[0112] The packaging unit is arranged for receiving a plurality of containers containing each a unit dosage of anhydrous radiopharmaceutical composition and / or capping the plurality of containers, and / or positioning the plurality of containers into one or more shielded transport containers. The packaging unit can receive therein the one or more shielded transport containers, for example through an access port of the packaging unit. The packaging unit is preferably contained within the single sterile and / or radiation-shielded environment of the arrangement by which the packaging unit is comprised.

[0113] When an arrangement of the present disclosure comprises a packaging unit, the arrangement may be referred to as an arrangement for integrated production and packaging of a plurality of unit dosages of an anhydrous radiopharmaceutical composition.

[0114] Any packaging unit may further be arranged for capping containers of the plurality of containers. Capping a container may imply providing the container with a final cap, or capping the container with a seal already applied to the container. Capping a container may thus further comprise applying a final cap to the container, wherein the final cap may be placed over an already present seal, such as a rubber stopper. The final cap may for example be a metal cap, in particular an aluminum cap.

[0115] In particular after containers have been capped, the containers may be positioned into one or more shielded transport containers. The packaging unit may comprise an access port as described herein, such that an operator can remove the one or more shielded transport containers containing the containers comprising each a unit dose of anhydrous radiopharmaceutical composition from the packaging unit.

[0116] Positioning containers into a shielded transport container may be performed by a packaging unit, for example comprising a robot arm. Alternatively, a manipulator may be comprised by the packaging unit allowing an operator operating an input of the manipulator outside the packaging unit to control an output of the manipulator inside the packaging unit. At the output, an end effector may be provided arranged for gripping or otherwise engaging a container, and for positioning the container into the shielded transport container. The manipulator may be further used for closing the shielded transport container.

[0117] For transporting material within the arrangement, any number of transportation units may be comprised by the arrangement. The envisioned transportation units include a bulk transportation unit, a container transportation unit, and a radionuclide transportation unit, any one or more of which may be comprised by any arrangement in any combination. In general, any transportation unit may be arranged for transporting matter from a first location to a second location, and optionally to a third location or further one or more locations.

[0118] Any transportation unit may be fully automated, meaning that no direct human intervention is required for transporting material. No direct human intervention does not exclude a human controlling the transportation unit, for example with electronic control signals. Alternatively, any transportation unit may comprise one or more manipulators as described above, such that a human operator can transport bulk, containers, and / or radionuclide through the arrangement – i.e. inside the sterile and / or radiation-shielded environment.

[0119] Any transportation unit may be fully positioned inside the same single sterile and / or radiation-shielded environment of the arrangement comprising the respective transportation unit. When the transportation of radioactive matter takes place within the radiation-shielded environment, it may be prevented that a human operator has to handle radioactive matter that is not contained within a radiation-shielded container.

[0120] A bulk transportation unit may be used for transportation of aqueous radiopharmaceutical composition from the preparation unit to the dispensing unit, for transportation of aqueous radiopharmaceutical composition from the preparation unit to the pH controlling unit and / or for transportation of aqueous radiopharmaceutical composition from the pH controlling unit to the dispensing unit. Preferably, the bulk transportation unit comprises a conduit for transporting an aqueous radiopharmaceutical composition from the preparation unit to the dispensing unit and a fluid transportation unit for transporting the aqueous radiopharmaceutical composition through the conduit. In some preferred embodiments, if the arrangement comprises a pH controlling unit, the arrangement further comprises a conduit for transporting an aqueous radiopharmaceutical composition from the preparation unit to the pH controlling unit, a conduit for transporting aqueous radiopharmaceutical composition from the pH controlling unit to the dispensing unit, and one or more fluid transportation units for transporting the aqueous radiopharmaceutical composition through the conduits. The fluid transportation units may for example be a pump.

[0121] For transporting a plurality of containers, the container transportation unit may be configured to transport a carrier carrying the plurality of containers. The carrier may be a tray into or onto which the plurality of containers are placed. The container transportation unit is in particular used for transporting a plurality of containers containing each a unit dosage of the anhydrous radiopharmaceutical composition from the dehydration unit to the packaging unit. The same or a further container transportation unit may be used for transporting a plurality of containers containing each a unit dosage of the aqueous radiopharmaceutical composition from the preparation unit to the dehydration unit.

[0122] Any container discussed herein may be a vial. Any container may have a capacity of e.g. 100 µl to 250 ml, such as of 0.5 ml to 125 ml. In preferred embodiments, a container may have a capacity of 150 µl – 2 ml, to be able to contain a unit dosage of 100 µl to 1 ml, such as a unit dosage of 150-500 µl, or about 250 µl. Any container typically has an access opening, in particular a single access opening, allowing access into an internal volume of the container. It will be appreciated that any headspace may be left in any container after the container is filled with a unit dose of aqueous radiopharmaceutical composition. The capacity disclosed above may be including or excluding the headspace. In general, the total capacity of a container may be between 0.5 ml and 125 ml.

[0123] Any container transportation unit may comprise a belt or other continuous transportation member, onto which a carrier carrying a plurality of containers and / or containers themselves can be positioned. By operating the belt or other continuous transportation member the carrier and / or containers can be transported from a first position on the belt or other continuous transportation member to a second position on the belt or other continuous transportation member.

[0124] Any container transportation unit may comprise one or more robot arms, each comprising one or more articulated joints, one or more actuators for operating the joints, and an end effector designed to grip or support one or more containers or even a carrier holding a plurality of containers. Any arrangement disclosed herein, in particular when comprising the reception unit, may comprise a radionuclide transportation unit for transporting radionuclide to the preparation unit, in particular from the reception unit. For example, one or more manipulators may be comprised by the radionuclide transportation unit to allow an operator to transport the radionuclide from the reception unit to the preparation unit.

[0125] Any arrangement disclosed herein, in particular when comprising the reception unit, may comprise a transportation unit for transporting further components of the bulk volume of aqueous radiopharmaceutical composition to the preparation unit, in particular from the reception unit. Preferred examples of such components include but not limited to a targeting moiety and optionally a chelating agent, optionally linked together, one or more stabilizing agent, one or more bulking agents, buffer and / or water, which components are described herein below in more detail.

[0126] A radionuclide transportation unit and a transportation unit for transporting further components of the bulk volume of aqueous radiopharmaceutical composition may be the same or different.

[0127] A second aspect of the present disclosure provides a method of producing a plurality of unit dosage of an anhydrous radiopharmaceutical composition. The method comprises preparing a bulk volume of aqueous radiopharmaceutical composition using a radionuclide, and optionally a targeting moiety and optionally a chelating agent, optionally linked together, one or more stabilizing agent, one or more bulking agents, buffer and / or water, transporting the bulk volume of aqueous radiopharmaceutical composition to a dispensing unit, dispensing unit dosages of the bulk volume of aqueous radiopharmaceutical composition into a plurality of containers, transporting the containers each containing a unit dosage of aqueous radiopharmaceutical composition from the dispensing unit to a dehydration unit, dehydrating the aqueous radiopharmaceutical composition in the containers to form unit dosages of anhydrous radiopharmaceutical composition in the containers. These steps are preferably respectively carried out in a preparation unit, by a bulk transportation unit, optionally by a pH controlling unit, by a dispensing unit, by a container transportation unit, and by a dehydration unit.

[0128] In the method, preferably, the preparation unit, the dispensing unit, and the dehydration unit and optionally the pH controlling unit, are contained within a single sterile and radiation-shielded environment. Additionally or alternatively, the preparation of the bulk volume of aqueous radiopharmaceutical composition using a radionuclide, transporting the bulk volume of aqueous radiopharmaceutical composition to a dispensing unit, dispensing unit dosages of the bulk volume of aqueous radiopharmaceutical composition into a plurality of containers, transporting the containers each containing a unit dosage of aqueous radiopharmaceutical composition from the dispensing unit to a dehydration unit and dehydrating the aqueous radiopharmaceutical composition in the containers to form unit dosages of anhydrous radiopharmaceutical composition in the containers are performed in a single sterile and radiation- shielded environment.

[0129] Any method according to the second aspect may further comprise receiving a radionuclide, and optionally a targeting moiety and optionally a chelating agent, optionally linked together, one or more stabilizing agent, one or more bulking agents, buffer and / or water, and transporting the radionuclide and optional further components to a preparation unit. These steps are preferably respectively carried out in a reception unit and by a radionuclide transportation unit.

[0130] Any method according to the second aspect may at least in part be executed using an arrangement according to the first aspect.

[0131] In a further aspect the invention provides an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent. In a further aspect the invention provides an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety and at least one stabilizing agent, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent. In preferred embodiments, the anhydrous radiopharmaceutical composition of the invention is in unit dosage form. An anhydrous radiopharmaceutical composition of the invention is preferably in unit dosage form comprising a therapeutically or diagnostically effective amount of a single dose.

[0132] In a further aspect, the invention provides a method for preparing a plurality of unit dosages of an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, the method comprising:

[0133] (i) radiolabeling a targeting moiety with a radionuclide in aqueous solution to provide a bulk aqueous radiopharmaceutical composition comprising said complex; (ii) adding a buffer to the bulk aqueous radiopharmaceutical composition to increase the pH to or stabilize the pH at >6; (iii) dispensing a plurality of unit dosages of the radiopharmaceutical composition into a plurality of containers; and

[0134] (iv) dehydrating, preferably lyophilizing, the plurality of unit dosages, optionally further comprising:

[0135] v) sealing the plurality of containers, and / or

[0136] vi) labelling the plurality of containers. In preferred embodiments, the method is performed within a single sterile and radiation-shielded environment, preferably a sterile and radiation-shielded environment as described herein. In some preferred embodiments, the method is performed in an arrangement according to the invention.

[0137] As used herein, in the arrangements, compositions and methods of the invention, “anhydrous” refers to compositions which are substantially free of water or free of water. In particular, it refers to compositions comprising a content of less than or equal to 1% by weight of water with respect to the total weight of said anhydrous composition, preferably less than or equal to 0.75% by weight, more preferably less than or equal to 0.5% by weight of water with respect to the total weight of said anhydrous composition.

[0138] As used herein, in the arrangements, compositions and methods of the invention, ’’radiopharmaceutical” refers to compositions comprising a compounds comprising a radionuclide. Radiopharmaceuticals are used for diagnostic and / or therapeutic purposes. Hence, in some preferred embodiments, a radiopharmaceutical composition is a radioactive diagnostic agent. In other preferred embodiments a radiopharmaceutical composition is a radioactive therapeutic agent. In some embodiments, radiopharmaceuticals include small molecules that are labeled with one or more radionuclides. In some embodiments, radiopharmaceutical compositions comprise a polypeptide or protein that is labeled with one or more radionuclides.

[0139] As used herein, in the arrangements, compositions and methods of the invention, “radionuclide”, also referred to as a radioactive isotope, refers to a nuclide that has an excess number of either neutrons or protons, giving it excess nuclear energy. The term includes alpha-emitting, beta-emitting and gammaemitting radionuclides. In some preferred embodiments, the radionuclide is a betaemitting radionuclide. In some embodiments, a radionuclide is one used in positron emission tomography (PET). In some embodiments, a radionuclide is one used in single-photon emission computed tomography (SPECT). In some embodiments, a radionuclide is one used in radiotherapeutic treatment. Any radionuclide with a half-life suitable for therapeutic or diagnostic applications can be used, e.g. radionuclides with a half-life of e.g. 2 days or longer. Nondimiting examples of radionuclides that can be used in accordance with the invention are111In,67Ga,

[0140]

[0141] 82Br, and192Ir. In some preferred embodiments, the radionuclide is a metal radionuclide. In some preferred embodiments, the radionuclide is a lanthanide metal radionuclide. Lanthanides are the chemical elements with atomic numbers 57-70, include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium and ytterbium. Lutetium is also sometimes considered a lanthanide. Hence, in preferred embodiments, the radionuclide is a lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium or lutetium radionuclide. In some preferred embodiments, the radionuclide is selected from the group consisting of225Ac,177Lu,161Tb,131I,67Cu,227Th, and89Zr. In further preferred embodiments, the radionuclide is selected from the group consisting of225Ac,177Lu,131I,161Tb, and67Cu. In some preferred embodiments, the radionuclide is225Ac. In some preferred embodiments, the radionuclide is177Lu.

[0142] The amount of radionuclide present in a radiopharmaceutical composition of the invention and radioactivity it provides, depends on the specific radionuclide that is included. A skilled person will be able to determine the correct dose, in particular unit dosage of each radionuclide. For instance,177Lu, is preferably present in an anhydrous radiopharmaceutical composition in an amount that provides at least 5 GBq, preferably at least 7 GBq more preferably about 7.4 Gbq. As another example,225Ac is preferably present in an anhydrous radiopharmaceutical composition in an amount that provides at least 5 MBq, preferably at least 8 MBq more preferably at least about 10 Mbq. As yet another example,161Tb is preferably present in an anhydrous radiopharmaceutical composition in an amount that provides at least 3 GBq, preferably at least 4.5 GBq more preferably at least about 5 Gbq.

[0143] The compositions of the invention comprise a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent.

[0144] As used herein, in the arrangements, compositions and methods of the invention, “targeting moiety” refers to a moiety that targets the radionuclide to a site of interest, i.e. in the subject’s body. The targeting moiety can be a chemical moiety or a peptide, polypeptide, peptidomimetic or protein. The target can be a diagnostic or therapeutic target. Non-limiting examples of preferred targeting moieties target a receptor or antigen that is expressed at the cell-surface, in particular cell-specific receptor or antigen. In some preferred embodiments, the receptor or antigen is a tumor-associated or tumor-specific receptor or antigen. A tumor- associated receptor or antigen is relatively restricted to tumor cells, whereas a tumor -specific receptor or antigen is unique to tumor cells. Hence, in some preferred embodiments, the targeting moiety targets the radionuclide to a tumor, precancerous or cancerous tissue. In some preferred embodiments, the targeting moiety is selected from a prostate-specific membrane antigen (PSMA) binding agent, a somatostatin binding agent, a gastrin-releasing peptide receptor binding agent, a seprase, fibroblast activation protein alpha (FAP-alpha) binding agent, an incretin receptor binding agent, a glucose-dependent insulinotropic polypeptide receptor binding agent, a gastrin-releasing peptide receptor binding agent and a integrin binding agent. In particularly preferred embodiments, the targeting moiety binds a somatostatin receptor or PSMA. Preferred PSMA targeting moieties are PSMA-618 (Vipivotide), PSMA-I& T (zadavotide guraxetan) and PSMA-R2. Further suitable PSMA binding agents are described in WO 2023 / 152671, which is incorporated by reference herein, and include MIP-1095, MIP-1545, MIP- 1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA- TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA- 7 I& T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074. Preferred somatostatin receptor targeting moieties are tyr 3-octreotide and tyr3-octreotate.

[0145] As used herein, in the arrangements, compositions and methods of the invention, “chelating agent”, also referred to as a chelator, refers to an agent that is able to form complexes with metal ions, including radionuclide metal ions.

[0146] Chelating agents are preferably present when the radionuclide is a metal ion, such as225Ac,177Lu,161Tb,67Cu,227Th, and89Zr, in which case the radionuclide and the targeting moiety are linked by the chelating agent. Exemplary chelating agents include EDTA-based chelators, DTPA-based chelators, NTA-based chelators and DOTA-based chelators. Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylene triamine backbone with five carboxymethyl groups. Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid that is widely used to bind to iron (Fe2+ / Fe3+) and calcium ions (Ca2+). 1,4,7,10- Tetraazacyclododecane- 1,4, 7, 10-tetraacetic acid (tetraxetan or DOTA) is an organic compound with the formula (CH2CH2NCH2CO2H)4. DOTA and DOTA-based chelators are used as a complexing agent in particular for lanthanide ions. DOTA-based chelators include, but are not limited to DOTA, 1,4,7,10-tetraazacyclododecane-l-(glutamic acid)-4,7, 10-triacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA),

[0147] If a chelating agent is present in the complex, the radionuclide forms a covalent bond with the targeting moiety and a non-covalent bond with the chelating agent. Optionally, a linker or spacer may be present between the targeting moiety and the chelating agent.

[0148] In some preferred embodiments, the DOTA-based chelators coupled to a somatostatin receptor targeting moiety is selected from the group consisting of DOTA- TATE (oxodotreotide), DOTA-TOC (edotreotide or DOTA- [Tyr 3] -octreotide), DOTA-NOC (DOTA-l-Nal-octreotide), DOTA- LAN (DOTA-(D)betaNall-lanreotide) and DOTA-VAP (based on VAP peptide). In further preferred embodiments, the DOTA-based chelators coupled to a somatostatin receptor targeting moiety is selected from DOTA-TATE and DOTA-TOC.

[0149] DOTA- TATE and DOTA-TOC are composed of DOTA covalently attached to the cyclic octapeptide D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol) (tyr 3-octreotide; DOTA-TOC) or D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (tyr3-octreotate; DOTA-TATE) that target somatostatin receptors and DOTA. In preferred embodiments, the somatostatin receptor targeting moiety, in particular DOTA-TATE or DOTA-TOC, is coupled to a radionuclide selected from the group consisting of68Ga,177Lu,90Y and64Cu. Such radiolabeled DOTA-TATE is suitable for use in the detection and / or treatment of somatostatin positive tumors, including neuroendocrine tumors (NETs).

[0150] The anhydrous radiopharmaceutical composition of the invention may comprise one or more stabilizing agents. Stabilizing agents are agents that reduces radiolysis of radiopharmaceutical compositions. As used herein “radiolysis” refers to the decomposition of the radiopharmaceutical induced by direct or indirect effect of radiation. Radiolysis can occur in the course of the synthesis and storage of radiopharmaceuticals. It results in degradation of the radiopharmaceutical compounds. Radiolytic degradation of radiopharmaceuticals resulting from radiation from an incorporated radionuclide may occur in two ways, either direct damage to the pharmaceutical by particles that are emitted by the radionuclide (direct effect) and degradation of the pharmaceutical due to interaction with radicals formed during radiolysis of water (indirect effect). In preferred embodiments, a stabilizing agent refers to an antioxidant or a radical scavenger. The scavenger is preferably a patient-safe scavenger. Suitable, non-limiting examples of a stabilizing agent are gentisic acid (2,5-dihydroxybenzoic acid), ascorbic acid (L-ascorbic acid), ethanol, methionine, histidine, melatonin. When added in the preparation of the aqueous bulk radiopharmaceutical composition, the one or more stabilizing agents can be added to, and present in, the aqueous radiopharmaceutical composition in the form of a salt of the agent, e.g. a salt of gentisic acid (such as a sodium salt), a salt of ascorbic acid (such as sodium ascorbate), etc.

[0151] In some preferred embodiments, the anhydrous or aqueous radiopharmaceutical compositions of the invention comprise at least two stabilizing agents. In further preferred embodiments, a radiopharmaceutical compositions of the invention comprise at least gentisic acid or a salt thereof and / or ascorbic acid or a salt thereof, more preferably gentisic acid or a salt thereof and ascorbic acid or a salt thereof

[0152] It has been previously demonstrated that ethanol, in combination with a mixture of gentisic acid and ascorbic acid has a superior effect in stabilizing radiolabelled peptides (De Zanger et al. Journal of Radioanalytical and Nuclear Chemistry-Articles, 2019321(1), 285-291. https: / / doi.org / 10.1007 / s10967-019-06573-y). Previously, however, the use of ethanol as a stabilizing agent in radiopharmaceutical compositions was considered unfavourable and advised against because of its toxicity. With the present invention it has become possible to additionally use ethanol as a stabilizing agent against radiolysis because the combination of use of such agents and subsequent dehydration, e.g. freeze-drying, ensure the removal or near-complete removal of ethanol, thereby mitigating any concerns related to its toxicity. Hence, in preferred embodiments, a combination of gentisic acid or a salt thereof, ascorbic acid or a salt thereof an ethanol is used in the methods and compositions of the invention.

[0153] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention therefore comprises gentisic acid and ascorbic acid and optionally trace amounts of ethanol. In particular, an anhydrous radiopharmaceutical composition of the invention comprises ethanol in amount of less than 1 wt.% of the total composition.

[0154] In some preferred embodiments, an aqueous radiopharmaceutical compositions of the invention comprises gentisic acid, ascorbic acid and ethanol.

[0155] Stabilizing agents can be present in an anhydrous radiopharmaceutical composition of the invention in an amount that provides stability against radiolysis during preparation of an aqueous bulk radiopharmaceutical composition and further preferably after reconstitution.

[0156] If present, gentisic acid is preferably present in an anhydrous radiopharmaceutical composition of the invention in an amount of at least 125 pg, preferably from 125-250 pg, more preferably 150-200 pg, such as about 175 pg.

[0157] If present, ascorbic acid is preferably present in an anhydrous radiopharmaceutical composition of the invention in an amount of at least 7.5 mg, preferably from 15-40 mg, more preferably from 20-30 mg, such as from 23-27 mg, or about 25 mg.

[0158] In some embodiments, an anhydrous radiopharmaceutical composition of the invention comprises at least 125 pg, preferably from 125-250 pg, more preferably 150-200 pg, such as about 175 pg, of gentisic acid and at least 7.5 mg, preferably from 15-40 mg, more preferably from 20-30 mg, such as from 23-27 mg, or about 25 mg of ascorbic acid.

[0159] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention does not comprise gentisic acid and ascorbic acid. In some preferred embodiments, the anhydrous radiopharmaceutical composition does not comprise gentisic acid, ascorbic acid, ethanol, methionine, histidine or melatonin. As demonstrated herein, dehydration and in particular, increasing the pH of the radiopharmaceutical composition to a pH > 6, in particular using a TRIS containing buffer, reduces dependency on stabilizing agents as described herein during the preparation of the aqueous radiopharmaceutical composition.

[0160] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention comprises TRIS. In some preferred embodiments, the anhydrous radiopharmaceutical composition comprises TRIS, and does not comprise gentisic acid and ascorbic acid, more preferably does not comprise gentisic acid, ascorbic acid and ethanol, more preferably does not comprise gentisic acid, ascorbic acid, ethanol, methionine, histidine or melatonin. In some preferred embodiments, the composition comprises TRIS as the sole radical scavenger. TRIS can be present in the anhydrous radiopharmaceutical composition if a TRIS buffer is used to increase or maintain the pH following preparation of an aqueous radiopharmaceutical composition to pH > 6, preferably pH >7, more preferably pH 7-9, more preferably pH 7.4-8.5, more preferably pH 7.8-8.5, more preferably pH 8-8.5, more preferably pH 8.3-8.5, before dehydration as described herein.

[0161] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention comprises ethanol as the sole stabilizing agent, comprises methionine as the sole stabilizing agent or comprises a combination of ethanol and methionine as the sole stabilizing agents. The anhydrous radiopharmaceutical composition may comprise trace amounts of ethanol. In particular, an anhydrous radiopharmaceutical composition of the invention comprises ethanol in amount of less than 1 wt.% of the total composition as the sole stabilizing agent, or comprise ethanol in amount of less than 1 wt.% of the total composition and methionine as the sole stabilizing agents.

[0162] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention comprises TRIS as the sole radical scavenger and optionally ethanol and / or methionine. In some preferred embodiments, the anhydrous radiopharmaceutical composition does not comprise any other stabilizing agent. In some preferred embodiments, the anhydrous radiopharmaceutical composition does not comprise gentisic acid and ascorbic acid.

[0163] In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention does not comprise a stabilising agent. In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention does not comprise an oxidant or a radial scavenger. In some preferred embodiments, an anhydrous radiopharmaceutical composition of the invention does not comprise gentisic acid, ascorbic acid, ethanol, methionine, histidine or melatonin.

[0164] In a method according to the invention for preparing a plurality of unit dosages of an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety the pH of the bulk aqueous radiopharmaceutical composition is increased to pH 7-9, if the pH after step (i) is below 7 or maintained at pH 7-9 is the pH after step (i) is between 7 and 9. In preferred embodiments, the pH is increased to 7-9.

[0165] In some preferred embodiments, the pH is increased to or maintained at pH > 7, more preferably pH 7-9, more preferably pH 7.4-8.5, more preferably pH 7.8-8.5, more preferably pH 8-8.5, more preferably pH 8.3-8.5.

[0166] In some preferred embodiments, the pH of the bulk aqueous radiopharmaceutical composition prior to step (ii) is 3.5-6. Hence, in some preferred embodiments, the Ph is increased to pH > 7, more preferably pH 7-9, more preferably pH 7.4-8.5, more preferably pH 7.8-8.5, more preferably pH 8-8.5, more preferably pH 8.3-8.5.

[0167] The buffer that is used to adjust the pH can be any buffer useful for adjusting, in particular increasing, pH. Examples of suitable buffers include a buffer, in particular an aqueous buffer, selected from the group consisting of a 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES), acetate, succinate, Tris (hydroxymethyl) aminomethane (TRIS), 2-Morpholinoethanesulfonic acid (MES), glutamate, lactate, oxalate, or tartrate buffer. In some preferred embodiments, the buffer comprises TRIS or is a TRIS buffer.

[0168] Thus, in some preferred embodiments, the bulk aqueous radiopharmaceutical composition following step (i), the unit dosages of the radiopharmaceutical composition and the plurality of anhydrous unit dosages comprises TRIS. In some preferred embodiments, the bulk aqueous radiopharmaceutical composition following step (i), the unit dosages of the radiopharmaceutical composition and the plurality of anhydrous unit dosages comprises TRIS as the sole radical scavenger and optionally ethanol and / or methionine. In the anhydrous unit dosages, ethanol may be present in trace amounts because it is removed during dehydration.

[0169] In some preferred embodiments no stabilizing agent as defined herein is preferably added to the bulk radiopharmaceutical composition prior to step (ii). I.e. any stabilizing agent that is added, is added to the bulk aqueous radiopharmaceutical composition after step (i). In some preferred embodiments, no further radical scavenger is added to the bulk radiopharmaceutical composition or unit dosages of the radiopharmaceutical composition.

[0170] In some preferred embodiments, the bulk aqueous radiopharmaceutical composition following step (i), the unit dosages of the radiopharmaceutical composition and the plurality of anhydrous unit dosages do not comprise any other stabilizing agent. In some preferred embodiments, the bulk aqueous radiopharmaceutical composition following step (i), the unit dosages of the radiopharmaceutical composition and the plurality of anhydrous unit dosages do not comprise gentisic acid and ascorbic acid.

[0171] In some preferred embodiments, the bulk aqueous radiopharmaceutical composition comprises one or more patient-safe scavengers.

[0172] In some preferred embodiments, the bulk aqueous radiopharmaceutical composition comprises methionine.

[0173] The method comprises dehydration of the plurality of unit dosages.

[0174] Dehydration can be performed by any known method, e.g. as described herein. In preferred embodiments dehydration comprises or is lyophilization.

[0175] An anhydrous radiopharmaceutical composition of the invention may comprises further constituents, such as one or more bulking agents. Suitable examples of such bulking agents include lactose, sorbitol, sucrose, mannitol and other disaccharides. Amino acids, such as histidine, glycine, and arginine, can also be used as bulking agents. Non-reducing agents such as mannitol and sucrose are preferred for protein-based compositions. In preferred embodiments, the bulking agent comprises or is mannitol. In further preferred embodiments, the bulking agent, preferably mannitol, is present in an amount of at least 7.5 mg, preferably 7.5-25 mg, more preferably 10-15 mg, such as about 12 mg.

[0176] In some embodiments, an anhydrous radiopharmaceutical composition of the invention comprises:

[0177] the radionuclide, preferably225Ac,177Lu,131I,161Tb,68Ga or67Cu more preferably225Ac or177Lu,

[0178] at least 125 pg, preferably from 125-250 pg, more preferably 150-200 pg, such as about 175 pg, of gentisic acid, and

[0179] at least 7.5 mg, preferably from 15-40 mg, more preferably from 20-30 mg, such as from 23-27 mg, or about 25 mg of ascorbic acid.

[0180] The total weight of an anhydrous radiopharmaceutical composition according to the invention, i.e. in unit dosage form, is preferably about 20-60 mg, more preferably about 22.5-52.5 mg, more preferably 25-50 mg, more preferably 30-42 mg, more preferably 34-40 mg, more preferably about 37-38 mg. A bulking agent, e.g. as described herein, can be used to supplement the components in the unit dosage form to the desired total weight.

[0181] In particular, the anhydrous radiopharmaceutical compositions in unit dosage form have a radiochemical purity of more than 95% for prolonged period of time, e.g. a radiochemical purity of virtually 100% for up to 15 days in case of a Lutetium-177-radiolabelled molecule. As used herein “radiochemical purity” refers to the fraction of the total radioactivity in the radiopharmaceutical. For most radiopharmaceuticals, radiochemical purity above 95% is desirable since the impurities may have consequential impact on patient treatment.

[0182] With a method of the invention it has become possible to prepare radiopharmaceutical composition in higher volumes than previously thought possible because of the increased radiochemical stability over time and dispensing the composition into unit dosages which are subsequently dehydrated. In particular, a method of the invention allows the preparation of 100-200 doses, or even higher.

[0183] The invention further provides an aqueous radiopharmaceutical composition comprising a complex formed by a radionuclide as defined herein and a targeting moiety as defined herein, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent as defined herein, and at least one stabilizing agent as defined herein, wherein the at least one stabilizing agent comprises ethanol. In some preferred embodiments, the aqueous radiopharmaceutical composition comprises ethanol or methionine as the sole stabilizing agent or a combination of ethanol and methionine as the sole stabilizing agents. In some preferred embodiments, the aqueous radiopharmaceutical composition comprises TRIS. In some preferred embodiments, the composition has a pH >6, preferably a pH > 7, more preferably a pH of 7-9, more preferably pH of 7.4-8.5, more preferably pH 7.8-8.5, more preferably pH 8-8.5, more preferably pH 8.3-8.5.

[0184] Such aqueous radiopharmaceutical composition is for instance particularly suitable as the bulk volume from which unit dosage are prepared in accordance with the invention. After dispensing the bulk volume and prior to dehydration, e.g. lyophilization, it may contain a unit dosage as defined herein.

[0185] In some embodiments, the aqueous radiopharmaceutical composition comprises:

[0186] - a complex formed by a radionuclide selected from the group consisting of225Ac,177Lu,131I,161Tb,68Ga, and67Cu and a somatostatin receptor targeting moiety, wherein the radionuclide and the targeting moiety are linked by a chelating agent selected from the group consisting of DOTA and DOTA- based chelating agents, and

[0187] stabilizing agents gentisic acid or a salt thereof, ascorbic acid or a salt thereof and ethanol.

[0188] As used herein, in the arrangements, compositions and methods of the invention, an aqueous radiopharmaceutical composition refers to a composition comprising a radiopharmaceutical in water, in particular in an aqueous buffer. Suitable buffers are known in the art and include HEPES (4-(2-hydroxyethyl) piperazine- 1-ethanesulfonic acid), acetate, succinate, Tris (tris(hydroxymethyl)aminomethane), glutamate, lactate, oxalate and tartrate buffers.

[0189] In preferred embodiments, the radionuclide is present in an aqueous radiopharmaceutical composition of the invention in an amount that provides a radioactivity level that is sufficient to provide at least 200 unit dosages.

[0190] In some preferred embodiments, an aqueous radiopharmaceutical composition of the invention comprises at least two stabilizing agents, i.e. ethanol and one further stabilizing agent, or at least three stabilizing agents, i.e. ethanol and at least two further stabilizing agents. In some preferred embodiments, an aqueous radiopharmaceutical composition comprises ethanol and one or both of gentisic acid and ascorbic acid as stabilizing agents. In some preferred embodiments, an aqueous radiopharmaceutical composition comprises ethanol, gentisic acid and ascorbic acid as stabilizing agents.

[0191] The stabilizing agents are present an aqueous radiopharmaceutical composition of the invention in an amount sufficient to protect the radiopharmaceutical composition from radiolysis.

[0192] Gentisic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least at least 12.5 mg, more preferably 12.5-25 mg, more preferably 15-20 mg, such as about 17.5 mg, which is sufficient to provides at least 100 unit dosages. In other preferred embodiments, gentisic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least at least 18.5 mg, more preferably 26-37.5 mg, more preferably 22.5-30 mg, such as about 26 mg, which is sufficient to provides at least 150 unit dosages. In other preferred embodiments, gentisic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least 25 mg, more preferably 25-50 mg, more preferably 30-40 mg, such as about 35 mg, which is sufficient to provides at least 200 unit dosages.

[0193] Ascorbic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least 0.75 g, preferably from 1.5-4 g, more preferably from 2-3 g, such as from 2.3-2.7 g, or about 2.5 g, which is sufficient to provides at least 100 unit dosages. In other preferred embodiments, ascorbic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least 1.1 g, preferably from 2.2-6 g, more preferably from 3-4.5 g, such as from 3.5-4 g, or about 3.75 g, which is sufficient to provides at least 150 unit dosages. In other preferred embodiments, ascorbic acid is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least 1.5 g, preferably from 3-8 g, more preferably from 4-6 g, such as from 4.6-5.2 g, or about 5 g, which is sufficient to provides at least 200 unit dosages.

[0194] Ethanol is preferably present in an aqueous radiopharmaceutical composition of the invention in an amount of at least 2.5% v / v more preferably at least 5% v / v, more preferably from 5-20% v / v, more preferably 5-10% v / v.

[0195] The aqueous radiopharmaceutical composition of the invention further preferably comprises one or more bulking agents, as defined herein above. In preferred embodiments, the bulking agent comprises or is mannitol.

[0196] The aqueous radiopharmaceutical composition of the invention further preferably comprises a buffer. Suitable buffers are known in the art and include HEPES (4-(2-hydroxyethyl) piperazine- 1-ethanesulfonic acid), acetate, succinate, Tris (tris(hydroxymethyl)aminomethane), glutamate, lactate, oxalate and tartrate buffers.

[0197] The pH of the aqueous radiopharmaceutical composition of the invention preferably is from about 7-9, more preferably from about 7.4-8.5, more preferably pH 7.8-8.5, more preferably pH 8-8.5, more preferably pH 8.3-8.5.

[0198] The anhydrous radiopharmaceutical compositions unit dosages can be reconstituted before administration to a patient. Suitable buffers for reconstitution are known in the art and include the same buffers that can be used for the bulk aqueous pharmaceutical compositions of the invention, i.e. HEPES, acetate, succinate, Tris, glutamate, lactate, oxalate and tartrate buffers. Reconstitution may be in any volume suitable for administration, in particular intravenous infusion, and may range for instance from about 100 µl to 5 ml. In preferred embodiments, an anhydrous radiopharmaceutical composition of the invention is reconstituted in about 100 µl to 2 ml, preferably in about 150-500 µl, such as about 250 µl.

[0199] When reconstituting the unit dose dehydrated, preferably lyophilized, composition, additional stabilizing agent, preferably ascorbic acid and / or gentisic acid, maybe added to ensure the product's stability during patient infusion.

[0200] In a further aspect, the invention provides a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention, comprising:

[0201] a) preparing said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent, by:

[0202] i. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent and the at least one stabilizing agent, or ii. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent, and adding the at least one stabilizing agent; b) allowing preparation of said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent;

[0203] c) optionally diluting the mixture with an aqueous solution optionally comprising a bulking agent; d) dispensing a plurality of unit dosages of the optionally diluted mixture into a plurality of containers;

[0204] e) dehydrating, preferably lyophilizing, the plurality of unit dosages, wherein said method is performed within a single sterile and radiation-shielded environment.

[0205] The complex, radionuclide, targeting moiety and at least one stabilizing agent are as defined herein above.

[0206] Step a) and b) of a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention comprises preparing the complex and include radiolabeling of the targeting moiety. Such radiolabeling can be performed using conventional in the art.

[0207] Steps a) and b) can be performed by mixing 1) an aqueous solution comprising the radionuclide and 2) an aqueous solution comprising both the targeting moiety optionally linked to the chelating agent and the at least one stabilizing agent. Alternatively, this is performed by mixing 1) an aqueous solution comprising the radionuclide, and 2) an aqueous solution comprising the targeting moiety optionally linked to the chelating agent, and adding 3) the at least one stabilizing agent. Subsequently, the mixture obtained in step a) is heated.

[0208] In preferred embodiments, the following components are mixed in step a): the targeting moiety optionally linked to the chelating agent

[0209] the radionuclide,

[0210] gentisic acid in an amount of at least at least 12.5 mg, more preferably 12.5- 25 mg, more preferably 15-20 mg, such as about 17.5 mg, or in an amount of at least at least 18.5 mg, more preferably 26-37.5 mg, more preferably 22.5- 30 mg, such as about 26 mg, or in an amount of at least 25 mg, more preferably 25-50 mg, more preferably 30-40 mg, such as about 35 mg, ascorbic acid in an amount of at least 0.75 g, preferably from 1.5-4 g, more preferably from 2-3 g, such as from 2.3-2.7 g, or about 2.5 g, or in an amount of at least 1.1 g, preferably from 2.2-6 g, more preferably from 3-4.5 g, such as from 3.5-4 g, or about 3.75 g, or in an amount of at least 1.5 g, preferably from 3-8 g, more preferably from 4-6 g, such as from 4.6-5.2 g, or about 5 g, which is sufficient to provides at least 200 unit dosages,

[0211] ethanol in an amount of at least 2.5% v / v more preferably at least 5% v / v, more preferably from 5-20% v / v, more preferably 5-10% v / v of the final aqueous radiopharmaceutical composition. Step b) is performed under conditions that allow the preparation of the complex of the specific radionuclide and specific targeting moiety and optionally chelating agent. The temperature may range for instance from room temperature to up to 170°C or even higher depending on e.g. the radionuclide, and targeting moiety. Typical reaction times are from about 10 minutes.

[0212] In some embodiments, e.g. if the radionuclide is 177Lu and the chelating agent is a DOTA based agent, heating in step b) is to a temperature of at least 70°C, preferably at least 80°C, more preferably to a temperature of 80-100°C.

[0213] Further, heating is preferably for at least 10 minutes, more preferably between 10 and 60 minutes, more preferably between 10 and 30 minutes.

[0214] Optionally, the mixture can be diluted following heating to obtain the desired volume for dispensing into unit dosages. Dilution is preferably with an aqueous solution, such as an aqueous buffer. Suitable buffers are known in the art and include HEPES, acetate, succinate, Tris, glutamate, lactate, oxalate and tartrate buffers. The pH of the resulting aqueous radiopharmaceutical composition of the invention preferably is from about 7-9, more preferably from about 7.4-8.

[0215] In preferred embodiments, a bulk aqueous radiopharmaceutical composition is prepared that is sufficient for at least 100 unit dosages, more preferably at least 150 unit dosages, more preferably at least 200 unit dosages. Such unit dosages preferably have a volume of 0.1-1 mL, more preferably 150-500 µl, such as about 250 µl. Hence, in step c), the mixture is for instance diluted to a volume of between about 10 ml and 1000 ml, between 10 and 500 ml, between 10 and 200 ml, between about 10 and 100 ml, between 20 and 80 ml, or between 25 and 50 ml, e.g. to obtain at least between 100 and 200 unit dosages, such that the bulk volume of aqueous radiopharmaceutical composition has such volume before it is dispensed into a plurality of unit dosages.

[0216] Optionally, one or more bulking agents as described herein above are added to the mixture. Optionally, the one or more bulking agents are present in the aqueous solution that is used to dilute the mixture to the desired volume. In preferred embodiments, the bulking agent is or comprises mannitol.

[0217] In step d) of a method of the invention for the preparation of an anhydrous radiopharmaceutical composition, the optionally diluted mixture is dispensed into a plurality of unit dosages, preferably at least 100 unit dosages, more preferably at least 150 unit dosages, more preferably at least 200 unit dosages, into a plurality of containers as described herein above. In step c) the plurality of unit dosages, contained in a plurality of containers, is dehydrated. In preferred embodiments, dehydration is selected from the group consisting of freeze-drying, vacuum drying, and spray drying.

[0218] In preferred embodiments, said dehydration comprises lyophilization.

[0219] Lyophilization, also referred to as freeze-drying, is well known in the art. A typical freeze-drying process comprises 1) freezing of the product, most often under atmospheric pressure, 2) Primary drying (ice sublimation), most often at reduced pressure and 3) Secondary drying (desorption drying), drying the product to the required final humidity. A typical freeze-drying cycle can be applied, which comprises about 1 h pre-freeze at up to -50°C. After that, the temperature can be gradually increased until all the ice is removed from the product after approximately 20 hours of primary drying. Then, the samples can be further dried using a 4 hours-long secondary drying at lower pressure and higher temperature to remove sorbed water and moisture. Reference is for instance made to US 2007 / 0248533, which is incorporated by reference herein, for suitable freeze-drying processes of radiopharmaceutical compositions.

[0220] In some preferred embodiments, a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention, further comprises sealing the plurality of containers.

[0221] In some preferred embodiments, a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention, further comprises labelling the plurality of containers.

[0222] In preferred embodiments, a method for the preparation of an anhydrous radiopharmaceutical composition according to the invention is performed using an arrangement according to the invention.

[0223] Detailed description of the drawings

[0224] FIG 2 shows a schematical depiction of a first example of an arrangement 100 for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition of the present disclosure. The arrangement 100 comprises a preparation unit 110 for preparation of a bulk volume of aqueous radiopharmaceutical composition 112 using a radionuclide. The arrangement 100 further comprises a dispensing unit 120 for receiving the bulk volume of aqueous radiopharmaceutical composition 112 and for dispensing a plurality of unit dosages 122 of aqueous radiopharmaceutical composition into a plurality of containers 124. The arrangement 100 further comprises a dehydration unit 130 for receiving a plurality of containers 124 each containing a unit dosage of the aqueous radiopharmaceutical composition and for forming a plurality of unit dosages of anhydrous radiopharmaceutical composition 136 from the plurality of unit dosages of the aqueous radiopharmaceutical composition in the plurality of containers 124 by dehydration.

[0225] The bulk volume of aqueous radiopharmaceutical composition 112 is preferably formed in a single bulk container 114. The equipment used in the preparation process is for conciseness not depicted in the figures. It will be appreciated that the preparation units in the figures may comprise any of the preparation modules disclosed herein.

[0226] The arrangement 100 further comprises a bulk transportation unit 140 for transporting the aqueous radiopharmaceutical composition from the preparation unit 110 to the dispensing unit 120, and a container transportation unit 150 for transporting a plurality of containers 124 containing each a unit dosage of the aqueous radiopharmaceutical composition 126 from the dispensing unit to the dehydration unit.

[0227] In the first example of the arrangement 100, the preparation unit 110, the dispensing unit 120, and the dehydration unit 130 are contained within a single sterile and radiation-shielded environment 101 indicated with the dashed-dotted line. Also the bulk transportation unit 140 and the container transportation unit 150 are contained within the same single sterile and radiation-shielded environment 101. The sterile and radiation-shielded environment 101 may be formed by a housing of particular material composition as discussed herein, to provide the sterile and radiation-shielded properties. As options, the sterile and radiation-shielded environment 101 may be provided by a single continuous housing. Alternatively, one or more of the units may be positioned in housings, which are interconnected to allow transfer of matter between the units. Multiple housings with sterile and radiation-shielded interconnections are also considered a sterile and radiation-shielded environment 101.

[0228] The dehydration unit 130 as depicted in FIG. 2, but also generally applicable for any dehydration unit of the present disclosure, comprises a dehydration chamber 132 into which a plurality of containers 124 can be positioned. Containers 124 can be positioned into the chamber 132 on a carrier 125, or individually. The dehydration unit 130 as shown in FIG. 2 is as a particular example arranged for performing freeze-drying as dehydration. The dehydration unit 130 thus further comprises a cooling unit 134 for reducing the temperature of aqueous radiopharmaceutical composition inside the chamber 132, and a vacuum unit 136 for reducing pressure inside the chamber 132. The dehydration unit 130 here further comprises a condenser 138, and a heating unit 139. It will be understood that FIG. 2 very schematically shows the dehydration unit 130.

[0229] In the example of FIG. 2, as a particular option, the bulk transportation unit 140 comprises a conduit 142 for transporting aqueous radiopharmaceutical composition from the bulk volume 112 in the preparation unit 110 to the dispensing unit 120. The bulk transportation unit 140 further comprises a fluid transportation unit, such as a pump 144, for transporting the aqueous radiopharmaceutical composition through the conduit 142.

[0230] The dispensing unit 120 comprises a liquid dispenser 121 arranged to receive aqueous radiopharmaceutical composition from the bulk transportation unit 140, in particular via the conduit 142. The liquid dispenser 121 has a liquid outlet 122 from which aqueous radiopharmaceutical composition 126 can be dispensed into individual containers 124 as unit doses. For example, the liquid outlet 122 can be moved relative to the containers 124 and / or the containers 124 can be moved relative to the liquid outlet 122, to align the liquid outlet 122 with a particular container 124. FIG. 2 shows a left container 124 filled with a unit dose of aqueous radiopharmaceutical composition 126, and the rest of the containers yet to be filled.

[0231] FIG.2 depicts a plurality of containers 124, which are not all provided with a separate reference sign. As an option depicted in FIG. 2, multiple containers 124 can be supported on a carrier 125, for example for transporting the multiple containers 124 simultaneously. The container transportation unit 150 may thus be arranged for transporting the carrier 125. As a particular option depicted in FIG. 2, the container transportation unit 150 comprises a transportation belt 152 onto which individual containers 124 or a carrier 125 can be transported. Additionally or alternatively to a transportation belt, for example one or more robot arms may be comprised by the container transportation unit for transporting individual containers or one or more carriers holding multiple containers.

[0232] FIG. 3 schematically depicts a second example of an arrangement 100 of the present disclosure, which arrangement is for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition. The arrangement 100 comprises a similar preparation unit 110, dispensing unit 120, and dehydration unit 130 as disclosed in conjunction with the first example. The second example of the arrangement 100 comprises further optional components, one or more of which may be readily combined into the arrangement 100 disclosed in conjunction with FIG. 2 and any other arrangement disclosed herein.

[0233] As an option for any dispensing unit 120, depicted in FIG. 3, it is envisioned that the dispensing unit 120 comprise a sealing unit 128 arranged for placing a seal 129, such as a rubber stopper, onto individual containers 124. The seal is to be placed onto the containers 124 after a unit dose of aqueous radiopharmaceutical compound has been dispensed into the containers. The sealing unit 128 is typically arranged for moving the seal 129 relative to the container 124 onto which it is to be placed.

[0234] As indicated in FIG. 3, the arrangement 100 further comprises a reception unit 160 for receiving radionuclide therein, for example through an access port 191. The arrangement 100 also comprises an optional radionuclide transportation unit 180 for transporting radionuclide from the reception unit 160 to the preparation unit 120.

[0235] As another optional feature disclosed in conjunction with FIG. 3, the arrangement 100 comprises a packaging unit 170. The packaging unit 170 is arranged for receiving a plurality of containers 124 containing each a unit dosage of anhydrous radiopharmaceutical composition.

[0236] As a particular option depicted in FIG. 3, the packaging unit 170 comprises a capping unit 172 for capping containers 124. Capping containers 124 here results in a cap 179 being positioned onto the container 124. The cap 179 may be placed over a seal already present on the container 124. The capping unit 172 may be arranged for moving a cap 179 relative to the container 124 onto which the cap is to placed.

[0237] In the packaging unit 170, one or more containers 124 can be positioned into a shielded transport container 174. After the one or more containers 124 are placed into the shielded transport container 174, a lid 176 can be placed onto the shielded transport container 174. The shielded transport container 174 can be retrieved from an access port 191 of the packaging unit 170.

[0238] As indicated in FIG. 3, the container transportation unit 150 may be further arranged for transporting a plurality of containers 124, preferably on a carrier 125, containing each a unit dosage of the anhydrous radiopharmaceutical composition from the dehydration unit 130 to the packaging unit 170.

[0239] The packaging unit 170 is contained within the same single sterile and radiation-shielded environment 101. An optional labelling unit 173 of the packaging unit 170 is also depicted in FIG. 3. The labelling unit 173 can be used for providing individual containers with a label. In general, any arrangement of the present disclosure may comprise a labelling unit 173.

[0240] As for example indicated for the reception unit 160 and the preparation unit 110 in FIG. 3, but generally applicable for any unit of any assembly, a viewing window 196 may be comprised by any unit. The viewing window 196 allows an operator to view inside the respective unit, in particular from outside the single sterile and radiation-shielded environment 101. Any viewing window 196 may provide a sterile and / or radiation-shielded barrier to form part of the sterile and radiation-shielded environment 101.

[0241] As a further option depicted in conjunction with the arrangement 100 of FIG.

[0242] 3, the arrangement 100 is shown comprising a manipulator 199. The manipulator 199 allows an operator to manipulate matter inside the sterile and radiation-shielded environment 101, while the operator is positioned outside the sterile and radiation-shielded environment 101. The manipulator 199 comprises an input 197 located outside the sterile and radiation-shielded environment 101, and an output 198 linked to the input located inside the sterile and radiation-shielded environment 101. Although a single manipulator 199 is depicted, any arrangement and any unit may comprise one or two or more manipulators.

[0243] As an even further option depicted in conjunction with the arrangement 100 of FIG. 3, the arrangement 100 is shown comprising two access ports 191, one associated with the reception unit 160 and one associated with the packaging unit 170. Any access port 191 can be selective opened and closed. In the open state, matter can be transferred through the access port 191. In the closed state, the access port 191 can form part of the sterile and radiation-shielded environment 101. Further access ports 191 envisioned include an access port for providing empty containers to the preparation unit and an access port for supply stoppers and / or caps to the arrangement 100. In general, any single access port may be used for multiple purposes as described herein.

[0244] For conciseness, only two particular examples of arrangements have been depicted in the drawings. It will be understood that the examples depicted may be augmented with any optional feature as disclosed herein, for example but not limited to optional features related to the preparation unit, dispensing unit, dehydration unit, container, carrier, bulk transportation unit, container transportation unit, reception unit, sterile and radiation-shielded environment, radionuclide transportation unit, packaging unit, shielded transport container, any further feature, in any combination thereof.

[0245] The arrangements in the drawings may be used to perform one, more, or all steps of any method of producing a plurality of unit dosage of an anhydrous radiopharmaceutical composition as disclosed herein and / or any method for the preparation of an anhydrous radiopharmaceutical composition as disclosed herein.

[0246] Features maybe described herein as part of the same or separate aspects or embodiments of the present invention for the purpose of clarity and a concise description. It will be appreciated by the skilled person that the scope of the invention may include embodiments having combinations of all or some of the features described herein as part of the same or separate embodiments.

[0247] Examples

[0248] Example 1 Proof-of-concept study lyophilization

[0249] A proof-of-concept study was performed using a peptide (A) radiolabeled with Lutetium- 177. The radiolabeled samples were kept in dry ice after preparation (4, 24, 48, 168 and 360 hours) or were a lyophilized. A Typical freeze-drying cycle was applied: About 1 h pre-freeze up to -50 Celsius degrees. After that, the shelf temperature was gradually increased until all the ice was removed from the product after 20 hours of primary drying. Then, the samples were further dried using a 4 hours-long secondary drying at lower pressure and higher temperature to remove sorbed water and moisture. Before HPLC- analysis, samples were thawed (the ones kept in dry ice) or resuspend (lyophilized) in water and the results are shown in FIG 1 and the table 1.

[0250] Table 1. Radiochemical purity of Lu- 177-A.

[0251]

[0252] Radiochemical purity (RCP) is the fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical. For most radiopharmaceuticals, radiochemical purity above 95 % is desirable since the impurities may have consequential impact on patient treatment (Reference: DOI: 10.1186 / s41181-022-00181-0). As shown in the figure 1, the Lutetium- 177-radiolabelled molecule presented a RCP above 95% up 24 hours, when kept in dry ice. However, the same Lutetium-177-radiolabelled molecule presented a RCP of virtually 100% for up to 15 days when freeze-dried immediately after preparation. Example 2 The effect of post-labeling pH increase on pre-lyophilization stability

[0253] Results

[0254] TRIS titration to reach pH ≈8.4 after labeling

[0255] A 100 mM TRIS buffer was prepared (165 mg TRIS base to 10 mL; adjusted with 100 µL of 1 M HCl). In the radiolabeling matrix, addition of TRIS after completion of labeling shifted the bulk pH from ~5.0 to the target basic range. Empirically, addition of 37–60 µL of 100 mM TRIS produced final pH values between 8.05 and 8.43; a nominal dose of 50 µL yielded pH ≈8.35 and was used in subsequent studies (Table 2).

[0256] Table 2. Post-labeling addition of 100 mM TRIS and resulting bulk pH.

[0257] TRIS (100 mM) volume added (pL) Resulting pH

[0258] 37 8.05

[0259]

[0260]

[0261] 45 8.20

[0262]

[0263] 177Lu-PSMA-617: stability at pH 5 vs pH 9 (n=3)

[0264] Radiolabeling of PSMA-617 with177Lu was performed at pH ≈5. Immediately after labeling, the batch was split into two holds: (A) maintained at pH 5; (B) raised to basic pH using TRIS (50 pL of 100 mM), targeting pH ≈8.3–8.5. Radiochemical purity (RCP) was monitored by HPLC and iTLC over time. Across n=3 independent preparations, the basic-pH branch exhibited higher RCP at each time point relative to the acidic branch. See Figure 1 (overview of RCP vs time for n=3).

[0265] 161Tb-PSMA-617: stability at pH 5 vs pH 9 (n=3)

[0266] The protocol of Example 2 was repeated with161Tb. Again, the basic-pH branch maintained higher RCP over time than the acidic branch. See Figure 2 (overview of RCP vs time for n=3).

[0267] 111In control (y-only emission) Using the same workflow with111In, minimal degradation was observed over time relative to177Lu / 161Tb, supporting that B-emission drives most radiolysis under these conditions. See Figure 6 for RCP vs time at pH 5 and basic pH.

[0268] Methods: Analytical and process conditions

[0269] Radiolabeling was performed at pH 4.5-5.5 in an aqueous buffer using PSMA-617 and the indicated radionuclide (e.g.,177LuCl3or161TbCl3) for 15 minutes without added stabilizer. After complexation, the bulk pH was either maintained at ~5.0 or set within 7.8–8.4 by adding 50 µL of 100 mM TRIS (prepared as 165 mg TRIS base in 10 mL, adjusted with 100 µL 1 M HCl); the resulting pH was measured with a calibrated pH meter (3-point calibration at 4.00 / 7.00 / 10.01). Batches were held prior to lyophilization under identical conditions. For161Tb and111In, identical procedures were used.

[0270] HPLC: reversed-phase analytical column; mobile phase A = water + 0.1% TFA; mobile phase B = acetonitrile + 0.1% TFA; gradient program as per internal method; flow, temperature and injection volume per method; UV wavelength and radio-HPLC detector specified. Radiochemical purity (RCP) was calculated as the fraction of total radioactivity under the product peak across the chromatogram window.

[0271] iTLC: silica plates with specified mobile phase; run distance per method; radio-TLC scanner model specified; RCP calculated as % activity at the product R_f window versus total activity.

[0272] Comparative design: Except for the post-labeling pH operation (maintain ~5.0 vs set within 7.8-8.4), all process variables were identical. Each condition was run in triplicate (n = 3) and reported as mean ± SD.

Claims

Claims1. A method for preparing a plurality of unit dosages of an anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, the method comprising:(i) radiolabeling a targeting moiety with a radionuclide in aqueous solution to provide a bulk aqueous radiopharmaceutical composition comprising said complex; (ii) adding a buffer comprising tris(hydroxymethyl) aminomethane (TRIS) to the bulk aqueous radiopharmaceutical composition to increase the pH to or stabilize the pH at 7-9;(iii) dispensing a plurality of unit dosages of the radiopharmaceutical composition into a plurality of containers; and(iv) dehydrating, preferably lyophilizing, the plurality of unit dosages, optionally further comprising:v) sealing the plurality of containers, and / orvi) labelling the plurality of containers,wherein said method is performed within a single sterile and radiation-shielded environment.

2. The method according to claim 1, wherein no further radical scavenger is added to the bulk radiopharmaceutical composition or unit dosages of the radiopharmaceutical composition.

3. The method according to claim 1, wherein any stabilizing agent is added to the bulk aqueous radiopharmaceutical composition after step (i).

4. The method according to any one of the preceding claims, wherein dehydration, preferably lyophilization, is initiated within 60 minutes after adding the buffer comprising tris(hydroxymethyl) aminomethane (TRIS).

5. The method according to any one of the preceding claims, wherein the pH of the bulk aqueous radiopharmaceutical composition is increased to or stabilize at 7.8-8.5.

6. The method according to any one of claims 1 and 3-5, wherein the bulk aqueous radiopharmaceutical composition comprises methionine.

7. The method according to any one of claims 1 and 3-6, wherein the bulk aqueous radiopharmaceutical composition comprises one or more additional patient-safe radical scavengers.

8. The method according to any one of the preceding claims, wherein the pH of the bulk aqueous radiopharmaceutical composition prior to step (ii) is 3.5-6.

9. The method according to any one of the preceding claims, wherein said method is performed in an arrangement according to any one claims 10-17.

10. Arrangement for integrated production of a plurality of unit dosages of an anhydrous radiopharmaceutical composition, the arrangement comprising:a preparation unit for preparation of a bulk volume of aqueous radiopharmaceutical composition using a radionuclide;a dispensing unit for receiving the bulk volume of aqueous radiopharmaceutical composition and for dispensing a plurality of unit dosages of aqueous radiopharmaceutical composition into a plurality of containers; and a dehydration unit for receiving a plurality of containers each containing a unit dosage of the aqueous radiopharmaceutical composition and for forming a plurality of unit dosages of anhydrous radiopharmaceutical composition from the plurality of unit dosages of the aqueous radiopharmaceutical composition in the plurality of containers by dehydration;wherein the arrangement further comprises:a bulk transportation unit for transporting the aqueous radiopharmaceutical composition from the preparation unit to the dispensing unit; anda container transportation unit for transporting a plurality of containers containing each a unit dosage of the aqueous radiopharmaceutical composition from the dispensing unit to the dehydration unit;further wherein the preparation unit, the dispensing unit, and the dehydration unit are contained within a single sterile and radiation-shielded environment.

11. Arrangement according to claim 10, wherein the arrangement further comprises:a reception unit for receiving radionuclide therein; anda radionuclide transportation unit for transporting radionuclide from the reception unit to the preparation unit;wherein the reception unit is contained within the single sterile and radiation-shielded environment.

12. Arrangement according to claim 10 or 11, wherein the arrangement further comprises a packaging unit arranged for:receiving a plurality of containers containing each a unit dosage of anhydrous radiopharmaceutical composition;capping the plurality of containers; andpositioning the plurality of containers into one or more shielded transport containers;wherein the container transportation unit is further arranged for transporting a plurality of containers containing each a unit dosage of the anhydrous radiopharmaceutical composition from the dehydration unit to the packaging unit, and wherein the packaging unit is contained within the same single sterile and radiation-shielded environment.

13. Arrangement according to any one of claims 10-12, wherein the bulk transportation unit comprises a conduit for transporting an aqueous radiopharmaceutical composition from the preparation unit to the dispensing unit and a fluid transportation unit for transporting the aqueous radiopharmaceutical composition through the conduit.

14. Arrangement according to any one of claims 10-13, further comprising a pH controlling unit for increasing the pH of a bulk aqueous radiopharmaceutical composition to or stabilizing the pH of a bulk aqueous radiopharmaceutical composition at 7-9, wherein the pH controlling unit is contained within the single sterile and radiation-shielded environment.

15. Arrangement according to claim 14, wherein said pH controlling unit is located between the preparation unit and the dispensing unit.

16. Arrangement according to claim 14 or 15, wherein the arrangement further comprises a conduit for transporting a bulk aqueous radiopharmaceutical composition from the preparation unit to the pH controlling unit, a conduit for transporting the aqueous radiopharmaceutical composition from the pH controlling unit to the dispensing unit, and one or more fluid transportation units for transporting the aqueous radiopharmaceutical composition through the conduits.

17. Arrangement according to any of claims 10-16, wherein the container transportation unit is arranged for transporting a carrier carrying a plurality of containers from the dispensing unit to the dehydration unit.

18. A method of producing a plurality of unit dosage of an anhydrous radiopharmaceutical composition, the method comprising:in a preparation unit, preparing a bulk volume of aqueous radiopharmaceutical composition using a radionuclide;by a bulk transportation unit, transporting the bulk volume of aqueous radiopharmaceutical composition to a dispensing unit;by the dispensing unit, dispensing unit dosages of the bulk volume of aqueous radiopharmaceutical composition into a plurality of containers;by a container transportation unit, transporting the containers each containing a unit dosage of aqueous radiopharmaceutical composition from the dispensing unit to a dehydration unit;by the dehydration unit, dehydrating the aqueous radiopharmaceutical composition in the containers to form unit dosages of anhydrous radiopharmaceutical composition in the containers;wherein the preparation unit, the dispensing unit, and the dehydration unit are contained within a single sterile and radiation-shielded environment.

19. The method according to claim 18, further comprising:in a reception unit, receiving a radionuclide;by a radionuclide transportation unit, transporting the radionuclide to a preparation unit;by the container transportation unit, transporting the containers each containing the unit dosage of anhydrous radiopharmaceutical composition to a packaging unit; andby the packaging unit, capping the plurality of containers and positioning the plurality of containers into one or more shielded transportation containers.

20. The method according to claim 18 or 19, which method is performed in an arrangement according to any one claims 10-17.

21. An anhydrous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent.

22. The anhydrous radiopharmaceutical composition according to claim 21, wherein the radiopharmaceutical composition is a radioactive diagnostic agent or a radioactive therapeutic agent.

23. The anhydrous radiopharmaceutical composition according to claim 21 or 22, wherein the radionuclide and the targeting moiety are linked by a chelating agent, wherein the chelating agent is tetraxetan (DOTA) and the radionuclide is a radioactive lanthanide ion, preferably lutetium- 177 (Lu- 177) or actinium-225 (Ac-225).

24. The anhydrous radiopharmaceutical composition according to any one of claims 21-23, wherein the composition is in unit dosage form, comprising a therapeutically or diagnostically effective amount of said complex.

25. The anhydrous radiopharmaceutical composition according to any one of claims 21-24, wherein the composition does not comprise a stabilizing agent.

26. The anhydrous radiopharmaceutical composition according to any one of claims 21-24, wherein the composition comprisestris (hydroxymethyl) aminomethane (TRIS).

27. The anhydrous radiopharmaceutical composition according to claim 26, wherein the composition does not comprise a further radical scavenger or stabilizing agent.

28. The anhydrous radiopharmaceutical composition according to any one of claims 21-24 and 26 further comprising a stabilizing agent.

29. The anhydrous radiopharmaceutical composition according to claim 28, wherein the stabilizing agent is selected from the group consisting of gentisic acid, ascorbic acid, sodium ascorbate, methionine, ethanol and combinations thereof, preferably wherein the at least one stabilizing agent comprises gentisic acid, ascorbic acid and ethanol.

30. The anhydrous radiopharmaceutical composition according to claim 29 wherein gentisic acid is present in an amount of at least 125 pg, preferably at least 175 pg, and ascorbic acid is present in an amount of at least 7.5 mg, preferably at least 25 mg.

31. The anhydrous radiopharmaceutical composition according to any one of claims 21-24, 26 and 28-29, wherein the composition comprises ethanol or methionine as the sole stabilizing agent or a combination of ethanol and methionine as the sole stabilizing agents.

32. The anhydrous radiopharmaceutical composition according to any one of claims 21-24, 26, 28-29 and 31, wherein the composition comprises trace amounts of ethanol.

33. A method for the preparation of an anhydrous radiopharmaceutical composition according to any one of claims 21-32, comprising:a)preparing said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent, by:i. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent and optionally at least one stabilising agent, or ii. mixing an aqueous solution comprising the radionuclide and an aqueous solution comprising the targeting moiety optionally linked to the chelating agent, and adding the at least one optional stabilising agent;b)allowing preparation of said complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally both linked to a chelating agent;c) optionally diluting the mixture with an aqueous solution optionally comprising a bulking agent;d)dispensing a plurality of unit dosages of the optionally diluted mixture into a plurality of containers;e) dehydrating, preferably lyophilizing, the plurality of unit dosages, wherein said method is performed within a single sterile and radiation-shielded environment, optionally further comprising:f) sealing the plurality of containers, and / org) labelling the plurality of containers34. Use of an arrangement according to any one of claims 10-17 for preparing a plurality of anhydrous radiopharmaceutical compositions in unit dosage form according to any one of claims 21-32.

35. An aqueous radiopharmaceutical composition comprising a complex formed by a radionuclide and a targeting moiety, wherein the radionuclide and the targeting moiety are optionally linked by a chelating agent, and at least one stabilizing agent, wherein the at least one stabilizing agent comprises ethanol.

36. The aqueous radiopharmaceutical composition according to claim 35, further comprising TRIS.

37. The aqueous radiopharmaceutical composition according to claim 35, comprising ethanol or methionine as the sole stabilizing agent or a combination of ethanol and methionine as the sole stabilizing agents.

38. The aqueous radiopharmaceutical composition according to claim 36 or 37, wherein ethanol is present in an amount of at least 2.5% v / v, preferably at least 5% v / v.

39. The aqueous radiopharmaceutical composition according to any one of claims 36-38, wherein the composition has a pH of 7-9, preferably a pH of 7.8-8.5.

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