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1. Introduction
This chapter deals with regulatory considerations related to radiopharmaceutical precursors within Europe. Outside, different aspects may apply, with the exception of certain harmonized documents. Radiopharmaceuticals are considered a safe class of medicinal products. Due to the small chemical quantities administered they are not expected to exhibit any measurable pharmacological effect [1]. However, since they are radioactive, the rules for minimizing the risk associated with the use of ionizing radiation to the patients and to the personnel must be observed. Depending on the chemical and physical properties, radiopharmaceuticals are used in major clinical areas for diagnostics and/or therapy [2]. As defined by the European Pharmacopeia (Ph. Eur.) general monograph (0125) radiopharmaceutical preparations or radiopharmaceuticals are medicinal products which, when ready for use, contain one or more radionuclides (radioactive isotopes) included for a medicinal purpose [3]. Importantly, they can also have the form of kits for radiopharmaceutical preparation, radionuclide generators and radionuclide precursors. For the latter it is understood that they are not used in patients as such but only after attaching them to the suitable pharmaceutical vector. Although according to Ph. Eur. monograph (0125) radionuclide precursor is any radionuclide produced for radiolabeling of another substance prior to administration, and according to Ph. Eur. general monograph (2902) the substance, which is used as such vector, is defined as a chemical precursor for radiopharmaceutical preparations [4], the term radiopharmaceutical precursor is used interchangeably for either of the two above defined precursors (Figure 1).
Figure 1.
Radiopharmaceutical precursors according to Ph. Eur.
2. Current regulatory framework
Given the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. Therefore, the quality requirements and test methods specifications of precursors for use in preparation of theranostic radiopharmaceuticals can be discussed only in the light of current regulatory framework.
The preparation and use of radiopharmaceuticals are regulated by number of directives, regulations and rules. These documents may be classified with respect to the status of radiopharmaceutical preparation:
radiopharmaceuticals with marketing authorization (MA), regulated by:
and soon to be replaced by Regulation EU No 536/2014 [11];
unlicensed radiopharmaceuticals extemporaneously (just before use) prepared, not for CT [12, 13].
Radiopharmaceuticals with marketing authorization (MA) meet the requirements of GMP Annex 3 (Manufacture of Radiopharmaceuticals) [8] and EMA Guideline on Radiopharmaceuticals [12]. For the small scale preparation of radiopharmaceuticals outside the marketing authorization the guide of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) [14], the Guidelines on Good Radiopharmacy Practice (CRPP) issued by the Radiopharmacy Committee of European Association of Nuclear Medicine (EANM) [13] and the Chapter 5.19. Extemporaneous preparation of radiopharmaceutical preparations of the Ph. Eur. [15] are setting standards for good practices.
The translation of new radiopharmaceuticals from the preclinical stage into clinical trials requires appropriate quality assessment essential to ensure efficacy and safety of both drug substance and drug product [16, 17]. The specific regulatory framework for the use of radiopharmaceuticals in clinical trials has been established in Europe [9, 11, 18]. From the radiopharmaceutical development perspective, the essential step is the preparation of an Investigational Medicinal Product Dossier (IMPD). This document includes information related to the chemical and pharmaceutical quality of the drug substance and drug product, as well as non-clinical data related to pharmacology, pharmacokinetics, radiation dosimetry and toxicology [19]. IMPD contains two main sections related to the production and quality control of the radiopharmaceutical: the drug substance (the active pharmaceutical ingredient, or API) and the drug product.
An active pharmaceutical ingredient (API) is defined as any substance or mixture of substances intended to be used in the manufacture of a drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis as well as treatment of disease or to affect the structure and function of the body. Radiopharmaceutical preparations are often formulated using predefined radionuclide precursors and chemical precursors. If such a preparation does not need a purification step prior to its administration to the patient, both precursors used in the synthesis are considered to be an API in the drug substance part of IMPD. This in particular applies to precursors for theranostic applications where a radiometal is used to radiolabel a vector targeting the receptor, e.g. peptide. On the other hand, chemical precursors used in the manufacture of radiopharmaceuticals, which are purified after the radiolabeling process, are defined as API starting material (e.g. chemical precursors for most F-18 and C-11 PET radiopharmaceuticals).
The manufacture of APIs should be carried out following general GMP requirements. In a GMP-based system, all processes are defined, systematically reviewed, and shown to be capable of consistently providing medicinal products of the required quality and complying with their specifications [20]. Written and approved protocols specifying critical steps, acceptance criteria, must be in place. Process validation is a crucial part of GMP, meaning that all critical steps of manufacturing processes as well as significant changes to these processes are validated. It should be noted that the requirements for validations differ depending whether marketing authorization, clinical trials or in-house preparation of radiopharmaceuticals are planned (see also Figure 2.) [21]. The qualification and validation aspects related to the small-scale “in house” preparation of radiopharmaceuticals are covered in the EANM guidance [22].
Figure 2.
Requirements for chemical precursors used in preparation of radiopharmaceuticals depending on their regulatory status.
In the process of IMPD preparation the prime challenge is to establish quality specifications for radiopharmaceutical precursors. They are supposed to comprise a set of tests that are necessary to confirm identity, purity and strength of the drug substance. Issues under consideration are the definition of release criteria, analytical procedures and especially their validation. Main references to address these issues are the European Pharmacopeia and guidance provided by the International Conference on Harmonization (ICH). Ph. Eur. provides general requirements for quality control of radiopharmaceutical precursors, in addition, a number of monographs for individual radiopharmaceuticals and chemical precursors are available in the Ph. Eur.
The use of analytical methods described in the pharmacopeia allows to reduce the work load related to analytical method validation. This does not mean that a pharmacopeia method may be implemented without any preliminary testing and verification. As a minimum, the most critical parameters should be verified, depending on the intended method. If no pharmacopeia monograph exists, analytical methods need to be fully validated. As stated by the general reference document issued by ICH the objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose [23]. To validate an analytical method, the following characteristics may be considered: specificity, accuracy, linearity range, precision (repeatability and intermediate precision), limit of detection (LOD), limit of quantitation (LOQ) and robustness. Recently, recommendations for the validation of analytical methods which are specific for radiopharmaceuticals has been published by EANM [24].
3. Chemical precursors for radiopharmaceutical preparations
Chemical precursors for radiopharmaceutical preparations, are non-radioactive substances obtained by chemical synthesis for combination with a radionuclide in contrast to precursors manufactured using substances of human or animal origin [4].
The quality specification for chemical precursors is built upon three elements: exact methods, test limits and selection of reference standard. Pharmacopeia monographs comprise a set of critical attributes categorized into three subdivisions: identity, tests (related substances, residual solvents, metal catalyst or metal reagent residues, microbial contamination, bacterial endotoxin) and assay of the active substance. To ensure the appropriate quality, reference substances (like primary standards e.g. Ph. Eur. Chemical Reference Substance, CRS, or Pharmaceutical Secondary Standard, PSS) are used as a standard in an assay, identifications, or purity test. CRS or PSS are often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing [25].
For in-house prepared radiopharmaceuticals the confirmation of the chemical identity and purity of the precursor are the minimum quality control required, in order to qualify the material for subsequent clinical radiolabeling. Additional testing may apply if necessary for the specific process. For example, testing of trace metals content may not be necessary when the material will be subsequently radiolabeled with halogens, but is absolutely critical when the material is intended for labelling with radiometals [26].
To bring a novel radiopharmaceutical into the clinic it is needed that specific quality requirements for the radiopharmaceutical precursor are established, the range of testing would depend on their status and/or intended use. It is worth noting that for Phase I clinical trials full analytical validation is not necessary (only method suitability should be confirmed) [21]. While analytical methods used to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound [27].
There are some specific requirements for the large-sized molecules (e.g. proteins or monoclonal antibodies) as radiopharmaceutical precursors [28]. Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Their biological activities are characterized by a specific binding characteristic to a target ligand (e.g. antigen) and they may be generated by recombinant DNA (rDNA) technology, hybridoma technology, B lymphocyte immortalization or other technologies. Generally, when chemical precursors are manufactured using substances of human or animal origin, the requirements of Ph. Eur. chapter 5.1.7. Viral safety [29] and the general monograph Products with risk of transmitting agents of animal spongiform encephalopathies (1483) [30] apply.
Stability testing is part of the chemical precursor’s characterization. Detailed requirements for carrying out stability studies are included in the ICH guideline Q1A (R2) [31]. The purpose of stability testing is to provide evidence on how the quality of a substance varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period and recommended storage conditions. Stability studies should be carried out on at least three batches and include testing parameters of the chemical precursor that are susceptible to changes during storage and may affect quality, safety and efficacy (e.g. chemical purity and/or assay). The validated analytical methods should be used in these tests. For method validation, it is essential to investigate degradation products and establish degradation pathways under stress conditions (e.g. heat, humidity, light, acid/base hydrolysis and oxidation).
4. Peptides as precursors for radiopharmaceutical preparations
4.1 General consideration
Peptides are an emerging class of compounds that have application in theranostics of several diseases, mainly in cancer [32, 33, 34, 35, 36]. These chemical precursors are positioned between the classic small organic molecules and the high molecular weight biomolecules. The interest of the scientific community for peptide drugs has been continuously growing. Currently, more than 60 peptide-based pharmaceuticals are marketed, over 150 peptides are in active clinical trials and estimated 500 more are in preclinical stages of development [37, 38]. Chemically, peptides have poly-amino acids structure ranging from 3 to 100 amino acids (less than 10 kDa) linked by a peptide (amide, –CONH–) bond, and are lacking a tertiary structure. From the biological point of view, peptides are important regulators of growth and cellular functions in normal tissue and tumors. They can act as cytokines, chemokines, neurotransmitters, hormones and growth factors. Generally, they offer many advantages over other groups for radiopharmaceutical applications. Peptides demonstrate high receptor specificity and selectivity, as well as binding affinity, good tissue penetration and favorable pharmacokinetic profiles. Most of them is characterized by low toxicity and immunogenicity [39, 40]. Their compact size results in rapid targeting and blood clearance. As a consequence low nonspecific uptake in non-targeted tissues and high target-to-background ratios are achieved. Moreover, peptides can be easily chemically synthesized in high purity, modified and stabilized to obtain optimized pharmacokinetic parameters. These all attributes together with ability to attach different chelating agents, prosthetic group and availability of various bioconjugation techniques make peptides an important target platform for theranostic radiopharmaceuticals [41, 42].
Peptide-based radiopharmaceuticals were introduced into the clinic more than three decades ago [43]. Since that time, several theranostic radioligand platforms are used for diagnosis and peptide receptor radionuclide therapy (PRRT) of different cancer types. In this concept, peptide analogs directed against somatostatin receptors (SSTR) play a crucial role [44]. The most prominent example of the theranostic pair of radiolabeled peptides are DOTA-conjugated SSTR agonist DOTA-(D-Phe1, Tyr3, Thr8)-octreotate (DOTA-TATE) labeled with 68Ga and 177Lu (Figure 3). The marketing authorization of NETSPOT® ([68Ga]Ga-DOTATATE) in 2016 and LUTATHERA® ([177Lu]Lu-DOTATATE) in early 2018 [45] encouraged the research in this field to develop improved radiolabeled peptides targeting other receptor/antigen families, exemplified by the prostate specific membrane antigen (PSMA) [46], gastrin-releasing peptide receptor (GRPr) [47] and cholecystokinin-2 receptor (CCK2R) [48, 49]. Some of these peptides are currently under clinical investigation.
Figure 3.
Structure of DOTA-TATE for labelling with theranostics pair of radionuclides: Gallium-68 (68Ga) and lutetium-177 (177Lu).
4.2 Quality aspects
Peptides as precursors for radiopharmaceutical preparations, similarly to other chemical precursors, require adequate specification as a part of their quality assurance in order to demonstrate the safety and efficacy of the final radiopharmaceutical preparation. Currently, no individual pharmacopeia monograph of peptide used as radiopharmaceutical precursors is available. Thus, the quality specification should be established according to the general requirements [4, 50]. Herein, we provide an overview of recommended methods and test limits for the characterization of peptides. The set of analytical procedures that need to be considered is presented in Table 1. However, it should be noted that new analytical methods and modifications to existing ones are continuously being developed and should be utilized where appropriate.
4.2.1 Appearance
The preliminary quality evaluation of peptides is based on the visual inspection of the appearance/color and solubility. This parameter is given only for information, it is not a requirement in a strict sense. If any of the characteristics change during storage, this change should be investigated and appropriate action taken. A typical description of peptide appearance is: white to almost white, freeze-dried powder and solubility is stated in water, ethanol and dilute solutions of acids and alkali [38, 51].
4.2.2 Identification
According to the ICH Q6A guideline [25] identification testing should allow to discriminate between compounds of closely related structure which are likely to be present (e.g. peptides with altered sequences or functional groups that may be formed during the synthesis). The identification test should include combination of different procedures (mostly two) and should be specific and unequivocal. Several techniques are currently in use for confirmation of peptide identity: HPLC-UV, nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MS), infrared absorption spectrophotometry (IR), amino acid analysis (AAA) or peptide sequencing [51]. The method of choice is typically HPLC-UV based on retention time by comparison with reference standard, since the separation by RP-HPLC is often utilized and the method is widely available. UV detection of peptides is realized at 210–220 nm and 250–290 nm for aromatic side chains of phenylalanine, tyrosine and tryptophan. Identification solely by a chromatographic retention time is not regarded as specific and should be complemented by spectrometric techniques. The NMR spectroscopy is the method that allows to unequivocally define the structure of a peptide in the terms of amino acid composition, sequence and chirality. Identification by NMR spectrometry is usually limited to peptides comprising up to 15 amino acids and requires complex data interpretation. For this reason NMR technique is primarily replaced by mass spectroscopy (MS). This technique provides highly accurate molecular weight information on intact molecules, which is an advantage of MS for peptide identification. The peptide molecular mass is most commonly determined by using the electrospray ionization method (ESI), which occurs through the addition or removal of protons and appears as singly or doubly charged ions. As alternative for the more sophisticated spectroscopic methods, amino acid analysis (AAA) could be considered. This technique involves the hydrolysis of the peptide (usually in acidic conditions) to its individual amino acid residues, followed by chromatographic separation and detection/quantification. The method also enables the determination of the enantiomeric purity with the use of appropriate reference standards. However, this method may not be applicable to peptides containing unnatural amino acids and/or specific chelators. The NMR and AAA as well as peptide sequencing techniques are generally used for characterization of PSS.
In the two recently published papers the identity of DOTA-TATE has been confirmed using suitable instrumental techniques; Sikora et al. [52] confirmed the identity of DOTA-TATE using three different methods: MS, IR and HPLC. Similarly, in the work by Raheem at al [53] the final product was analyzed using high resolution mass spectrometry for identification and analytical HPLC for purification; it was detected via analytical HPLC at a retention time of 9.52 min and detected by HRMS-ESI (calc m/z for [(DOTA-TATE +2H)/2]+: 718.3028, found: 718.3046 with −0.1144 ppm error).
In our experience ESI-MS in positive ionization mode was used to confirmed whether the masses of ions at m/z 1435.6 ± 1.0 [M + H]+ and 718.3 ± 1.0 [M + 2H]2+correspond to the monoisotopic mass of peptide [M] as presented in Figure 4. DOTA-TATE PSS was used as reference in IR analysis. Also a gradient HPLC-UV (220 nm) served as identity test of DOTA-TATE by comparison with the reference standard (Rt ± 5.0%). The same HPLC method was used for determination of peptide purity and assay. The representative HPLC chromatograms of DOTA-TATE and DOTA-TATE PSS are given in Figure 5.
Figure 4.
ESI-MS spectrum for DOTA-TATE.
Figure 5.
HPLC-UV (220 nm) chromatograms of (I) DOTA-TATE Rt = 19.831 min and (II) DOTA-TATE PSS Rt = 19,936 min. HPLC method: Luna C18(2) column; Mobile phase - A: water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; gradient profile – From 0 to 25 min: 0–50% B; flow - 0.8 mL/min, oven temperature - 30°C.
4.2.3 Related substances
Peptides are usually chemically synthesized using solid-phase peptide synthesis (SPPS) [54]. In this multi-stage process, amino acids are linked to each other during individual coupling steps, thus constructing the desired peptide sequence. This occurs when the carboxylic end of the sequence is covalently attached to a solid support matrix. The complexity of the peptide production process results in a greater diversity of potential impurities. Heterogenicity of the impurity profile is observed even among peptides manufactured by the same synthetic route. The impurities can originate from raw materials, the manufacturing process, degradation or may be formed during storage. Although protecting groups, scavengers or activated functional groups are used to prevent undesired side-chain reactions the peptide manufacturing process leads to formation of closely related impurities. The most common impurities are products of racemization, deamidation, amino acid deletion or insertion, acetylation, oxidation, β-elimination, cyclization, reduction and incomplete deprotection [51]. The presence of related peptide impurities is typically determined using gradient reversed-phase HPLC method with UV detection, because of its selectivity, high sensitivity, low limit of detection, quantification and robustness. The developed HPLC method should allow sufficient separation of potential impurities from manufacturing process as well as degradation products. The acceptance criteria for related substances according to the Ph. Eur. General Monograph 2902 [4] are presented in Table 2.
Parameters
Typical methods
Typical acceptance criteria
Characters
- Appearance/color
Visual inspection
White or almost white powder
- Solubility
Visual inspection
Solubility in water, ethanol and dilute acid or alkali
Specific thresholds should be applied for impurities known to be unusually potent or to produce toxic or unacceptable pharmacological effects.
4.2.4 Metallic impurities
The presence of inorganic impurity should also be considered, in particular when radiolabeling of the peptide with radiometals is concerned. According to the Ph. Eur. general monograph (2902), the metal residues in peptides should be determined if the manufacturing process is known or suspected to lead to its presence, e.g. due to the use of specific metal catalyst (e.g. Pd) or metal containing reagents. The content for each of the following metals: Pt, Pd, Ir, Rh, Ru, Os, Mo, Ni, Cr, V, Pb, Hg, Cd, Tl in the peptide precursors are limited to 0.01%. The metal impurities are typically examined using atomic absorption spectrometry (AAS), inductively coupled plasma with atomic emission spectrometry detection (ICP-AES) or mass spectrometry detection (ICP-MS) techniques. Determination of residual metals in peptides can be crucial for precursors intended for radiometal labeling [55]. It has been proven that the presence of certain metals can significantly affect the labeling efficiency through competitive chelation.
4.2.5 Residual solvents
In addition to related substances the residual solvents are required to be examined as impurities in peptide precursors. Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the manufacturing process. The solvents are not completely removed by practical manufacturing techniques (e.g. lyophilization process). General guidelines established by the ICH divide solvents into three classes [56]. The Class 1 solvents should not be used in the final step of the manufacturing process of chemical precursors, because of toxicity and environmental impact. The use of the Class 2 solvents should be limited due to potential toxicity and Class 3 solvents are regarded as posing a lower risk to human health. Based on the permitted daily exposure (PDE), Class 2 and 3 solvents are limited to 0.5%. Residual solvents are typically determined using chromatographic techniques such as gas chromatography (GC) coupled with static headspace sampling. Many solvents are usually used in the peptides synthetic process. However, as the advantage of the SPPS and lyophilization process, the most frequently detected solvent is only acetonitrile (Class 2 solvent), used as the component of the mobile phase in the final purification process by preparative HPLC.
4.2.6 Counter-ion content
Synthetic peptides usually contain counter-ions on protonated amino functional groups (N-terminus, Arg, His, Lys, etc.). The presence of counter-ions such as acetate, chloride or trifluoroacetate results from the peptide post synthetic cleavage and/or purification process. Depending on the peptide sequence they reduce the net peptide content by 5 to 25%, but are not considered as impurity. Radiopharmaceutical preparations for diagnostic or therapeutic purposes are based on the net peptide content and thus the amount of residual counter-ions needs to be assessed. To determine counter-ion amounts different method are being used such as: GC, HPLC-UV or ion chromatography (IC). Trifluoroacetic acid (TFA) determined by IC at the level of ca. 20% in DOTA-TATE [52], corresponded to three TFA molecules associated to single peptide molecule. TFA is commonly used as a chemical reagent to remove residual protecting groups during purification of peptides and also as a mobile-phase modifier in a reversed-phase chromatography. Therefore, when the counter-ion finally is AcOH or HCl, determination of the TFA residual content is mandatory.
4.2.7 Water content
In order demonstrate a lot-to-lot consistency the test for water content (residual moisture remaining from the lyophilization process) should be also performed. This parameter may affect the stability of the peptide. For residual water Karl-Fischer titration method as well as GC method with thermal conductivity detector (TCD) [57] are commonly used and water content is limited to max. 10%.
4.2.8 Assay
Generally, assay is defined as a net peptide content. The lyophilized peptide contains also water, counter ions and residual solvents. The net peptide content is referred to percentage of peptide material in the lyophilized peptide. According to ICH guideline Q6A, a specific stability-indicating procedure should be included in the specifications to determine the content of the drug substance. There are two main approaches to determine net peptide content. The first method is a relative assay against a well-defined chemical reference substance, performed using comparative chromatographic procedures. Usually the same RP-HPLC method is used for both assay, identification and related substances. The second approach is an absolute assays involving a functional group (e.g. AAA or titration methods) or a nitrogen content analysis. The nitrogen content is determined from the results of elemental analysis CHN. The calculation of the net peptide content is based on the relation between determined %N to the theoretical content in the peptide structure. For example, this method was used to DOTA-TATE assay determination. Peptide content calculated from elemental analysis was ca. 78.0%, which was in agreement with the generally accepted limit ≥75% [52].
4.2.9 Microbiological assays
The presence of microorganisms may affect the stability of drug substances due to their propensity to degrade/metabolize peptides. Microbiological examinations involve the bioburden control (Ph. Eur 2.6.12) and content of bacterial endotoxins (Ph Eur. 2.6.14). The microbial enumeration tests for total aerobic microbial counts (TAMC) and total yeast and mold counts (TYMC) must adhere to the acceptance criteria of 103 CFU/g and 102 CFU/g for bulk material and 102 CFU/g and 101 CFU per container for chemical precursors packed in single and multi-dose containers, respectively. Bacterial endotoxin can be determined by the gel-clot or photometric methods (turbidimetric and chromogenic techniques) and acceptance criteria are limited to a maximum 100 IU/g for bulk material or maximum 10 IU per container for chemical precursors packed in single-dose and multidose containers.
5. Radionuclide precursors
Radionuclide precursors are offered as solutions for radiolabeling with MA, they are also locally produced for the in-house preparation of radiopharmaceuticals. There is an ongoing debate whether radionuclide precursors always have to be considered as medicinal product, or also can be provided as a starting material [58]. Unlike for chemical precursors for radiopharmaceutical preparation, up to date there is no monograph in the Ph. Eur. that sets out general requirements for radionuclide precursors. This is due to the fact that the quality requirements for radionuclides used to obtain diagnostic and therapeutic preparations are highly varying and depend on the irradiation route and chemical processing involved, which mainly affect the parameters of radionuclide purity or specific activity.
However, there are several individual Ph. Eur. monographs for radionuclide precursors. Two of these concern radionuclide precursors used to prepare radiopharmaceuticals for therapeutic use. These are: Lutetium (177Lu) solution for radiolabelling (mon. 2798) [59] and Yttrium (90Y) chloride solution for radiolabelling (mon. 2803) [60]. There are also six monographs published for radionuclide precursors for preparation of diagnostic radiopharmaceuticals: Fluoride (18F) solution for radiolabelling (mon. 2390) [61], Sodium iodide (123I) solution for radiolabelling (mon. 2314) [62], Sodium iodide (131I) solution for radiolabelling (mon. 2121) [63], Indium (111In) chloride solution (mon. 1227) [64] and Gallium (68Ga) chloride solution for radiolabelling (mon. 2464) [65] and a newly published monograph for Gallium (68Ga) chloride (accelerator-produced) solution for radiolabelling (mon. 3109) [66].
Focusing attention on theranostic radiopharmaceuticals, herein the quality requirements only for metallic radionuclide precursors used in diagnostics and therapy are compared. Table 3 shows the exemplary quality requirements for radionuclide precursor for therapeutic use (177Lu) and a matching radionuclide precursor for diagnostic use (68Ga).
Lutetium (177Lu) solution for radiolabelling (Ph. Eur. 2798 [59])
Gallium (68Ga) chloride solution for radiolabelling (Ph. Eur. 2464 [60])
pH: 1.0 to 2.0, using a pH indicator strip R.
pH: maximum 2, using a pH indicator strip R.
Lutetium: Inductively coupled plasma-atomic emission spectrometry (2.2.57), for determination of specific radioactivity. Copper: maximum 1.0 μg/GBq Iron: maximum 0.5 μg/GBq Lead: maximum 0.5 μg/GBq Zinc: maximum 1.0 μg/GBq
Iron: maximum 10 μg/GBq Zinc: maximum 10 μg/GBq
RADIONUCLIDIC PURITY Lutetium-177: minimum 99.9 per cent of the total radioactivity. Gamma-ray spectrometry. Results: - the total radioactivity due to ytterbium-175 (impurity B) is not more than 0.1 per cent; – the total radioactivity due to lutetium-177 m (impurity A) is not more than 0.07 per cent; – the total radioactivity due to radionuclidic impurities other than A and B is not more than 0.01 per cent.
RADIONUCLIDIC PURITY Gallium-68: minimum 99.9 per cent of the total radioactivity. A. Gamma-ray spectrometry. Limit: peaks in the gamma-ray spectrum corresponding to photons with an energy different from 0.511 MeV, 1.077 MeV, 1.022 MeV and 1.883 MeV represent not more than 0.1 per cent of the total radioactivity. B. Germanium-68 and gamma-ray-emitting impurities. Gamma-ray spectrometry. Result: the total radioactivity due to germanium-68 and gamma-ray-emitting impurities is not more than 0.001 per cent.
RADIOCHEMICAL PURITY [177Lu]lutetium(III) ion: minimum 99 per cent of the total radioactivity due to lutetium-177.
RADIOCHEMICAL PURITY [68Ga]gallium(III) ion: minimum 95 per cent of the total radioactivity due to gallium-68.
Bacterial endotoxins (2.6.14): less than 175 IU/V, V being the maximum volume to be used for the preparation of a single patient dose, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins.
Bacterial endotoxins (2.6.14): less than 175 IU/V, V being the maximum volume to be used for the preparation of a single patient dose, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins.
Sterility: If intended for use in the manufacture of parenteral preparations without a further appropriate sterilization procedure, it complies with the test for sterility prescribed in the mon. 0125. The preparation may be released for use before completion of the test.
Table 3.
Comparison of Ph. Eur. requirements for selected radionuclide precursors.
Comparing the requirements of these two monographs there are apparently large differences in numerical values seen, especially for metal ion content and radiochemical purity. However, when the radioactivity of these radionuclides (different for therapeutic or diagnostic use) is considered, there are basically no differences in quality requirements for both radionuclides. This can be demonstrated on the example of the DOTA-TATE preparations with 177Lu and 68Ga. For therapy 7.4 GBq of [177Lu]Lu-DOTA-TATE is used and this preparation contains ca. 0.2 mg of DOTA-TATE. Typical dose of [68Ga]Ga-DOTA-TATE is 200 MBq and the ligand content in the preparation should not exceed 0.05 mg. Therefore, when analyzing the limit of metallic impurities, e.g. Zn in the radionuclide precursor, similar values are obtained in both cases, i.e. maximum 37 ng and 40 ng per microgram of DOTA-TATE for lutetium-177 and gallium-68, respectively.
When the radiochemical purity is compared, the higher limit of permissible other forms of diagnostic radionuclide ([68Ga]gallium(III) ion: minimum 95%) than for the therapeutic radionuclide ([177Lu]Lutetium(III) ion: minimum 99%) does not result in a higher risk to the patient. Thus, 5% of other forms of a trivalent gallium-68 ion may result in the deposit of 10 MBq of this radionuclide in undesirable chemical form in non-target organs, while for 1% lutetium-177 it is as much as 74 MBq of uncontrolled chemical form. However, it must be noted that a stricter limit for the latter radionuclide is difficult to achieve due to the limitations of the analytical methods, which are characterized by an approximate 1% uncertainty of determination.
Bearing in mind that the differences in the profile of radionuclide contamination depend on the radionuclide production process [67], it is unlikely that uniform quality requirements for radionuclide precursors will be set in numerical terms. Each radionuclide precursor should be evaluated on a case-by-case basis, taking into account the physical characteristics of the radionuclide, its mode of irradiation and chemical processing as well as the envisaged clinical use and the dose planned for administration to the patient. This is clearly reflected in monographs referred in this Chapter. The monograph for 177Lu [59] applies to both the direct and indirect production routes of 177Lu in nuclear reactors and covers all quality aspects regardless the different specific radioactivity and impurity profiles. The decision is left to the producer of the final radiopharmaceutical preparation to use the appropriate solution for radiolabeling. However, the relevant information needs to be stated on the label. This is different in case of 68Ga, there are two different monographs specifying its quality requirements depending whether it’s generator [65] or accelerator produced [66]. One can expect that a similar individual approach applies to the future monographs for new theranostic radionuclides, for example 47Sc, which can be either accelerator or reactor produced [68].
6. Conclusion
Are the requirements for radiopharmaceutical precursors overregulated? With the development of new theranostic procedures involving radiopharmaceuticals, there is a need for proper qualitative evaluation of the final radiopharmaceutical preparation and both of the radiopharmaceutical precursors to ensure efficacy and safety of the treatment. An excellent example of the long pathway of a radiopharmaceutical, 111In-CP04, a peptide targeting the cholecystokinin-2 receptor, from the preclinical development over establishing the required pharmaceutical documentation to designing and submitting a clinical trial in patients with Medullary Thyroid Carcinoma, was recently presented [16]. All the quality aspects of CP04 as chemical precursor have been addressed in the IMPD in view of the quality and suitability of the radiolabeled preparation, 111In-CP04, in order to bring it to the clinic.
In this Chapter, the quality requirements applicable to radiopharmaceutical precursors in the context of their regulatory status in Europe were reviewed. EMA and Ph. Eur. provide public standards for manufacture and quality control of these precursors by establishing specifications and acceptance criteria. While in the case of radiopharmaceuticals with MA and CT regulations quite strictly define the quality and documentation requirements, such standards for in-house produced radiopharmaceuticals are still awaited.
\n',keywords:"radiopharmaceutical precursors, radionuclide precursor, chemical precursor, peptides, IMPD, clinical trials",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74628.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74628.xml",downloadPdfUrl:"/chapter/pdf-download/74628",previewPdfUrl:"/chapter/pdf-preview/74628",totalDownloads:38,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 6th 2020",dateReviewed:"December 9th 2020",datePrePublished:"January 19th 2021",datePublished:null,dateFinished:"December 29th 2020",readingETA:"0",abstract:"Due to the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. In this Chapter we present and discuss the requirements for precursors which are used in the preparation of theranostic radiopharmaceuticals, in particular for preparation of new radiopharmaceuticals for clinical trials within the EU. In discussion on the available methods for assessing the quality of radiopharmaceutical precursors and on the specified limits the reference to Ph. Eur. is made. Since the EANM guidelines for in-house preparation of radiopharmaceuticals also specify the need for testing the quality of radiopharmaceutical precursors, information provided herein might help the radiopharmacist working on the development of new theranostic agents to adequately define identity, strength, quality, purity and stability of the final radiopharmaceutical preparation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74628",risUrl:"/chapter/ris/74628",signatures:"Justyna Pijarowska-Kruszyna, Piotr Garnuszek, Clemens Decristoforo and Renata Mikołajczak",book:{id:"10232",title:"Theranostics - An Old Concept in New Clothing",subtitle:null,fullTitle:"Theranostics - An Old Concept in New Clothing",slug:null,publishedDate:null,bookSignature:"Dr. Elisabeth Eppard",coverURL:"https://cdn.intechopen.com/books/images_new/10232.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"245845",title:"Dr.",name:"Elisabeth",middleName:null,surname:"Eppard",slug:"elisabeth-eppard",fullName:"Elisabeth Eppard"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Current regulatory framework",level:"1"},{id:"sec_3",title:"3. Chemical precursors for radiopharmaceutical preparations",level:"1"},{id:"sec_4",title:"4. Peptides as precursors for radiopharmaceutical preparations",level:"1"},{id:"sec_4_2",title:"4.1 General consideration",level:"2"},{id:"sec_5_2",title:"4.2 Quality aspects",level:"2"},{id:"sec_5_3",title:"4.2.1 Appearance",level:"3"},{id:"sec_6_3",title:"4.2.2 Identification",level:"3"},{id:"sec_7_3",title:"Table 1.",level:"3"},{id:"sec_8_3",title:"4.2.4 Metallic impurities",level:"3"},{id:"sec_9_3",title:"4.2.5 Residual solvents",level:"3"},{id:"sec_10_3",title:"4.2.6 Counter-ion content",level:"3"},{id:"sec_11_3",title:"4.2.7 Water content",level:"3"},{id:"sec_12_3",title:"4.2.8 Assay",level:"3"},{id:"sec_13_3",title:"4.2.9 Microbiological assays",level:"3"},{id:"sec_16",title:"5. Radionuclide precursors",level:"1"},{id:"sec_17",title:"6. 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DOI:10.1097/MNM.0000000000000276.'},{id:"B2",body:'WHO Expert Committee on Specifications for Pharmaceutical Preparation – Radiopharmaceuticals, Final text for addition the International Pharmacopeia, Document QAS/08.262/FINAL, 2008. https://www.who.int/medicines/publications/pharmacopoeia/Radgenmono.pdf'},{id:"B3",body:'EDQM, General Monograph: 0125, Radiopharmaceutical preparations, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B4",body:'EDQM, Monograph: 2902, Chemical precursor for radiopharmaceutical preparations, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B5",body:'EU Commission, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use. 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DOI: 10.1007/s00259-008-0853-7.'},{id:"B18",body:'EU Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections.'},{id:"B19",body:'Todde S, Windhorst AD, Behe M, Bormans G, Decristoforo C, Faivre-Chauvet A, Ferrari V, Gee AD, Gulyas B, Halldin C, Peitl PK, Koziorowski J, Mindt TL, Sollini M, Vercouillie J, Ballinger JR, Elsinga PH. EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD). Eur J Nucl Med Mol Imaging. 2014 Nov;41(11):2175-85. doi: 10.1007/s00259-014-2866-8.'},{id:"B20",body:'Penuelas I, Elsinga PH, The Clinical Translation Process in Europe. In Lewis JS, Windhorst AD, Zeglis BM, editors. Radiopharmaceutical Chemistry. Springer Nature Switzerland AG2019. 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Peptide-based radiopharmaceuticals: future tools for diagnostic imaging of cancers and other diseases. Med Res Rev. 2004; 24:357-97. DOI:10.1002/med.20002.'},{id:"B33",body:'Kaspar AA, Reichert JM. Future directions for peptide therapeutics development. Drug Discov. Today. 2013; 18 (17-18): 807-17. DOI: 10.1016/j.drudis.2013.05.011.'},{id:"B34",body:'Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003; 24:389-427. DOI: 10.1210/er.2002-0007.'},{id:"B35",body:'Langer M, Beck-Sickinger AG. Peptides as carrier for tumor diagnosis and treatment. Curr Med Chem Anticancer Agents. 2001; 1:71-93. DOI:10.2174/1568011013354877.'},{id:"B36",body:'Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market, Drug Discov. Today. 2010; 15:40-56. DOI: 10.1016/j.drudis.2009.10.009.'},{id:"B37",body:'Lau JL and Dunn MK Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 2017;26:2700-2707. DOI: 10.1016/j.bmc.2017.06.052.'},{id:"B38",body:'Rastogi S, Shatrunajay S, Kalaivani M, Singh GN. Peptide-based therapeutics: quality specifications, regulatory considerations, and prospects. Drug Discov. Today. 2019;24:148-162. DOI:10.1016/j.drudis.2018.10.002220-33.'},{id:"B39",body:'Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov. Today. 2015;20:122-8. DOI: 10.1016/j.drudis.2014.10.003.'},{id:"B40",body:'Opalinska M, Hubalewska-Dydejczyk A, Sowa-Staszczak A. Radiolabeled peptides: current and new perspectives, Q J Nucl Med Mol Imag. 2017;61(2):153-67. DOI: 10.23736/S1824-4785.17.02971-5.'},{id:"B41",body:'Chatalic KLS, Kwekkeboom DJ, de Jong M. Radiopeptides for imaging and therapy: a radiant future. J Nucl Med. 2015;56(12):1809-12. DOI: 10.2967/jnumed.115.161158.'},{id:"B42",body:'Fani M, Maecke HR, Okarvi SM. Radiolabeled Peptides: Valuable Tools for the Detection and Treatment of Cancer. Theranostics 2012; 2(5):481-501. DOI:10.7150/thno.4024.'},{id:"B43",body:'Krenning EP, Bakker WH, Breeman WA, Koper JW, Kooij PP, Ausema L, et al. Localisation of endocrine-related tumours with radioiodinated an-alogue of somatostatin. Lancet. 1989;1:242-4. DOI: 10.1016/s0140-6736(89)91258-0.'},{id:"B44",body:'Eychenne R, Bouvry C, Bourgeois M, Loyer P, Benoist E, Lepareur N. Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy. Molecules. 2020;25(17):4012. DOI:10.3390/molecules25174012.'},{id:"B45",body:'Ballinger JR. Theranostic radiopharmaceuticals:established agents in current use. Br J Radiol. 2018;91:20170969. DOI:10.1259/bjr20170969.'},{id:"B46",body:'Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny C. Current status of theranostics in prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45(3):471-495. DOI:10.1007/s00259-017-3882-2.'},{id:"B47",body:'Nock BA, Kaloudi A, Lymperis E, Giarika A, Kulkarni HR, Klette I, Singh A, Krenning EP, de Jong M, Maina T, Baum RP. Theranostic perspectives in prostate cancer with the gastrin-releasing peptide receptor antagonist NeoBOMB1: preclinical and first clinical results. J Nucl Med. 2017;58:75-80. DOI: 10.2967/jnumed.116.178889.'},{id:"B48",body:'Maina T, Konijnenberg MW, KolencPeitl P, et al. Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with (111)In-CP04 in medullary thyroid carcinoma patients. Eur J Pharm Sci. 2016;91:236-242. DOI:10.1016/j.ejps.2016.05.011.'},{id:"B49",body:'Uprimny C, von Guggenberg E, Svirydenka A. et al. Comparison of PET/CT imaging with [18F]FDOPA and cholecystokinin-2 receptor targeting [68Ga]Ga-DOTA-MGS5 in a patient with advanced medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging (2020). DOI:10.1007/s00259-020-04963-z.'},{id:"B50",body:'EDQM, Monograph: 2034, Substances for pharmaceutical use, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B51",body:'Vergote V, Burvenich C, Van de Wiele C, De Spiegeleer B, Quality specifications for peptide drugs: a regulatory pharmaceutical approach. J. Peptide Sci. 2009;15: 697-7. DOI:10.1002/psc.1167.'},{id:"B52",body:'Sikora AE, Maurin M, Jaron A, Pijarowska-Kruszyna J, Kordowski L, Garnuszek P. Optimization of microwave assisted solid -phase synthesis of octreotate peptide and coupling with protected bifunctional chelator DOTA(tBu)3. Acta Poloniae Pharmaceutica - Drug Research,. 2020;77(4):589-600. DOI: 10.32383/appdr/124745.'},{id:"B53",body:'Raheem SJ, Schmidt BW, Solomon VR, Salih AK and Price EW. Ultrasonic-Assisted Solid-Phase Peptide Synthesis of DOTA-TATE and DOTA-linker-TATE Derivatives as a Simple and Low-Cost Method for the Facile Synthesis of Chelator–Peptide Conjugates. Bioconjugate Chem. 2020; DOI:10.1021/acs.bioconjchem.0c00325.'},{id:"B54",body:'Merrifield RB, Solid phase peptide synthesis - Synthesis of a tetrapeptide, J. Am. Chem. Soc. 1963; 85:2149-2154. DOI: 10.1021/ja00897a025.'},{id:"B55",body:'Asti M, Tegoni M, Farioli D, Iori M, Guidotti C, Cutler CS, Mayer P, Versari A, Salvo D. Influence of cations on the complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions. Nucl Med Biol. 2012;39(4):509-17. DOI: 10.1016/j.nucmedbio.2011.10.015.'},{id:"B56",body:'ICH guideline Q3C (R6) on impurities: guideline for residual solvents (2016).'},{id:"B57",body:'Nußbaum R, Lischke D, Paxmann H. et al. Quantitative GC determination of water in small samples. Chromatographia 2000;51:119-121. DOI: 10.1007/BF02490705.'},{id:"B58",body:'Neels O, Patt M, Decristoforo C. Radionuclides: medicinal products or rather starting materials? EJNMMI Radiopharm Chem. 2019;4(1):22. DOI: 10.1186/s41181-019-0074-3.'},{id:"B59",body:'EDQM, Monograph: 2798, Lutetium (177Lu) solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B60",body:'EDQM, Monograph: 2803, Yttrium (90Y) chloride solution for radiolabelling Yttrium (90Y) chloride solution for radiolabelling European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B61",body:'EDQM, Monograph: 2390, Fluoride (18F) solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B62",body:'EDQM, Monograph: 2314, Sodium iodide (123I) solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B63",body:'EDQM, Monograph: 2121, Sodium iodide (131I) solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B64",body:'EDQM, Monograph: 1227, Indium (111In) chloride solution, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B65",body:'EDQM, Monograph: 2464, Gallium (68Ga) chloride solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B66",body:'EDQM, Monograph: 3109, Gallium (68Ga) chloride (accelerator-produced) solution for radiolabelling, European Pharmacopeia, 10th edition, Council of Europe, Strasbourg (2020).'},{id:"B67",body:'Mikolajczak R, van der Meulen NP, Lapi SE. Radiometals for imaging and theranostics, current production and future perspectives. J Labelled Comp Radiopharm. 2019;62(10):615-634. DOI: 10.1002/jlcr.3770.'},{id:"B68",body:'Jalilian AR, Gizawy MA, Alliot C, Takacs S, Sudipta Chakarborty, Rovais MRA, Pupillo G, Nagatsu K, Park JH, Khandaker MU, Mikolajczak R, Bilewicz A, Okarvi S, Gagnon K, Al Rayyes AH, Lapi SE, Starovoitova V, Korde A, Osso Jr JA, IAEA Activities on 67Cu, 186Re, 47Sc Theranostic Radionuclides and Radiopharmaceuticals, Curr Radiopharm 2020;13:1. DOI:10.2174/1874471013999200928162322.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Justyna Pijarowska-Kruszyna",address:"justyna.pijarowska@polatom.pl",affiliation:'
Radioisotope Centre POLATOM, National Centre for Nuclear Research, Poland
Radioisotope Centre POLATOM, National Centre for Nuclear Research, Poland
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Iraq.\n\nEmloyment (Afternoon):\n2011-2013: ABDULMAJEED HUSSEIN Private Hospital / Clinical Laboratory (Technician), Iraq.\n2007-2011: JENIN Private Hospital / Clinical Laboratory (Technician), Iraq.\n\nResearch Interest:\nHe is interested in studying stem cells and their therapeutic applications.",institutionString:null,institution:{name:"Newcastle University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"183247",title:"Prof.",name:"Kazuhito",surname:"Satomura",slug:"kazuhito-satomura",fullName:"Kazuhito Satomura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Tsurumi University",institutionURL:null,country:{name:"Japan"}}},{id:"183399",title:"Dr.",name:"Omar",surname:"Sarheed",slug:"omar-sarheed",fullName:"Omar Sarheed",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"183402",title:"Prof.",name:"Anne",surname:"Dickinson",slug:"anne-dickinson",fullName:"Anne Dickinson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"183403",title:"Prof.",name:"Penny",surname:"Lovat",slug:"penny-lovat",fullName:"Penny Lovat",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"183404",title:"Dr.",name:"Xiao",surname:"Wang",slug:"xiao-wang",fullName:"Xiao Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"186249",title:"Ms.",name:"Reiko",surname:"Tokuyama-Toda",slug:"reiko-tokuyama-toda",fullName:"Reiko Tokuyama-Toda",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"188082",title:"Mr.",name:"Asif",surname:"Ahmed",slug:"asif-ahmed",fullName:"Asif Ahmed",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"partnerships",title:"Partnerships",intro:"
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Crossref
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Altmetric and Dimensions from Digital Science
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CLOCKSS
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Counter
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COUNTER provides the Code of Practice that enables publishers and vendors to report usage of their electronic resources in a consistent way. This enables libraries to compare data received from different publishers and vendors.
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DORA
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iThenticate
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Enago
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SPi Global
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Amazon
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
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OASPA
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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The International Association of Scientific, Technical and Medical Publishers (STM) is the leading global trade association for academic and professional publishers. As a member, IntechOpen has not only made a commitment to STM's Ethical Principles.
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COPE
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Crossref is the official Digital Object Identifier (DOI) Registration Agency for scholarly and professional publications with a goal of making scholarly communications more effective. IntechOpen deposits metadata and registers DOIs for all content using the Crossref System. IntechOpen also deposits its references and uses the Crossref Cited-by service that enables researchers to track citation statistics.
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Altmetric and Dimensions from Digital Science
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\n\t
Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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CLOCKSS
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\n\t
CLOCKSS preserves scholarly publications in original formats, ensuring that they always remain available and openly accessible to everyone.
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Counter
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COUNTER provides the Code of Practice that enables publishers and vendors to report usage of their electronic resources in a consistent way. This enables libraries to compare data received from different publishers and vendors.
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DORA
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DORA is a worldwide initiative covering all scholarly disciplines which recognizes the need to improve the ways in which the outputs of scholarly research are evaluated and seeks to develop and promote best practice. To date it has been signed by over 1500 organizations and around 14,700 individuals.
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iThenticate
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iThenticate is the leading provider of professional plagiarism detection and prevention technology and is used worldwide by scholarly publishers and research institutions to ensure the originality of written work before publication. IntechOpen uses the iThenticate plagiarism software to ensure content originality and the research integrity of our published work.
\n
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Enago
\n\n
\n\t
IntechOpen collaborates with Enago, through its sister brand, Ulatus, one of the world’s leading providers of book translation services. Their services are designed to convey the essence of your work to readers from across the globe in the language they understand.
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IntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit https://www.enago.com/intech
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SPi Global
\n\n
\n\t
SPi Global is the market leader in technology-driven solutions for the extraction, enrichment and transformation of content assets. IntechOpen publishing services are designed to meet the unique needs of Authors. As part of our commitment to that objective, we have an ongoing partnership agreement for production solutions.
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Amazon
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Amazon is the world’s largest online retailer and cloud services provider. IntechOpen books have been available on Amazon since 2017, guaranteeing more visibility for our Authors and Academic Editors.
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
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