Comparison of mean (
\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
Gastroschisis (GS) or more aptly “laparoschisis” is a congenital abdominal wall defect (AWD) leading to herniation of the gut more commonly to the right of the umbilical cord (Figure 1). It differs from other AWDs in causality, risk factors, and associated anomalies [1, 2, 3].
\nGastroschisis with prolapsed bowel to the right of the umbilicus.
GS incidence is increasing worldwide [4, 5] and is estimated around 1 in 2200 live births [6, 7]. Antenatal scans detect most cases [8], survival in developed countries is excellent [7] and apart from some gastrointestinal dysfunction, long-term problems are rare [9].
\nThis chapter is dedicated to discuss in simplified flowchart-form the initial, operative and post-operative management of GS with emphasis on low-resource settings. In addition it aims to outline salient topics such as fluid management and complications.
\nThough unexplained, a young maternal age and low socioeconomic status are the commonest risk factors for GS [10, 11]. Smoking, drugs, environmental toxins and poor nutrition have also been implicated [12]. A genetic link in the form of homozygous gene polymorphisms has been reported [13] and is substantiated by an increased prevalence among familial cases of birth defects and twins [14].
\nThe embryological origin of GS is still a matter of conjecture. Several theories have been put forward attempting to expound the abdominal wall defect: failed body-wall folding [15]; a vascular insult to the omphalo-mesenteric artery [16] or to the right umbilical vein [17]; a localized disruption of the amniotic membrane [18] or teratogen-induced mesenchymal failure [19]. None of the theories are fully satisfactory [20]. The right-sided occurrence of the defect has been linked to the position of the yolk sac [15, 21] without clear reasoning as to why. Left-sided defects have also been described [22].
\nIn high-income countries (HICs) routine antenatal scans may detect more than 97% of cases [23]. A diagnosis can be made as early as 10 weeks of gestation [24] and aids counseling, transfer and delivery [25, 26]. Ultrasound will typically pick up herniated bowel not covered by amnion, to the right of the umbilical cord (Figure 2). In contrast, an exomphalos will be covered by a membrane, lies in the midline and may involve solid organ prolapse. Ultrasound is instrumental in picking up closing GS which is defined as a worsening ratio of intra vs. extra peritoneal bowel dilatation [27]. Further aids to diagnosis of GS are high levels of maternal serum alpha-fetoprotein (MSAFP) [28], intrauterine growth retardation with or without oligo-/an-hydramnios [7, 29, 30]. As GS is usually an isolated anomaly with very few risks to the mother or child, termination of pregnancy is not habitually offered [2, 31, 32].
\nAntenatal scan showing GS.
A spontaneous onset of labor will typically occur around 36 weeks gestation and the route of delivery is dependent on obstetric indications [33, 34]. There is a lack of high-level evidence to support early induction of labor in uncomplicated GS cases [35, 36] and a similar lack of evidence to support cesarean section [37]. Early (emergency) delivery is beneficial in closing GS [26].
\nLMICs have an overall high mortality rate in neonates with correctable congenital anomalies [38, 39] and suffer from a lack of medical facilities and personnel [40]. Non-governmental and governmental organizations have been criticized for not doing enough [41, 42] though new partnerships are attempting to redress this [43, 44].
\nMortality from GS in low-to-middle-income countries (LMICs) can reach up to 80–100% [45, 46, 47, 48] which is in sharp contrast to the <10% in HICs [49]. Sepsis is a major culprit in most cases of neonatal mortality in LMICs [48]. The Gastroschisis International (GiT) network has suggested that poor resuscitation combined with sepsis and abdominal compartment syndrome is directly linked to the poor outcome [50].
\nAntenatal care may not be well developed [51] or mothers may engage poorly with it [52] which risks births in areas far from the reach of the pediatric surgeon. A delay in transfer of the neonate with GS remains a main concern [47, 53] however a recent study from South Africa has suggested that resuscitation at the initial point of care and throughout transfer may be the key to improving the end result [51].
\nA GS infant is ideally delivered at or near a facility with pediatric surgical support [25]. Conversely, outborn cases have been shown to have worse outcomes such as longer days on parenteral nutrition and longer duration to achieving full feeds [54].
\nThe accepted approach to managing GS is to cover the gut with a sterile bag (Figure 3), nasogastric decompression and fluid resuscitation. Hypothermia is a major risk due to the exposed gut and significant fluid losses [55]. Premature babies are particularly prone to hypothermia because of their high ratio of skin surface to weight and a lower amount of subcutaneous and brown fat. They may also have respiratory issues which impact on their oxygen consumption and heat production [55].
\nCling film covering the bowel in gastroschisis.
The authors follow the protocol outlined in Figure 4. At the outset doctors and nurses are reminded that the triad of hypovolemia, hypothermia and sepsis are the major threats to this neonate and that resuscitation is directed to mitigating their effects. Almost simultaneously, certainly not sequentially, the baby is positioned lengthwise on a resuscitaire or warmer to facilitate access. Any wires, leads or lines are shifted away from the baby and the bowel. Kinking of the bowel is avoided by laying the child on their side or by propping up the bowel with gauze rolls in the supine position. Probes for temperature and oxygen saturation are connected. ECG leads are placed and connected to a monitor. A urinary catheter is placed with an aseptic technique. Resuscitation follows APLS guidelines of airway, breathing, circulation, rapid initial examination while the bowel is covered with cling film. An appropriately-sized nasogastric tube is placed on free drainage supplemented by 2-hourly active aspiration. Peripheral vascular access is secured and bloods are taken for blood sugar (if not done earlier), a complete blood picture, kidney and liver functions, clotting and cross-match. A fluid bolus is then administered followed by maintenance according to body weight. Broad-spectrum antibiotics are given according to the hospital protocol.
\nInitial management of gastroschisis. *Kinking can be avoided by laying the child on their side or by propping up the bowel with gauze rolls while the child is supine. **ABC of basic resuscitation. Do not forget blood sugar. CBC, complete blood count; UEs, urea and electrolytes; LFTs, liver function tests.
The aspired aim is to achieve full reduction of the bowel with muscle and skin closure of the abdominal wall, as cosmetically as possible. Safety of the child and the gut are paramount therefore if a complete primary closure is not possible staged reduction should be considered.
\nAll manipulations should be done in a sterile environment. The authors routinely take all cases to theatre, however bedside procedures are also possible. Central vascular access is secured and a urinary catheter would have been placed during initial resuscitation in all cases.
\nThe authors follow the guideline outlined in Figure 5: cases of simple GS with no obvious viscero-peritoneal disproportion (VPD) will undergo primary closure. If very straightforward, sutureless closure with steri-strip dressings is done. On occasion some cases will require division of bands or strands of omentum adherent to the defect and they go on to have formal sutured closure of the defect. Primary (sutured) closure has excellent cosmetic results (Figures 6 and 7). Sutureless closure is associated with a higher incidence of umbilical hernia [56, 57] Guided by ventilation pressures, cases with moderate VPD will undergo a skin closure with the size of the defect determining if the umbilicus, the skin or a prosthetic patch is needed. Marked VPD and high ventilation pressures call for staged silo closure. The authors fashion surgical silos from sterile intravenous fluid bags (Figure 8a–c). Surgical silos can be made from a variety of materials which are summarized in Box 1. Spring-loaded (pre-formed) silos are ready-made and obviate the need for suturing to the abdominal wall [20, 55]. They come in various sizes to allow for the variability in the GS defect (Figure 9). One may rely on gravity alone, active tucking or a combination of both to reduce the contents into the abdominal cavity. There is weak evidence in favor of the routine use of pre-formed silos instead of primary closure [20, 55, 58].
\n\n
Prolene mesh
Silicone sheet
Goretex mesh
Sterile adhesive drapes +/− prolene mesh
Biomaterials (Alloderm, Permacol)
IV fluid bag
Female condom
Alexis wound protector
Options for closure of gastroschisis. *Can be done cotside. **Silo material, see Box 2. ***Delayed repair is around 6 weeks post-operatively. ****Avoid stoma in a low-resource setting. GS, gastroschisis; VPD, viscero-peritoneal disproportion.
Cosmetic result after primary closure.
Primary Closure.
(a–c) Staged silo reduction.
Pre-formed silos http://bentecmed.com/bentec-medical-products/ventral-wall-defect-silo-bags/.
Complex GS is defined as any case with associated bowel atresia, stenosis, perforation or volvulus. In the presence of atresia, the authors’ preference is to plan a delayed repair but a primary resection and anastomosis at the time of abdominal closure is also acceptable if the bowel is healthy and not too edematous. Stoma formation is fraught with high-output stoma complications such as failure to thrive and peri-stoma skin breakdown—therefore is not the surgery of choice in low-resource settings. Closing GS represents a spectrum of disease where the defect has started to narrow down around the prolapsed gut. At its simplest form it can lead to intestinal stenosis but may progress to atresia, gut ischemia up to complete disappearance of the prolapsed bowel if the defect closes completely, aka closed GS or “vanishing gut syndrome” [61]. Closing GS is challenging even in HICs and is associated with worse outcomes compared to simple GS. Narrowing or atresia may lend themselves to resection and primary anastomosis (either at the time of reduction, or delayed). Necrotic gut will require resection (Figures 10 and 11) and vanished gut will indicate an ultra-short intra-abdominal segment. These cases will require either primary or delayed bowel lengthening procedures [62].
\nClosing gastroschisis with necrotic bowel.
Closing gastroschisis with necrotic bowel.
The staged reduction process should take between 1 day and 2 weeks and is dependent on the degree of VPD. Enteral feeds are started once the gastro-intestinal system shows signs of resumed function: decreased nasogastric aspirates <20 ml/kg and bowel motions. Ideally expressed maternal breast milk is used [63, 64, 65], but formula feeds are acceptable. Elemental feeds may help protect against necrotizing enterocolitis. GS infants fed at around 7 days post closure seem to have the best outcome [66]. If the bowels do not open within 10–14 days a water-soluble contrast enema should be done to rule out a bowel atresia. An atresia detected at the time of initial closure of by subsequent imaging may be safely repaired after 3–6 weeks. Albeit uncommon in GS, cases with any associated malformations will require further investigations and management according to the findings.
\nPublications frequently refer to a “consensus” among doctors on the optimal fluids required for GS. However, there is sparse evidence-based literature to guide the perioperative fluid management [65, 66]. Reports of fluid administration have varied from twice to three-times the normal maintenance volumes for neonates [67, 68] and were based on original research by Phillippart et al. in 1972 [69].
\nFluid overload in the absence of hypovolemia has been proven to be deleterious in neonates [70]. It affects a patent ductus arteriosus, may cause intracranial hemorrhage, bronchopulmonary dysplasia or may even be fatal [71, 72]. Therefore the mere assumption that GS cases need vigorous volume expansion may be harmful. Preterm neonates may also benefit from fluid restriction according to a recent Cochrane review [73]. It has been suggested that the fluid overload will contribute to intestinal edema leading to a longer hospital stay and longer duration of parenteral nutrition through the increase of total body water and salt [65]. It may also play a part in development of NEC [74].
\nThis practice of over transfusion is routinely carried out postoperatively as well [75]. While it may be of value in cases with a silo where there are ongoing losses of fluid from the base, it has no real justification in cases which undergo primary closure.
\nFew published sources will give an outright volume to go by. They will always be ranges and the clinician must be guided by continuous assessment of the child. Postnatal diuresis can complicate fluid-balance calculations but a useful milestone to assess the cardiovascular status is after administering 40 ml/kg of fluid. Albumin has been advocated as a volume expander in hypovolemic GS cases. It is not particularly useful in hypoalbuminemia associated with sepsis [76, 77]. An additional tool to help restore insensible water loss incurred through breathing is the humidification of incubator air.
\nA large degree of viscero-peritoneal disproportion and over-zealous reduction runs the risk of increased intra-abdominal pressure. The latter will result in restricting diaphragmatic movement and compression of the inferior vena cava, which will in turn result in respiratory distress, renal, liver and bowel ischemia, respectively. They manifest as metabolic acidosis, oliguria, renal and liver dysfunction [55].
\nReference values for safe abdominal closure [78, 79, 80, 81].
\n\n
Gastric/urinary bladder pressure < 20 cm H2O or < 15–20 mmHg
End-tidal CO2 < 50 mmHg
CVP < 4 mmHg or < 5.4 cm H2O
Ventilation <24 cm H2O
Frequent monitoring of oxygen saturation/ventilation setting, serial blood gases, urine output, serial abdominal examinations, lower limb perfusion are important in early detection of ACS. Oliguria alone is not a sensitive indicator of ACS as it may be due to hypovolemia. Pressure measurements can be taken using sophisticated transducers used with anesthesia machines or by simply connecting the tubing to a CVP water manometer. Reference values are quoted in Box 2 [78, 79, 80, 81].
\nSepsis is a common complication in LMICs. Most common sources are intra-abdominal, silo/wound infections, indwelling central lines or urinary catheters [50, 51].
\nAs always, prevention is better than cure. Meticulous antisepsis protocols and timely use of antibiotics are important first tools. Early suspicion of central line-associated blood stream infection (CLABSI) or urinary tract infection (UTI) should prompt urgent cultures to be sent to the lab. The authors remove the urinary catheter once there is a stable urine output and no further risk of abdominal compartment syndrome.
\nBoth pre-formed and surgical silos are prone to dislodgement and may cause bowel kinking, ischemia and perforation [58]. It is prudent to keep the silo and its contents visible at all times to allow early detection of any of these complications.
\nIatrogenic pneumothorax secondary to barotrauma is an unfortunate complication in ventilated neonates and occurs in around 8.7% of the cases [82]. In GS this may be due to high intra-abdominal pressure after bowel reduction. This is best anticipated in theatre and if pressures exceed 24 cm H2O, a staged reduction should be the surgery of choice. If post-operative ventilation is unavoidable then positive end-expiratory pressure (PEEP) or high-frequency oscillation ventilation (HFOV) is used. Neuromuscular paralysis may also help reduce ventilation pressures but is not always available in low-resource settings.
\nA pneumothorax is suspected when oxygen saturation drops and ventilation pressures rise sharply with absent ipsilateral air entry. An urgent plain chest x-ray will confirm this and should be followed by immediate needle decompression then a formal chest drain with an underwater seal. Bilateral asynchronous pneumothoraces are not uncommon [82].
\n\n
NEC: It follows the same patterns and risk factors as with non-GS infants. Prematurity, formula feeds, rapid increase in feed volume—have all been implicated. Treatment is standard: nasogastric tube decompression, gut rest and antibiotics will often suffice [83, 84].
Large abdominal defect: The GS defect is seldom large to start with and is occasionally enlarged by the surgeon to facilitate bowel reduction. Hence a large defect is a rare complication which may occur in long-standing cases of staged-reduction (Figure 12). Standard closure techniques include the use of a prosthetic material or plastic surgery techniques such as abdominal wall rotational flaps with or without lateral release incisions [85].
Enterocutaneous fistula: (Figure 13) rare complication which may occur secondary to wound infection, NEC, or a combination of both. Vacuum dressings have been of value in treating such a complication [55, 86]. It is the authors’ experience that vacuum dressings may paradoxically cause an enterocutaneous fistula if incorrectly placed or if the suction is too vigorous. Surgical closure when the infant is in a positive nitrogen balance is beneficial.
Large abdominal wall defect with granulation in long-standing silo.
Entero-cutaneous fistula.
In recent years, 68Ga-radiopharmaceuticals gained more and more attention due to their steadily growing clinical application. Facilitated is this development by increasing interest in the application of its “theranostic twin” lutetium-177. Combining both, gallium-68 and lutetium-177, enables diagnostic molecular imaging followed by personalized treatment based on the diagnostic scan [1].
This concept is well established for treatment of neuroendocrine tumors (NETs) using peptide receptor radionuclide therapy (PRRT). This approach allows the targeted treatment of inoperable or metastatic NETs already proven in multiple clinical trials employing radiolabeled somatostatin analogs [2, 3, 4, 5, 6, 7, 8, 9]. Based on the data received, the U.S. Food and Drug Administration (FDA) recently approved 177Lu-labeled DOTA-TATE for PRRT treatment. However, not only for NETs, but also for other types of cancer (e.g. prostate cancer (PC)), lutetium-177 is of interest, reflected in numerous clinical trials registered at
Although, gallium-68 was already proposed for medical use by Gleason [10] its way to clinical application was not possible without the advancement of the primary generator design. Providing [68Ga]GaCl3 and containing only trace levels of the long-living mother radionuclide germanium-68 regarding 68Ga-activity, the commercially availability of generator simplified research and motivated developments with a view to a broad routine application. The launch of this new type of 68Ga-generator together with decades of research in chelation chemistry and drug discovery resulted in the design of 68Ga-radiopharmaceuticals of high affinity/selectivity for their biological targets [11, 12, 13].
The advantages of the generator availability and the easy one-step chelation chemistry ensured the relatively fast and broad application of the 68Ga-radiopharmaceuticals even in smaller institutions. However, exactly these advantages lead to problems in the supply today and require new developments in order to meet the growing demands.
What is the advantage of radiometals for an application in nuclear medicine? With carbon-11 and mostly fluor-18, two radionuclides for positron emission tomography (PET) are available, which can be used for radiolabeling without appreciably altering the biological properties of the compounds in addition to their favorable decay characteristics. However, the disadvantage of radiometals, the need for a chelator is also their advantage over fluor-18 and carbon-11.
Due to this, radiolabeling with radiometals is very easy, can be conducted in aqueous solution and with the right choice of chelator possible under mild conditions. That enables radiolabeling of temperature or organic solvent sensitive compounds (e.g. antibodies). Additionally, the choice of chelator provides the possibility of radiolabeling one compound with different radiometals. Thus, widespread application (PET, single photon emission computed tomography (SPECT), magnet resonance tomography (MRT) and therapy) of the compound only by exchange of the radiometal with minimum changes in biological behavior is possible. This facilitates patient-centered care from diagnosis via molecular imaging, over treatment planning, prognosis and monitoring utilizing one compound (Figure 1).
Depiction of the theranostic concept: utilizing one compound for a variety of applications in patient-centered care radiolabeled with different radionuclide.
Advantages in favor of gallium-68 compared with other appropriate radiometals are its favorable decay characteristics, its (commercial) availability and the possible combination with lutetium-177 as theranostic pair (Figure 2). Also gallium-68 possibly provides patient care in places where cyclotron-produced fluor-18 is not obtainable.
PET-images (A; C) and SPECT-images (B) of a patient with metastatic castrate-resistant prostate cancer (mCRPC) undergoing therapy with [177Lu]Lu-PSMA-617 with pre- and posttherapeutic 68Ga-PET-imaging using the diagnostic counterpart [68Ga]Ga-PSMA-11.
Currently gallium-68 is most widely used in the diagnosis of prostate cancer in the form of [68Ga]Ga-PSMA-11, respectively. [68Ga]Ga-PSMA-617 together with [177Lu]Lu-DOTA-PSMA-617 forms a theranostic couple, which is very well suited for the diagnosis or treatment of prostate cancer as the 68Ga/177Lu-radiolabelled tracers show a very similar biological behavior. Due to similarities in chemical behavior, identical (in case of PSMA-617) precursors can be radiolabelled using the same or similar equipment, synthesis and quality control methods [14].
The second, but longest known and best evaluated, 68Ga theranostic pair is used for neuroendocrine tumors in combination with various somatostatin analogs. The three most widely used analogs of somatostatin with gallium-68 are [68Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-LAN or [68Ga]Ga-DOTA-NOC [15]. As a therapeutic counterpart, yttrium-90 and lutetium-177 are used.
Besides these two main applications of gallium-68, a variety of studies work on the extension of the application scope.
For imaging of insulinoma pancreatic islets, several versions of 68Ga-radiopharmaceuticals based on Exendin-4, a glucagon-like protein-1 receptor agonist, exist and it was demonstrated that [68Ga]Ga-DOTA-exendin-4 localizes insulinoma significantly better than 111In-radiolabelled radiopharmaceuticals [16].
Integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) are usually overexpressed in human breast cancer, prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, glioma, lung cancer, ovarian cancers, endometrial cancers, renal cell cancer and gastrointestinal stromal tumors. An amphibian homolog of the mammalian gastrin-releasing peptide bombesin was intensively investigated, also radiolabelled with gallium-68, for imaging of GRPR. For integrin αvβ3, specific imaging probes usually use the peptide arginine-glycine-aspartic acid (RGD). For imagine of GRPR, several radiopharmaceuticals based on gallium-68 were proposed, in particular [68Ga]Ga-BBN-RGD for breast cancer imagine [17], [68Ga]Ga-NOTA-Aca-BBN for glioma imagine [18], [68Ga]-NOTA-DUPA-RM26 for prostate cancer imagine.
Another promising area of application of 68Ga-based radiopharmaceuticals is the labeling of human epidermal growth factor receptor family (HER2) [19] and carcinoembryonic antigen (CEA) [20].
Even though gallium-68 is a very convenient radionuclide for use in radiopharmacy, it is widespread in radiopharmaceuticals in comparison with other diagnostic isotopes. But usability and the commercially availability of generator simplified research and motivated developments with a view to a broad routine application.
Radiolabeling with radiometals is in some ways challenging. Due to the very low amount of substance, other metals present in the reaction mixture can be serious problem and noticeably effect the radiolabeling. These metallic impurities can compete with gallium-68 for the chelating function of the precursor and are compared with gallium-68 (1 GBq equals to 9.73×10−12 mol) even when present at low levels (<ppm) clearly in excess number. They are result of external influences (e.g. production of starting materials) or are an intrinsic generator property (e.g. matrix; decay product). To avoid additional or larger impurities than necessary, the following is recommended by the IAEA [21]:
Use plastic disposables/contact materials
Avoid contact with metals of your working equipment during preparation of reagents (e.g. pipettes, spatulas, vials, etc.)
Protect your working materials from direct contact with metals (e.g. surfaces, etc.)
Use chemicals and water with lowest metal content as possible (e.g. ultra-pure grade)
Do not use standard laboratory glassware (e.g. beakers, etc.)
Consider coating of your fume hood.
Gallium is located in group 13 in the 4th period. It has 31 known isotopes and 11 metastable isomers including the two natural occurring stable isotopes gallium-69 (60.11%) and gallium-71 (39.89%). Two gallium isotopes are applied in nuclear medicine for PET-imaging: gallium-67, which has the longest half-life (T1/2 = 3.26 d) of the instable 68Ga-isotopes, and gallium-68 (T1/2 = 67.71 min).
Ga(III) is a hard Lewis acid forming complexes coordinating four, five or six ligands. The most stable complexes are the last-mentioned with a octahedral coordination sphere in which oxygen, nitrogen and sulfur donor atoms form coordination bonds with Ga(III). To ensure the complex formation thorough pH, control is required to ensure deprotonation of the electron donor and to protect Ga(III) from forming Ga(OH)3 precipitating at pH 3–7 [22].
Gallium-68 is a positron emitter that decays with a half-life of 67.71 min and 89% positron branching to stable zinc-68. The transition is accompanied by low-abundant photon emission (1077 keV, 3.22%) [23]. Table 1 shows the mean and maximum energies of the positrons emitted in comparison to fluorine-18.
Positron emitter | Half-life | Eβ, max | |
---|---|---|---|
[MeV] | |||
Gallium-68 | 67.71 min | 0.829 | 1.899 |
Flourine-18 | 109.77 min | 0.250 | 0.634 |
Comparison of mean (
One of the reasons of the emerging application of gallium-68 in nuclear medicine is its cyclotron-independency and availability via radionuclide generator. Since the application of gallium-68 was a long time limited to research, advancements in generator design facilitated research on new 68Ga-radiopharmaceuticals as well as clinical use of the known.
Physical basis for radionuclide generators is the existence of the radioactive equilibria. The differentiation between radionuclide generations is based on the half-lives of the parent (1) and its daughter (2). Depending on the ratio between the two half-lives, three principal cases can be distinguished:
Transient equilibrium. Longer living parent but not more than factor 100: T1/2, 2 < T1/2,1 < 100.
Secular equilibrium. Much longer living parent: T1/2, 2 < < T1/2,1.
No equilibrium. Shorter living parent.
The basis for the 68Ge/68Ga-generator is the secular equilibrium between the parent radionuclide germanium-68 and its daughter gallium-68. Germanium-68 decays with T1/2 = 270.95 days via electron capture to gallium-68. This transition is subsequently followed by decay of gallium-68 to stable zinc-68. At equilibrium, the quantity of gallium-68 produced is equal to the quantity of gallium-68 decaying, while the parent activity does not significantly decrease over many half-lives of the daughter. The theoretical maximum activity or equilibrium state for a certain generator system can be obtained at the time t (Figure 3):
Build-up kinetics of gallium-68 on the generator column after initial elution.
For the 68Ge/68Ga system, equilibrium is reached after 14.1 h, representing maximum obtainable activity. Even if idle times of 12.5 half-lives are necessary to obtain maximum activities, the generators can be used more frequently. Within two half-lives of gallium-68 already 75% of the maximum value is build-up and could be used.
The 68Ge/68Ga-generator system introduced in the 1960s by Gleason [10] underwent a lot of changes until today. From the first gallium cow providing gallium-68 after liquid–liquid extraction [10], nowadays the generators, based on a solid matrix (inorganic or organic) providing “ionic” 68Ga3+ eluates. The first commercially available generator of this type was developed by Cyclotron Ltd., Obninsk, Russian Federation [25] eluting gallium-68 with 0.1 M HCl with initial elution yields of ~80% and 68Ge breakthrough of 0.001% [26]. Since the introduction of this generator in 1996 [26], a lot has happened on the market. Today several manufacturers produce 68Ge/68Ga-generators, including ones with GMP grade (e.g. Isotopen Technologien Garching (ITG)) or with approval (e.g. GalliPharm® Eckert & Ziegler in the EU with marketing authorization, in the USA with type II drug master file (DMF) on file with FDA).
Even though these generators represent considerable improvements in 68Ga-production, there are still some obstacles to direct radiolabeling with gallium-68. Beside the low radioactive and high [H+] concentration and 68Ge breakthrough, especially the presence of other trivalent metal ions is an inconvenience. As 1 GBq gallium-68 is equal to 9.73 pmol (9.73×10−12 mol), these metallic impurities, even present at low levels (<ppm), can be a serious problem as they can compete with gallium-68 for the chelating function of the precursor. In addition to the IAEA recommendations on externally introduced metallic contaminations [21], several procedures are available to reduce those metallic impurities, either intrinsic or externally introduced. These post-elution purification methods, so called post-processing’s, aim to improve the radioactive and [H+] concentration and the radionuclidic as well as chemical purity of the 68Ga-eluate. Beside fractionation of the eluate [11], anion-exchange (AEX) [13], cation-exchange (CEX) [27, 28, 29] and a combination thereof [30, 31] found to be suitable but only for fractionation but also are commercially used for cation-exchange.
Although 68Ge/68Ga-generators represent a convenient possibility for persistent patient care with 68Ga-radiopharmaceuticals, their 68Ga-activity available for radiolabeling underlies several restrictions resulting from generator design and physics. In conjunction with the sharp increase in demand in recent years, alternative production routes, preferably realizable with existing medical cyclotrons, moved into the focus.
Small to medium energy medical cyclotrons are suitable for 68Ga-production via the 68Zn(p,n)68Ga reaction using either a solid or a liquid target. Among the possible nuclear reactions [32, 33], it is the most reasonable leading to large production yields. For optimal results, the starting material zinc-68 as well as the proton energy needs to be selected with care to reduce co-production of long-living radioisotopes of gallium. Nevertheless, co-production of gallium-66 and gallium-67 is unavoidable due to the starting material and the excitation function of the 68Zn(p,2n)67Ga reaction [32, 33]. This has to be taken into account when producing gallium-68 via cyclotron for radiopharmaceutical application as both radioisotopes cannot be separated from the desired gallium-68.
For production of gallium-68 via cyclotron, either a solid or a liquid target can be used. For both target types, a lot of options exist leading to a several considerations to be made. Solid targets, for example, can be pressed, electroplated, foil or fused, all types having their advantages and disadvantages which are not mentioned here. In a first instance, the choice of target will mostly be done due to the actual conditions of the site. An existing production site for 18F-compounds which want to implement gallium-68 would probably choose the liquid target route, as the preconditions for a solid target (target holder, cooling, target transfer and target processing) are expensive and likely not available. Compared with that, the liquid target is a quick and inexpensive option to obtain gallium-68 when a generator is not reasonable. A detailed overview about all possible alternatives and their advantages/disadvantages is given by the IAEA [21].
After irradiation, the gallium-68 needs to be purified from target material either if a solid or liquid target was used. The quantity of zinc necessary for the target need to be removed as it and all other metal impurities may perturb the radiolabeling reaction of gallium-68. Intense research on this topic lead to several purification methods based on solvent extraction [34, 35], precipitation [36] and solid phase separation [37, 38, 39, 40, 41, 42, 43, 44] and suitable for automation.
Solid-phase extraction using a cation exchange resin or hydroxamate resin is most appropriate for an effective separation of gallium-68 from unwanted metals and can be easily combined with a second resin. This second purification step allows an additional reduction of [H+] concentration to facilitate further processing of the final product [21]:
Local conditions (expertise and equipment)
Separation time (should be as short as possible)
Acids (concentration and volume)
Availability of materials
Robustness of technique
Ease of automation
Possibility to recycle zinc-68 from target solution
The manual radiolabeling approach is a leftover from times, where gallium-68 was mainly used for research purpose, with lower 68Ga-activities and not in a clinical setting for patient care. It is widely used in research and development of new tracers [11, 12, 13, 29, 30, 45, 46, 47, 48, 49, 50, 51]. Its main advantage is full control over the complete process (pH, time and temperature) and the possibility to easily access radiolabeling kinetics.
Due to its general setup, this method is not suitable and indented for clinical use. Nevertheless, before the introduction of module systems or the cold kits, it was a long time, the only available method.
In general (Figure 4), the first step is the preparation of the reaction mixture by mixing [68Ga]GaCl3 with a suitable buffer in the required pH range and the radiolabeling precursor. Here, the purified cyclotron-produced, generator eluate or post-processed gallium-68 can be used.
Schematic description of the 68Ga-radiolabeling procedure (I) preparation of the reaction mixture by adding gallium-68 eluted from a generator or after post-processing to a mixture of a suitable buffer and precursor, (II) incubation of the reaction mixture for a certain time. If elevated temperatures are needed or not depends on the chelator, (III) purification step using solid phase extraction (SPE). For example, the 68Ga-radiopharmaceutical is trapped on a SPE C18-cartridge where it is washed with water to remove free gallium-68, germanium-68 and buffer, (IV) the purified product is finally eluted with diluted ethanol solution and formulated after sterile filtration in the product vial.
Then, the reaction vial is incubated to form the 68Ga-complex. Reaction period and reaction temperature are selected in accordance to the kinetics of the complex formation of gallium with the used chelator.
After the reaction, the reaction mixture can be purified using, for example, solid phase extraction from, for example, free gallium-68 and residual germanium-68 impurities.
In the final step, the 68Ga-radiopharmaceutical is sterile filtrated and formulated in the product vial (Table 2).
With the growing interest for gallium-68 not only for research but also for clinical routine and patient care the need for pharmacopeia compliant preparation of 68Ga-radiopharmaceuticals. This led to promotion of the automation of the traditional manual synthesis from which numerous semi- and fully automated devices have emerged. Today, those systems are designed with respect to Good Manufacturing Practice (GMP) Guidelines provided, for example, by the FDA, EU/EMA, ICH, WHO or others [55]. They use software and methods designed to minimize user interventions and utilize single-use consumables produced under GMP standard.
While the module production requires a fully equipped laboratory and quality control, it reduces radiation exposure of the operator the production process in terms of higher reliability and reduced variability [56, 57, 58].
Accordingly, the amount of contaminated waste materials is higher due to the procedure as well the complete quality control. Nevertheless, these systems are suitable for a variety of tracers and in most cases for more radionuclides not only for gallium-68 (e.g. Scintomics GRP series; Eckert & Ziegler Modular-Lab PharmTracer; Trasis AllInOne).
Recently, cold kits for radiolabeling entered the scene enable production of 68Ga-radiopharmaceuticals as easy as that of 99mTc-radiopharmaceuticals. This method allows the reconstitution of the pre-formulated cold kit with no previous post-processing of the eluate or subsequent purification of the final product. They are available in GMP quality and leaves only minimum quality control tests to the final user responsibility to verify the reconstitution procedure.
For example, the European Pharmacopeia (Ph. Eur.) states the marketing authorization (MA) holder of a licensed kit is responsible to ensure compliance of the kit with the requirements of its MA, while the final user carries the responsibility for the quality of the preparation and the handling. If the given instructions are not strictly followed or if one or more components used for the reconstitution do not have MA, it is the responsibility of the final user to demonstrate that the quality of the final preparation is suitable for the intended, use [26].
Therefore, preparation as well as quality control requires at least the equipment according to the instructions provided by the manufacturer. In addition, minimum contaminated waste materials remain. It has to be noted, according to the Ph. Eur. that applies only for licensed kits in combination with the generator mentioned in the instructions from the manufacturer. In contrast, unlicensed kits or a licensed kit used with an unlicensed generator or cyclotron produced gallium-68 also require full quality control according to the monograph. Additionally, local authorities may require more detailed quality control even for licensed kits.
Indeed, these cold kits contain relatively high amounts of precursor and additional filler materials. They still require manual handling and are only commercially available as single-dose kits for radiolabeling PSMA-11 (e.g. illumet™) and DOTA-TOC (e.g. NETSPOT®). In addition, the use of unpurified generator eluates requires very strict specifications for the generators in terms of 68Ge-breakthrough to ensure the quality of the final product. Nevertheless, there is a possibility for small sites to offer 68Ga-radiopharmaceuticals to their patients without great expense.
Quality defects of pharmaceutical can lead to serious consequences when they are applied. Consequently, the regulatory framework for production and quality control is very strict. In general, one main requirement in the production of pharmaceuticals is a comprehensive, integrated system of quality assurance. Its purpose is the monitoring and documentation of all processes as well as their functionality with respect to the rules of GMP.
Because radiopharmaceuticals are pharmaceutical preparations containing minimum one radionuclide for diagnostic or therapeutic purpose, in principle the same rules apply. Their quality control is intended to ensure that the quality meets the predefined specifications for the radiopharmaceutical. These specifications take into account the radionuclide, the precursor, the preparation process, the formulation and the intended administration route. Due to the nature of the contained radionuclides, not all necessary quality control tests can be performed before release for administration and require retrospective examination. In the available monographs, it is indicated if a test need not to be completed before release of the batch.
In the case of gallium-68, the short half-live and the limited available activities lead to further challenges. Here are sophisticated logistics for preparation and quality control essential.
In general, quality control of 68Ga-radiopharmaceuticals should include the following tests and information [59, 60, 61]:
Characters/appearance. Should discover any visible container defects. The quality of the final product in terms of absence of particular matter [62] and/or turbidity should be ensured as well as its correct appearance. Typically performed by visual inspection.
pH determination. Should ensure that the pH of the final product is in the necessary range for its purpose. For the final injectable formulation of a radiopharmaceutical, the pH should be closed to the physiologic value of 7.4. With regard to the relatively low volume of radiopharmaceuticals and depending on the injected volume and rate, a wider range (3.5–8.5) is applicable. Contrary to this, the pH of the radionuclide precursor gallium-68 should not exceed 2 to prevent the formation of unwanted 68Ga-colloids.
Radionuclidic identification. Identification of a radionuclide is generally conducted by determination of its half-life and/the nature and energy of its radiation emitted. For positron emitters like gallium-68 instead of energy and nature of the radiation, the identification is based on a γ-spectrum additional to their half-life determination (e.g. with dose calibrator).
Radiochemical identification. Identification of the desired radiochemical species via HPLC and/or TLC exploiting different chemical behavior of the different radiochemical species.
Radionuclidic purity. Due to the contribution or formation of other radionuclides during the production of gallium-68, their amount present in the final radiopharmaceutical must be determined. Depending on the production route of gallium-68, different limits for radionuclidic impurities may apply. The test for those long-living radionuclides need to be performed after complete decay of the sample using γ-spectrometry, representing a test performed after release of the batch.
Radiochemical purity. Should discover all chemical forms containing the radionuclide and determine their percentage of the total radioactivity of the product. These radiochemical impurities arise from the synthesis method, radiolysis or the radionuclide production and can lower the quality of the final diagnostic examination. Principally be determined by any suitable analytical method but with respect to the short half-life and radiation TLC and HPLC are normally used for quality control of 68Ga-radiopharmaceuticals.
Chemical purity. The chemical purity refers to the amount of the specified chemical form of a preparation if radioactivity is present or not [61]. Purity assessment is of special importance when diagnostic or therapeutic properties are directly linked to chemistry [63]. Therefore, particular attention is necessary for pharmacologically active impurities as they can affect the diagnostic value of the examination. The chemical purity of 68Ga-radiopharmaceuticals is normally ascertained with TLC and/or HPLC.
Residual solvents. Ph. Eur. as well as US pharmacopeia defines residual solvents as organic volatile chemicals used in the manufacture of drug substances/active substances, excipients or in the preparation of medicinal products (Eur. Ph. 5.4.; USP 467). As they represent a risk of health, they should be determined. Determination can be performed using gas chromatography (GC)
It has to be noted that the texts about residual solvents not cover solvents added by purpose or solvates. For those other limits and regulations may apply.
Microbiological contamination. Parenteral administered radiopharmaceuticals need to be compliant in terms of bacterial endotoxins or pyrogens as well as sterility
Bacterial endotoxins are known to cause a wide spectrum of nonspecific pathophysiological reactions (fever, changes in white blood cell counts, hypotension, disseminated intravascular coagulation, shock and death) leading to death when injected in most mammals [64]. Thanks to the development of more and more efficient systems today tests (LAL-test) for bacterial endotoxins (BET) can be completed before release of the batch of the 68Ga-radiopharmaceuticals.
In contrary, the test for sterility of 68Ga-radiopharmaceuticals via direct inoculation is necessarily retrospective nevertheless indispensable. Additionally, to the direct inoculation test the integrity of the sterile filter used for sterile filtration of the final product is performed. Due to the need for sterilization to obtain a sterile parenteral solution and the not applicability of autoclaving for short-living radiopharmaceuticals membrane filtration is normally the method of choice. The tests for the filter integrity (e.g. bubble point, diffusion rate, pressure hold) have the advantage that they can be completed before batch release.
Radioactivity content/concentration. Defines the activity, measured with a dose calibrator, within the volume of the final preparation.
Specific radioactivity. The specific radioactivity (activity of the radionuclide per unit mass either of the element or the desired chemical form) is calculated using the concentrations of radioactivity and the chemical form. Referring to the consensus nomenclature rules for radiopharmaceutical chemistry [65], the specific activity is expressed as measured activity per gram of compound (e.g. MBq/μg), while it is called molar activity when expressing the measured activity per mole of compound (MBq/nmol) [65]. As gallium-68 requires a complex ligand which is normally not fully removed during the final product purification, the measured specific or molar activity is lower than actual. Then the correct terms are apparent specific or molar activity [65].
The specific or molar activity is always given with reference date and time.
For gallium-68 obtained from a 68Ge/68Ga-generator, the Ph. Eur. contains a distinct monograph (#2464). This monograph specifies the quality characteristics of 68Ga chloride solutions for radiolabeling independently if obtained directly from a generator or after post-processing the generator eluate. If a further purification of the generator eluate is performed, this has to be stated on the label.
Use of generator-produced gallium-68 in the USA is regulated under 10 CFR 35. 1000 and 10 CFR 30.33 [66] (Table 3).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of generator produced gallium-68 as defined by the Ph. Eur. (monograph #2464) [59].
For incoming starting materials, the GMP guidelines prescribe certain handling procedures to ensure their quality and suitability. For material acceptance of an incoming new 68Ge/68Ga-generator, minimum controls are needed. This include the conformation of the radionuclide identity, 68Ge-breakthrough and of activity stated in the Certificate of Analysis (CoA) all verified by activity measurement if possible [60]. Establishment of additional acceptance criteria may be required.
Nevertheless, the 68Ga-eluate used for radiolabeling should meet those specifications (Table 4), their verification is in clinical routine not possible for every production. This results from the different production routes of 68Ga-radiopharmaceuticals, which do not intend or allow an intervention for sampling of the eluate. Thus, the quality control of the starting material gallium-68 or of the final radiopharmaceuticals is allowed. This should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
Manufacturer | Type | Maximum nominal activity |
---|---|---|
Eckert & Ziegler (Germany) | GalliaPharm® | 2.4 GBq |
IGG100 | 2.4 GBq | |
Obninsk Cyclotron Ltd. (Russia) | 3.7 GBq | |
IRE Elit (Belgium) | Galio Eo® | 1.85 GBq |
Galli Ad® | 1.85 GBq | |
ITG (Germany) | 2 GBq | |
iThemba Labs (South Africa) | 1.85 GBq | |
Pars Isotopes (Iran) | Pars-GalluGEN | 2.59 GBq |
In all conscience a list of 68Ge/68Ga-generators available.
When produced via accelerator, the presence of the radioisotopes gallium-66 and gallium-67 is difficult to avoid due to zinc-66 and zinc-67 contaminating the target material. In return, germanium-68 is absent. Therefore, quality control and specifications for radionuclidic impurities are different to generator-produced gallium-68.
For gallium-68 obtained from a cyclotron, a new monograph (#3109) is already submitted for adoption to the Ph. Eur. [67]. This monograph specifies the quality characteristics of 68Ga-chloride solutions for radiolabeling obtained by irradiation of enriched zinc-68 in an accelerator with subsequent isolation of gallium-68 in acidic solution (Table 5).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<2% gallium-66 & gallium-67 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of accelerator-produced gallium-68 as defined by a draft of a monograph for the Ph. Eur. Submitted for adoption (#3109) [67].
Similar to generator-produced gallium-68, quality control can be performed of the starting material obtained via cyclotron or on the final radiopharmaceutical. If quality control of the final radiopharmaceuticals performed, it should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
As an example for the specifications and limitations for a 68Ga-radiopharmaceutical quality control as requested by the monograph #2464 of the Ph. Eur. [68Ga]Ga-DOTA-TOC is provided [59]. It has to be noted, that monograph #2464 is currently under revision which can lead to different limits in feature (Table 6).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | < 2 |
Radionuclide identity | Half-life determination | 62 to 74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >91% |
TLC | <3% [68Ga]Ga in colloidal form | |
HPLC | <2% [68Ga]Ga3+ | |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
HPLC | <50 μg/V DOTA-TOC and metal complexes of DOTA-TOC | |
TLC | <200 μg/V HEPES | |
GC | <10% V/V and <2.5 g per administration | |
Bacterial endotoxins | LAL test | ≤175 EU/total volume |
Sterility | Direct inoculation | sterile |
Quality control specifications [68Ga]Ga-DOTA-TOC as given by the Ph. Eur. For generator-produced gallium-68 (monograph #2464) [59].
The quality control for a certain 68Ga-radiopharmaceutical depends on the production route of gallium-68, the synthesis route of the radiopharmaceutical as well as of the relevant legislation.
As descripted in Section 7.2, the respective production route leads to different radionuclidic impurities (germanium-68 vs. gallium-66 & gallium-67) that need to take into account for the final product specifications. However, this is not yet implemented in the pharmacopeias but is in part already in progress. For example, the monograph for [68Ga]Ga-DOTA-TOC (#2464) of the Ph. Eur. is currently in revision to take into account the cyclotron production of gallium-68 [68].
In general, the quality of the final radiopharmaceutical needs to fulfill all specifications given by the relevant legislation or pharmacopeia independent from the synthesis route. Nevertheless, it may be possible to dispense individual tests given, for example, for licensed kit preparations. For example, the Ph. Eur. states in its general notices “An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process” [59]. Further details can be found in the general chapter on extemporaneous preparation of radiopharmaceuticals (5.19) and the general monograph radiopharmaceutical preparations (#0125) [59].
Nevertheless, the competent authorities may request further quality control testing. Therefore, it is strongly recommended, especially in case of doubt, to consult the competent authorities.
The implementation of a new radiopharmaceutical into the certain pharmacopeias is a protracted process. Therefore, several commonly used 68Ga-radiopharmaceuticals are not yet represented with own monographs in the pharmacopeias (e.g. [68Ga]Ga-PSMA-11). Nevertheless, such radiopharmaceuticals can be produced with consideration of the general notices, texts, monographs and along the lines of, for example, the monograph for [68Ga]Ga-DOTA-TOC. Again, in case of doubt, the competent authorities should be consulted.
Gallium-68 is a well-researched radionuclide with growing importance for clinical practice triggered by the development of new tracers expanding its application and the increasing demand for theranostic patient care.
Its availability via radionuclide generator in combination with comparably easy coordination chemistry enables a patient care even in places where the cyclotron-produced PET-radionuclides are unavailable and, in the case of NETs, enables patient care where no 18F-alternative exists.
This work was supported by the Ministry of Science and Higher Education of the Russian Federation project RFMEFI60719X0301.
The authors declare no conflict of interest.
AEX | anion-exchange |
API | active pharmaceutical ingredient |
BET | bacterial endotoxin test |
CEX | cation-exchange |
DMF | drug master file |
EU | European Union |
FDA | U.S. Food and Drug Administration |
GC | gas chromatography |
GMP | good manufacturing practice |
HCl | hydrochloric acid |
HPLC | high pressure liquid chromatography |
ICP-AES | inductively coupled plasma atomic emission spectroscopy |
ICP-MS | inductively coupled plasma mass spectrometry |
ITG | Isotopen Technologien Garching |
LAL-test | limulus amebocyte lysate test |
M | molarity (mol/liter) |
MA | marketing authorization |
mCRPC | metastatic castrate-resistant prostate cancer |
NET | neuroendocrine tumor |
PC | prostate cancer |
PET | positron emission tomography |
Ph. Eur. | European pharmacopeia |
pmol | picomol (10−12 mol). |
QC | quality control |
PRRT | peptide receptor radionuclide therapy |
SPE | solid phase extraction |
T1/2 | half-life |
TLC | thin layer chromatography |
USA | United States of America |
U.S. | United States |
USP | United States Pharmacopeia |
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\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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