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Ismail",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",keywords:"Thermodynamics, Heat Transfer Analyses, Geothermal Power Generation, Economics, Geothermal Systems, Geothermal Heat Pump, Green Energy Buildings, Exploration Methods, Geologic Fundamentals, Geotechnical, Geothermal System Materials, Sustainability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 29th 2020",dateEndSecondStepPublish:"November 26th 2020",dateEndThirdStepPublish:"January 25th 2021",dateEndFourthStepPublish:"April 15th 2021",dateEndFifthStepPublish:"June 14th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University, owner of a Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada and postdoctoral researcher (2004 to 2005) at McMaster University.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"62122",title:"Dr.",name:"Basel",middleName:"I.",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail",profilePictureURL:"https://mts.intechopen.com/storage/users/62122/images/system/62122.jpg",biography:"Dr. B. 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1. Introduction
Tick‐borne encephalitis (TBE) is an important human viral infection of central nervous system (CNS) endemic in a large part of Europe and Asia. The causative agents are three different TBE virus (TBEV) subtypes named European, Siberian and Far‐Eastern [1]. In spite of the pronounced genetic similarity of these flaviviruses, the illness caused by individual subtype is not entirely comparable to those caused by the other subtypes.
The clinical course of acute illness is highly variable. Due to the relatively high proportion of severe cases and a considerable proportion of patients with long‐lasting sequelae which may have a significant impact on quality of life, the disease represents high costs for healthcare system and society.
Herein we present an overview of TBE, including a short historical outline, basic information on TBEV, and of the epidemiology, pathogenesis, clinical manifestations, diagnosis and treatment of TBE, as well as on the course and outcome of the disease and its prevention.
2. History
Historically the first mention of the TBE existence dates back to the eighteenth century in Scandinavian church records from Åland Islands. However, the first medical description of disease was given and published in 1931 by the Austrian physician H. Schneider [2]. Six years later, an expedition headed by Zilber in the Russian Far East isolated for the first time the causative agent (TBEV) from humans, mice, and Ixodes persulcatus ticks; they determined the etiology of TBE and its vector [3]. In 1939, Pavlovsky confirmed the preliminary hypothesis on the transmission of the TBEV in nature (between ticks and mammals) and proposed the theory of natural foci [4]. In Europe, TBEV was first isolated, from humans and Ixodes ricinus ticks, in Czechoslovakia in 1948 by Gallia and colleagues [5]. In the following years, the disease and/or the virus has been identified in many other European countries and, later, also in the north of China and northern Japan [6].
3. Etiology
TBE is caused by TBEV, a small, neurotropic, lipid‐enveloped spherical RNA virus, the member of genus Flavivirus, family Flaviviridae. The viral RNA contains records for three structural (E (envelope), prM/M (precursor of membrane or membrane, respectively), and C (capsid)), and seven nonstructural viral proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). Glycoprotein E is a major viral antigen and is associated with the production of neutralizing antibodies and the induction of protective immunity. It also plays a key role in the viral life cycle mediating the binding of virions to cell receptors and subsequent intraendosomal fusion [7].
TBEV occurs in three subtypes named as European, Siberian, and Far‐Eastern subtype [1]. They are very closely related, both genetically and antigenically; variation in amino acids sequences between subtypes is 5–6% [8]. In spite of the pronounced genetic similarity of the subtypes the illness caused by individual subtype is not completely equivalent to those due to the other subtypes.
An important characteristic of the TBEV, which allows them alimentary route of infection, is their ability to maintain at least residual infectivity at acidic pH (above pH 1.42) [9]. TBEV maintains infectivity at very low environment temperatures (even below −70°C). On the contrary, it is heat labile; total inactivation of the virus occurs within 30 minutes at 56°C [10, 11]. It can be inactivated by pasteurization [12].
4. Epidemiology
TBE arises in an endemic pattern of so‐called natural foci over a large geographical area extending from Central Europe and Scandinavia through the Eurasian continent to North‐Eastern China and Northern Japan. Over the past few decades, a trend toward both an expansion of the endemic areas and an increase of reported cases have been observed [13, 14]. The increase in the incidence is the result of a complex interrelation of socioeconomic and ecological factors; a part of an increase may also be explained with an increased medical awareness, advanced diagnostics, and improvements in epidemiological surveillance [15, 16].
In Europe and Asia between 10,000 and 15,000 TBE cases are reported per year with pronounced annual fluctuations [17]. The number is very likely underreported mainly due to lack of standardized TBE case definition, the varying diagnostics procedures, and the wide differences in the quality of national surveillance systems.
In 2012, TBE became a notifiable disease at the European Union level. Currently the disease is endemic in 27 European countries; the reporting is mandatory in 18 of them. Two‐thirds of the countries where TBE is a notifiable disease use the European Centre for Disease Prevention and Control case definition [13, 18, 19]. A total of 2560 TBE cases were reported in Europe in 2012 with the overall notification rate of 0.52 cases per 100,000 inhabitants. Countries with the highest reported incidence (>5 cases per 100,000 inhabitants per year) were Estonia (13.35), Lithuania (11.69), Slovenia (7.98), and Czech Republic (5.46) [20].
The main hosts and reservoirs of TBEV in nature are wild vertebrate, in particular small rodents. Ticks act as both virus vectors and reservoir and carry the virus throughout their life. Humans are only accidental hosts and do not play any role in the maintenance of TBEV in nature [21, 22].
Most human infections occur through an infected hard tick bites. At least 11 tick species are capable of transmitting TBEV, but only 2 species are of clinical importance. I. ricinus is the principal vector throughout Europe and, therefore, the most important transmitter of the European TBEV subtype, while I. persulcatus occurs in regions of Eastern Europe, in Russia, and in far‐eastern Asia and is the main vector of the Siberian and Far‐Eastern TBEV subtype [21, 23]. The Siberian TBEV subtype is found in Siberia, the Baltics, and northern Finland, whereas the Far‐Eastern TBEV subtype is endemic in far‐eastern Asia and Japan, and also in central and eastern Siberia [13, 22]. In the Baltic States and Finland, where I. ricinus overlaps with I. persulcatus, all three TBEV subtypes co‐circulate [24–26]. The Far‐Eastern TBEV was found in Ixodes ovatus in Japan in south‐western China, while the European TBEV subtype was detected in Ixodes nipponensis ticks in Korea [1, 27].
In Europe, the TBEV prevalence in unfed I. ricinus ticks ranges from 0.1 to 5.0% (depending on the geographical location and time of the year) and increases with development stage, whereas in Siberia, the reported proportion of infected adult I. persulcatus ticks is up to 40% [13, 21]. In Slovenia, the prevalence of TBEV‐infected ticks was found to be 0.47%; 0.54% in 2005 and 0.43% in 2006 [28]. About 1% of all human TBEV infections are alimentary‐transmitted by consuming contaminated unpasteurized dairy products, especially goat milk [1]. This route of infection has to be considered in cases of local epidemics. The majority of outbreaks due to oral virus transmission are reported from Eastern Europe and Baltic states [29, 30]. A few cases of laboratory‐acquired TBEV infections have been documented [31]. Vertical transmission, person‐to‐person transmission including breast‐feeding, and transmission through blood transfusion have not been reliably described in humans.
TBE is a seasonal disease; most cases occur in the warm period of the year (usually between April and November) which correlates with the period of the highest tick activity and with increased exposure during this time period [32]. In Central Europe, a two‐peak distribution of TBE cases can be seen, first in June and July, and second in September and October, whereas in the regions where I. persulcatus is widespread, cases as a rule occur in May and June [11]. In all age groups men are affected more frequently than women. The highest notification rate is in the 45–64 year‐old age group, followed by the over 65‐year olds [20, 33]. On an average, 10–20% of all reported cases of TBE occur in children, with the lowest incidence in those less than 3 years of age [34, 35]. It should be pointed out that due to its unspecific clinical presentation, TBE in children is often missed and is diagnosed as aseptic meningitis of unknown etiology [36, 37].
TBE represents a potential risk for nonvaccinated travelers traveling to countries with high endemic foci and therefore should be included in the differential diagnosis of the CNS infections in case of an appropriate epidemiological history also in patients living outside endemic areas. The risk depends on the season of travel, duration of stay as well as on travel style (degree of unprotected outdoor exposure). In the different endemic areas, the risk for infection after a single tick bite varies from 1:200 to 1:1000 [21].
5. Pathogenesis and pathology
After the bite of an infected tick TBEV replication occurs locally. Dendritic cells (Langerhans cells) are considered to be the most important cells for local viral replication and to transport the virus to the regional lymph nodes where further replication takes place. After release into the bloodstream the virus disseminate to other organs, in particular to the reticulo‐endothelial system (mainly bone marrow, spleen, and liver) where the virus continue to multiply and maintain viremia for few days. During the viremic phase (which clinically matches to the initial phase of TBE) the virus probably reaches the brain [38, 39]. The precise mechanism of viral passage through the blood‐brain barrier is unclear, but depends on the presence of viremia. Four possible routes have been postulated: (i) peripheral nerves, (ii) highly susceptible olfactory neurons (especially relevant in laboratory infections by aerosols), (iii) transcytosis through vascular endothelial cells of brain capillaries, and (iv) diffusion of the virus between capillary endothelial cells. The primary targets of TBEV infection in central nervous system are neurons. Rarely, oligodendrocytes are infected [38].
TBEV in CNS induces inflammation with inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The exact mechanism of tissue destruction is unclear, but Ružek and coworkers demonstrated that inflammatory reaction mediated by CD8+ T cells significantly contributes to neuronal damage [40]. Limited data are available on the role of cytokines and chemokines.
Pathological lesions are widespread all over the CNS and involve leptomeninges and gray matter, with the brain stem, cerebellum, basal ganglia, thalamus, and spinal cord being most frequently affected. Histological findings are nonspecific; lesions consist of perivascular and parenchymal accumulation of lymphocytes, consisted of T and B cells, and macrophages (microglia), associated with nerve cells necrosis and neuronophagia in regions of viral replication. Residual lesions are characterized by loss of neurons and microglial scarring. Cerebral and spinal meninges usually show diffuse infiltration with lymphocytes and sometimes neutrophils. The most extensive meningeal inflammation is around the cerebellum [38, 41].
6. Clinical manifestations of TBEV infection
Seroepidemiological studies have demonstrated that TBEV infection is often asymptomatic. The exact proportion of such cases is not known, because those with mild clinical presentation may not be diagnosed, but data suggest rates between 70 and 98% [42–44].
Time interval from a tick bite to the beginning of the illness is usually 7–14 days, but it may be as short as 2 days and as long as 4 weeks. After alimentary route of infection, there is regularly a shorter incubation period of 3–4 days [30, 32, 45].
In at least three‐quarters of patients who develop CNS involvement, the disease caused by the European virus subtype has a biphasic course [46–48]. The initial phase corresponds to the viremia and usually presents with nonspecific systemic signs and symptoms; the most common are moderate fever (99%), fatigue (63%), general malaise (62%), headache and body pain (arthralgia and myalgia) (54%) [47]. In this phase, which lasts 2–7 days, there are no signs or symptoms of CNS involvement; cerebrospinal fluid (CSF) examination reveals normal findings. After an improvement or even an asymptomatic interval of about 1 week duration (range 1–21 days) the second phase presents as meningitis, meningoencephalitis, or meningoencephalomyelitis in 54, 37, and 9% of adult patients [49]. The far most frequent clinical manifestation of TBE in children is meningitis [34]. Fever in the second phase is typically 1–2°C higher than the peek temperature in the first phase and is of longer duration [12, 50].
In some patients the disease course is monophasic: they may either have CNS involvement or a febrile illness with headache with symptoms subsiding without developing into the second phase (i.e., the initial phase of TBE without subsequent CNS involvement), named abortive form of TBE or “febrile headache” [12, 32, 50, 51].
6.1. Abortive form of TBE
Data on the frequency of this clinical manifestation of the disease caused by European TBEV subtype are conflicting. According to some reports it represents more than a half of all clinically manifested TBEV infections [32, 52]. However, this is not confirmed by the results of a prospective clinical trial on the etiology of acute febrile illness after a tick bite carried out by Lotric‐Furlan and coworkers: of the 56 patients diagnosed with TBEV infection during the initial phase of illness, in 55 (98.2%), CNS involvement with pleocytosis later appeared, whereas only one (1.8%) had an isolated initial phase of the disease [51, 53]. In the Russian publications, this clinical manifestation is named “fever form” and is reported to represent up to 50% of all clinical presentations of TBE [54]. Abortive form of TBE most frequently presents itself by a moderate fever, headache, fatigue, and other nonspecific symptoms of the initial phase of the disease. The fever usually subsides in a few days and the disease does not have long‐term consequences [55, 56].
6.2. Meningitis, encephalitis, and myelitis
Meningitis is characterized by fever, headache, nausea, vomiting, and meningeal signs. These symptoms and signs are present in the majority but not in all the patients. In a study encompassing 448 adult patients with TBE from Slovenia, almost all reported headache and had fever, more than 50% suffered from nausea and/or vomiting, and 70% had clearly expressed meningeal signs [33]. Encephalitis may manifest by a variety of neurological symptoms and signs, most often with tremor (especially of the fingers of the upper extremities and tongue), sometimes with nystagmus, speech disorder, ataxia and movement disorders, occasionally with seizures, and very rarely with brain stem symptoms and/or cranial nerve abnormalities. Impaired consciousness, ranging from mild to severe, insomnia, and concentration and cognitive function disturbances are rather frequent. Mental disorders including amnesia, behavioral changes, psychosis, and delirium may also occur. Patients may have sensory impairment. Myelitis is virtually always associated with meningoencephalitis, and as a rule manifests with flaccid paralyses that are occasionally preceded by severe pain in the affected muscle groups. The involvement is usually asymmetrical. Most often extremities are affected, more frequently the upper than the lower limbs, and more often the proximal segments of the extremities than the distal ones. Patients with pareses of respiratory muscles usually require artificial ventilatory support [12, 32, 57].
6.3. Other manifestations in the acute phase of illness
6.3.1. Involvement of cranial nerves
According to rather limited data, involvement of cranial nerves is rare, mostly asymmetrical, typically associated with severe acute illness, and usually has a favorable outcome [46, 47, 58]. Ocular, facial, and pharyngeal muscles are most often affected, but hearing and vestibular defects are also encountered [42].
In a series of 1218 adult patients diagnosed with TBE at a single center, 11 (0.9%) developed peripheral facial palsy (2 bilateral, 9 unilateral); however, 3 out of 11 patients had associated borrelial infection. The latter finding suggests that in patients who develop peripheral facial palsy in the course of TBE, and who had been exposed to ticks in the region where both TBE and Lyme borreliosis are endemic, coexistent infection with Lyme borreliae have to be taken into account [59].
6.3.2. Autonomic disorders
Occasionally, autonomic nervous system disorders are present in patients with TBE [60].
6.3.3. Encephalitis with normal CSF cell counts
Literature review revealed some reports on a serologically confirmed TBEV infection in patient with encephalitis but without CSF pleocytosis [61, 62]. This disagrees with the large series of serologically proven TBE patients, in which CSF pleocytosis was found in all the cases [12, 42, 43, 47]. However, the latter finding might be the result of a selection bias because in the studies CSF pleocytosis was one of the essential inclusion criteria for the diagnosis of TBE.
6.4. TBE in patients who had been vaccinated against the disease
It seems that breakthrough TBE after vaccination is rare: 7 cases were reported in Slovenia, 25 in Austria, and 27 in Sweden in the periods 2000–2006, 2000–2008, and 2002–2008, respectively. The majority (70%) of patients were over 50 years old, but also a pediatric case has been described [63–67]. According to Kunz, disease severity in unvaccinated and vaccinated patients with TBE does not differ substantially; however, the information is limited [68].
6.5. Chronic progressive TBE
A chronic progressive form of TBE, believed to be associated with the Siberian subtype of TBEV, has been described in Siberia and Far East. It may manifest with epilepsia partialis continua [69–72].
6.6. Postencephalitic syndrome
According to published data postencephalitic syndrome occurs in up to 58% of patients after acute TBE caused by European subtype of TBEV, and may include various nonspecific neurological/neuropsychiatric symptoms and residual neurological dysfunctions [73]. It often affects the patient’s quality of life (sometimes requires a change in lifestyle) and also represents a high cost for the health care system and society.
The most commonly reported symptoms/signs have been cognitive or neuropsychiatric complaints (i.e., apathy, irritability, memory and concentration disorders, altered sleep pattern), headache, hearing defects, disturbances of vision, ataxia, and pareses or flaccid paralyses [46, 47, 58, 73, 74]. At this point it should be noted that most of the studies failed to include a control group; therefore, the findings are difficult to interpret due to unclear differences between postencephalitis syndrome, other consequences of TBE and symptoms present in the general population.
Lithuanian prospective clinical follow‐up study showed that 46% of patients with TBE had sequelae 1 year post infection [47]. In 2009, Misić‐Majerus et al. published a prospective study on TBE postencephalitic syndrome. One hundred and twenty‐four patients, aged 16–76 years, participated in the study with follow‐up period for at least 3 years. Forty‐nine patients (39.5%) developed moderate or severe sequelae lasting for 3 to 18 months; in 11 patients permanent sequelae were seen—spinal nerve paresis in five, hearing impairment in six, dysarthria in two, and severe mental disorder in one patient [74]. In 2011, Kaiser reported 10‐year follow‐up results in patients with encephalomyelitic manifestation of TBE; 11 (19%) out of 57 included patients fully recovered, 29 (51%) patients had long‐lasting sequelae (paresis or other impairments), and 17 (30%) died 1–10 years after the acute disease. The most substantial improvements were seen in the first year after acute disease [75]. Recently published case‐control study on the long‐term sequelae after TBE from Sweden has showed that the neurocognitive and motor symptoms in patients significantly differ from those in the age‐ and gender‐matched control group [76].
7. Diagnosis
For a diagnosis of TBE, three criteria should be fulfilled:
symptoms/signs indicating meningitis or meningoencephalitis,
elevated CSF cell count (>5 × 106 leukocytes/L), and
microbiologic evidence of TBEV infection (i.e., the presence of specific IgM and IgG antibodies) [77].
7.1. Blood and cerebrospinal fluid analysis
In the initial (viremic) phase of TBE leukopenia and/or thrombocytopenia are ascertained in around 70% of patients, and abnormal liver test results are seen in about 20% [78]. In the second (meningoencphalitic) phase, platelet count is normal, whereas peripheral blood leukocyte count is normal or mildly elevated (rarely >15 × 109/L). Concentration of C‐reactive protein and erythrocyte sedimentation rate is usually in normal range throughout the entire course of TBE. In the initial phase of TBE, CSF findings are in the normal range, whereas in the second (meningoencephalitic) phase, elevated CSF leukocyte counts (usually <500 × 106/L, extremely rarely ≥1000 × 106/L), a normal to moderately elevated protein concentration, and a normal glucose concentration are present. A typical finding is lymphocytic pleocytosis; however, in the first few days of the meningoencephalitic phase of TBE, neutrophils may predominate in CSF. Elevated lymphocyte counts may persist for several weeks after clinical recovery [32, 79].
7.2. Magnetic resonance imaging (MRI) abnormalities
MRI abnormalities of brain and spinal cord are present only in about 20% of patients with TBE. According to a study performed by Kaiser [46], they are found more often in patients with meningoencephalomyelitis (7/25, 29%) than in patients with meningoencephalitis (11/64, 17%), and are not seen in those with meningitis (0/13). Increased signal intensity is most often seen in the thalamus, but can (also) be present in basal ganglia, internal capsule, splenium, cerebellum, peduncles and brain stem [46, 80–92]; in patients with myelitis, the abnormalities are seen predominantly in the anterior horns of the spinal cord [84, 85, 89, 93–97]. Studies of specificity are lacking but the specificity is probably low [89].
7.3. Microbiological investigations
7.3.1. Detection of TBEV
Due to limited diagnostic yield, direct approaches to demonstrate TBEV, such as detection of viral RNA by reverse transcriptase PCR and isolation of the virus, are as a rule not used in clinical practice. TBEV is present in blood in the initial (viremic) phase of TBE but not in the meningoencephalitic phase of the disease and is only very exceptionally present in CSF [98].
7.3.2. Serology
In the routine clinical practice, demonstration of antibodies to TBEV in serum (and in some cases also in CSF) by enzyme‐linked immunosorbent assay (ELISA) is a standard microbiologic diagnostic approach with a high sensitivity and specificity [98, 99]. At the beginning of the meningoencephalitic phase, when patients are usually seen by their physicians and admitted to hospital, the large majority had specific serum IgM and IgG antibodies. In rare cases when only IgM antibodies to TBEV are found in the first serum sample, second sampling 1–2 weeks later reveals IgG seroconversion and enables a reliable diagnosis of (recent) TBEV infection. In CSF, IgM and IgG antibodies to TBEV appear several days later than in serum, but are detectable in almost all cases by day 10 [98, 100].
Although the interpretation of the results of serological testing is usually straightforward, there may be some obstacles which should be taken into account. TBEV IgM antibodies may be present in serum for several months (up to 10 months or even longer) after acute infection, whereas TBEV IgG antibodies persist for a whole life and mediate an immunity that prevents symptomatic reinfection [98, 101].
Thus, serum IgG antibodies to TBEV without the presence of specific IgM antibodies do not indicate a recent but previous (symptomatic or asymptomatic) TBEV infection or vaccination against TBE. On the other hand, specific TBE serum IgM antibodies, an indicator of a recent infection with TBEV, may be detectable for several months after acute TBEV infection (and also in some persons after the first two doses of primary immunization); their demonstration may result in incorrect interpretation if another CNS infection/disease developed within this time period [98, 101].
A further challenge is a close antigenic relationship between TBEV and other flaviviruses with cross‐reactive antibodies induced by infections or vaccinations, and a consequent diagnostic difficulties in persons vaccinated against Japanese encephalitis or yellow fever and in travelers having acquired dengue, West Nile or other flavivirus infections [7]. Such problems in TBE serodiagnosis can be sorted out by the quantification of IgM antibodies. High IgM values (>500 arbitrary units) are indicative of a recent infection with TBEV, whereas lower IgM levels may require the analysis of a follow‐up sample (that enables the assessment of antibody dynamics), and/or a specific neutralization assay, to rule out cross‐reactive IgM antibodies and prolonged persistence of IgM antibodies after infection or vaccination [102].
Knowledge in the understanding of TBE serology is required also in patients with meningitis or meningoencephalitis or who had been previously vaccinated against TBE. Serological response in patients with TBE vaccination breakthroughs is as a rule distinct from the response in patients who had not been vaccinated; unawareness of the pattern may result in fail to notice vaccination breakthrough cases. Serologic response in these patients is characterized by a delayed development of specific IgM response (during the initial days of the meningoencephalitic phase of TBE, specific IgM antibodies may not be detectable) associated with a high and rapidly increasing levels of specific serum IgG antibodies [63, 64, 67]. For a reliable diagnosis of TBE in persons previously vaccinated against TBE, demonstration of intrathecal production of TBEV antibodies is needed [45].
Subtype of TBEV influences the course of acute TBE as well as its long‐term outcome. The disease caused by the European TBEV subtype usually has a biphasic course, around 10% of adult patients have a severe neurologic deficit, case‐fatality rate is <2% [12, 32]. According to a prospective study the abortive form of TBE is rare—the initial phase most of the time move on to the second phase of the disease [51]. Long‐lasting sequelae are identified in up to 50% of adult patients [103]. The disease is less severe and has a better outcome in children than in adults [34, 50, 104, 105].
Symptomatic infections with Far Eastern TBEV subtype often cause an illness with a gradual onset, more severe course, higher rates of severe neurologic sequelae, and a fatality rate of 20–40%; the severity and outcome in adults and children are similar. Limited information about the clinical course of the disease is available for Siberian TBEV subtype. The case‐fatality rate is 2–3%; some reports from Russia suggest an association with a chronic progressive form of TBE [1, 11].
8.2. Age of patients
Published data suggest the relationship between age of patients and the severity of TBE and its outcome — the severity of acute illness and the proportion of patients with unfavorable outcome increase with age [33, 47, 50, 106].
The disease caused by European subtype of TBEV generally has a milder course and better outcome in children than in adults. The predominant form of TBE in children and adolescents is meningitis. A summary of 8 studies on 1169 children with TBE showed that meningitis was present in 802 (69%), meningoencephalitis in 356 (30%), and meningoencephalomyelitis in 11 (1%) patients. A total of 20 out of 945 patients (2.1%) had long‐term neurologic sequelae [34]. In contrary to children, in adults, and especially in elderly patients with TBE caused by European subtype of TBEV, the most frequent presentation is meningoencephalitis [33, 47].
Furthermore, fatality rate, the ratio of patients who develop pareses, and the frequency of postencephalic syndrome is also parallel with the increasing age [33, 47, 106].
8.3. Other factors associated with severe acute disease
Some clinical studies have shown that TBE with monophasic presentation is associated with a more severe course of the acute disease [42, 107–111].
Concomitant TBE and Lyme neuroborreliosis may occur with a more severe clinical course [59, 112, 113].
8.4. Severity of acute illness and other risk factors for unfavorable outcome
The outcome of TBE is associated with clinical presentation. The risk of incomplete recovery is higher for patients who have more severe clinical illness during acute phase of TBE [45, 47].
Other identified risk factors found to be associated with unfavorable outcome are CSF cell count > 300 cells/μL, impaired blood‐brain barrier (total protein >600 mg/L) and abnormal findings on MRI [46].
8.5. Genetic factors
Host‐related factors, particularly genetically determined variability of the inflammatory/immune response, very likely have an important impact on the course and long‐term outcome of TBE. In 2008, Kindberg and coworkers published the results of the study carried out on the Lithuanians, showing that a mutation in a chemokine receptor 5 (CCR5) gene increases the risk for the development of TBE after TBEV infection, but not for more severe disease [114]. Three years later the same group reported on an association between the wild‐type Toll‐like receptor 3 (TLR3) rs3775291 allele and increased risk of TBE and suggested that a functional TLR3 may be associated with disease severity [115]. Similar findings were also reported by Mickiene et al. [116]. Furthermore, Barkhash and coworkers found an association between polymorphism in the promoter region of CD209 gene and predisposition to severe illness, and a possible association between 5 OAS single nucleotide polymorphisms and the TBEV infection outcome in Russians [117, 118].
In the future we expect new interesting discoveries on the role of host genetic factors in TBEV infections.
9. Differential diagnosis
In addition to a variety of viral infections, differential diagnosis of the initial (viremic) phase of TBE includes also several diseases caused by bacteria. There is a striking similarity in clinical and laboratory presentation of the initial phase of TBE and human granulocytic anaplasmosis. For both diseases fever, headache, leukopenia, and thrombocytopenia are typical. However, the presence of clinical symptoms such as chills, myalgia and arthralgia, and laboratory findings of elevated concentration of C‐reactive protein and lactate dehydrogenase values direct toward the diagnosis of human granulocytic anaplasmosis and against the initial phase of TBE [119].
TBE needs to be differentiated from encephalitis or aseptic meningitis due to many other viruses. Differential diagnosis comprises also other tick‐borne diseases such as Lyme borreliosis, babesiosis, human granulocytic anaplasmosis, tick‐transmitted rickettsioses, and tularemia. Since these diseases are treatable with antibiotics, caution must be taken to distinguish them from TBE [32].
Concomitant TBEV and Borrelia burgdorferi sensu lato infections, as well as concomitant TBEV and Anaplasma phagocytophilum infections have been described [77, 113, 120–122].
10. Treatment
There is no specific antiviral treatment for TBE. Patients as a rule need hospitalization, supportive care, symptomatic treatment based on the presence and severity of signs/symptoms and therapy of neurologic and systemic complications. The symptomatic treatment usually includes antipyretics, analgesics, antiemetics, maintenance of fluid and electrolyte balance, and if necessary administration of anticonvulsive agents and treatment of cerebral edema [50, 123–125].
In some countries corticosteroids are often used in patients with TBE. However, until reliable studies prove the benefits of corticosteroids, their usage for the treatment of TBE is not recommended [47, 126].
Several patients need intensive care management; in those with neuromuscular paralysis leading to respiratory failure, intubation and ventilatory support are required. In a large prospective study, encompassing 635 patients diagnosed with TBE in the period from 1994 to 1998 in Germany, 12% of patients were treated in intensive care unit and 5% of patients required assisted ventilation [46]. Among patients with TBE, treated at a single medical center in Slovenia in the period from 2000 to 2004, 6.9% were hospitalized in the intensive care unit and 22.5% of them needed mechanical ventilation [33].
11. Prevention
11.1. Nonspecific preventive measures
TBEV is transmitted to humans by a tick bite or consumption of infected milk. Therefore, nonspecific preventive measures consist of reduction of tick population, personal protective procedures, and—as milk from endemic regions may contain TBEV—pasteurization of milk, and avoiding consumption of unpasteurized milk and dairy products [30, 42].
Tick population can be diminished by taking environmental measures, such as control of deer population, treatment with acaricides, and/or regular cutting of grass around the residence.
Nonspecific personal preventive measures include avoidance of ticks (i.e. avoidance of contact with vegetation, especially in deciduous and mixed forests with a rich understory), wearing light‐colored clothing (light colors enable that ticks are better noticeable) with long sleeves and slacks stuck in socks or footwear (to diminish tick access to the skin), use of repellents, careful examination of the whole body for the presence of ticks, and removal of the attached ticks as soon as possible. However, TBEV is present in salivary glands of the infected tick and may be transmitted from the saliva within a few minutes after attachment [42]. Although the recommended personal measures for the prevention of tick‐borne diseases such as TBE and Lyme borreliosis appear to be obvious, the efficiency of some of these procedures is inadequate, uncertain or has not been properly evaluated. Furthermore, in everyday life only a small proportion of exposed persons follow the recommended procedures [127, 128].
11.2. Prevention with immunoglobulins (passive immunization)
In the TBE endemic regions, immunoglobulins containing gamma globulin against TBEV had been used as postexposure prophylaxis within 96 hours after a tick bite. Because protection was rather unreliable [129], and because several reports pointed toward a more severe disease course in children who had received the immunoglobulin [81, 129, 130], passive immunization (the usage of the immunoglobulins) in the European Union has been abandoned [131]. However, the specific immunoglobulins are still used in Russia; the reported protection rate is about 80% [132].
11.3. Vaccination
Active immunization is the most effective and reliable way to prevent TBE [12, 42].
11.3.1. Recommendations for TBE vaccination
Given that TBE occurrence varies within and between individual endemic areas, vaccination strategies need to incorporate risk assessments for a particular region. According to WHO recommendations [133], in highly endemic TBE regions (≥5 cases/100,000/year) vaccination should be offered to whole population, including children, whereas in regions with a moderate or low TBE incidence (<5 cases/100,000/year), immunization has to target individuals at risk, i.e., those having outdoor activities or working under high‐risk conditions. Travelers from non‐endemic to endemic areas should be vaccinated if extensive outdoor activities are expected [133–136].
Similarly, Central European Vaccination Awareness Group (CEVAG) strongly recommends the introduction of universal TBE vaccination for persons >1‐year old for all countries at high risk of TBE [135]. Persons who had acquired TBE do not need vaccination as they are appreciated to be protected against the disease.
11.3.2. Vaccines
In Europe two vaccines against TBE are registered: FSME‐IMMUN® and Encepur® (in some countries named TicoVac). Both contain inactivated European subtype of TBEV (strain Neudorf 1 and strain K23, respectively), are prepared in a similar way (viruses are grown in chick embryo fibroblast cells, are inactivated by formaldehyde and are purified, adjuvant is aluminum hydroxide), are registered for adults and children aged 1 year and older (vaccines for children are called FSME‐IMMUN 0.25 ml Junior, and Encepur Kinder, respectively), and effectively prevent TBE caused by the European as well as Far‐Eastern and Siberian subtype of TBEV [131].
In addition to the European vaccines, three vaccines based on Far‐Eastern subtype of TBEV are registered: two are produced in Russia (TBE‐Moscow and EnceVir) and one in China [131].
11.3.3. Vaccination schedule
All of several vaccination schedules consist of primary (basic) vaccination followed by booster doses. Complete primary (basic) vaccination comprises three doses, usually given with an interval of 1–3 months between first and second dose, and 5–12 months between the second and third dose. When protection is wanted to be achieved in a short time, “fast schedule” (second dose is administered earlier, usually 14 days instead of 1–3 months after the first dose) can be used in accordance with the manufacturers’ instructions [12, 42]. The first booster dose is administered 3 years after completion of the primary vaccination; after that, one dose is required every 5 years except for persons aged >60 years (FSME IMMUN) or >50 years (Encepur) for whom boosters are recommended at 3 years intervals [131]. Immunization with the first two doses is preferably accomplished during the winter months to achieve protection before tick activity; however, vaccination can start at any time. A person who had not received the recommended doses according to the schedule but with longer intervals does not need to start vaccination again from the very beginning but just to continue with missing doses. Longer intervals between doses generally do not reduce antibody concentrations after completion of TBE vaccination, but protection in the period before the delayed dose is less consistent [137].
11.3.4. Mode of application and dosages
TBE vaccine is administered intramuscularly into the deltoid muscle; in young children, it can be given in the muscles of anterolateral thigh. It may be administered simultaneously with other vaccines (live or inactivated) but not on the same place [131]. Doses (0.25 or 0.5 ml) depend upon the age of the recipient. The age limits for vaccines available in Europe differ. In persons <16 years old, the dose of the FSME‐IMMUN vaccine is 0.25 ml, whereas for persons ≥16 years, 0.5 ml is advised; the corresponding age limits for Encepur vaccine are <12 and ≥12 years, respectively.
11.3.5. Efficacy and safety
Both European vaccines are safe and effective. Fourteen days after the second dose of basic vaccination protective antibodies develop in about 85% of the subjects, whereas after three doses, more than 98% of persons with normal immunity are protected [131]. As a rule the effectiveness of protection after vaccination against TBE is not verified by the detection of antibodies against TBEV in serum. However, the manufacturers of the vaccines and some authors recommend that in persons with immunodeficiency, the response to vaccination is assessed by serological testing approximately 4 weeks after the second dose, and that — if antibody response was not adequate — the second dose is repeated and followed by the third dose in accordance with the regular TBE vaccination timetable. Along with some proposals similar procedure may possibly refer also to the following doses. While such practice may appear reasonable, no convincing clinical data corroborate its usage.
TBE vaccine field effectiveness is estimated to be >98% in persons vaccinated in line with the advocated schedule, and >90% for those who received basic vaccination, but were later not vaccinated according to the planned timetable [138].
Side effects are mild and relatively rare. They are more frequent after the initial than with later doses of TBE vaccine. The most common side effects are local pain and tenderness on pressure at the injection site; redness and swelling occur less often. Short‐term fever after vaccination is relatively common in young children but rare in adults. Neurological complications are very infrequent [131].
11.3.6. Contraindications and limitations
11.3.6.1. Contraindications
The main contraindications are as follows:
Severe allergic reaction following preceding dose of TBE vaccine;
Information on severe allergic reactions to vaccine constituents (in addition to the active ingredients, TBE vaccine also contains remains of formaldehyde, protamine sulfate, gentamicin and neomycin); and
History on anaphylactic hypersensitivity to eggs (TBE viruses are grown in fibroblast cells of chick embryo).
Vaccination is not performed in persons with acute febrile illness.
11.3.6.2. Limitations
Pregnancy, breast‐feeding: Because information on the safety of TBE vaccine during pregnancy and lactation is inadequate, pregnant and lactating women should receive the vaccine only after a careful individual assessment of the potential risks and benefits. There is also no sufficient data on the safety of vaccination during lactation. However, since TBE vaccines are based on inactivated virus, the harm of breast‐feeding child or fetus is unlikely.
Autoimmune diseases: While there is no indication that vaccination may deteriorate the course of autoimmune diseases or trigger autoimmunity, caution is required in persons with an autoimmune disease because data on the safety of vaccination in this group are limited [131].
11.3.7. Storage
The vaccine must be stored in a refrigerator at a temperature between 2 and 8°C. Storage at higher temperatures and freezing are not suitable [131].
12. Conclusion
TBE is an important central nervous system infection endemic in European and Asian countries. Due to relatively high proportion of cases with severe clinical course and a considerable proportion of patients with permanent sequelae after acute illness, as well as due to high incidence, it represents a growing (public) health problem that could be substantially reduced with vaccination.
\n',keywords:"tick‐borne encephalitis, tick‐borne encephalitis virus, epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, prevention, vaccination",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54912.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54912.xml",downloadPdfUrl:"/chapter/pdf-download/54912",previewPdfUrl:"/chapter/pdf-preview/54912",totalDownloads:878,totalViews:447,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"May 3rd 2016",dateReviewed:"March 7th 2017",datePrePublished:null,datePublished:"August 30th 2017",dateFinished:null,readingETA:"0",abstract:"Tick-borne encephalitis (TBE) is an important central nervous system infection in Europe and Asia. It is caused by three subtypes of TBE virus (TBEV): European, Siberian and Far-Eastern, belonging to the genus Flavivirus. TBE is delineated by three criteria: the presence of clinical signs of meningitis, meningoencephalitis or meningoencephalomyelitis; cerebrospinal fluid pleocytosis (>5 × 106 cells/L); and demonstration of a recent infection with TBEV by the presence of specific serum IgM and IgG antibodies or IgG seroconversion. Imaging of the brain and spinal cord has a low sensitivity and specificity, but it is useful for the differential diagnosis. Clinical course and outcome of TBE depend on the subtype of TBEV (the disease caused by the European subtype has a milder acute course and a more favorable long-term outcome than the disease caused by the other two virus subtypes), age of patients (increasing age is associated with more severe acute course and poorer outcome) and probably on some host genetic factors. Due to relatively severe clinical course combined with the absence of etiologic treatment, considerable proportion of patients with incomplete recovery after acute illness, and increasing incidence, TBE represents a growing (public) health problem that could be substantially reduced with vaccination.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54912",risUrl:"/chapter/ris/54912",book:{slug:"meningoencephalitis-disease-which-requires-optimal-approach-in-emergency-manner"},signatures:"Perta Bogovič and Franc Strle",authors:[{id:"190724",title:"Prof.",name:"Franc",middleName:null,surname:"Strle",fullName:"Franc Strle",slug:"franc-strle",email:"franc.strle@kclj.si",position:null,institution:{name:"University of Ljubljana",institutionURL:null,country:{name:"Slovenia"}}},{id:"195498",title:"Dr.",name:"Petra",middleName:null,surname:"Bogovič",fullName:"Petra Bogovič",slug:"petra-bogovic",email:"petra.bogovic@kclj.si",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. History",level:"1"},{id:"sec_3",title:"3. Etiology",level:"1"},{id:"sec_4",title:"4. Epidemiology",level:"1"},{id:"sec_5",title:"5. Pathogenesis and pathology",level:"1"},{id:"sec_6",title:"6. Clinical manifestations of TBEV infection",level:"1"},{id:"sec_6_2",title:"6.1. Abortive form of TBE",level:"2"},{id:"sec_7_2",title:"6.2. Meningitis, encephalitis, and myelitis",level:"2"},{id:"sec_8_2",title:"6.3. Other manifestations in the acute phase of illness",level:"2"},{id:"sec_8_3",title:"6.3.1. Involvement of cranial nerves",level:"3"},{id:"sec_9_3",title:"6.3.2. Autonomic disorders",level:"3"},{id:"sec_10_3",title:"6.3.3. Encephalitis with normal CSF cell counts",level:"3"},{id:"sec_12_2",title:"6.4. TBE in patients who had been vaccinated against the disease",level:"2"},{id:"sec_13_2",title:"6.5. Chronic progressive TBE",level:"2"},{id:"sec_14_2",title:"6.6. Postencephalitic syndrome",level:"2"},{id:"sec_16",title:"7. Diagnosis",level:"1"},{id:"sec_16_2",title:"7.1. Blood and cerebrospinal fluid analysis",level:"2"},{id:"sec_17_2",title:"7.2. Magnetic resonance imaging (MRI) abnormalities",level:"2"},{id:"sec_18_2",title:"7.3. Microbiological investigations",level:"2"},{id:"sec_18_3",title:"7.3.1. Detection of TBEV",level:"3"},{id:"sec_19_3",title:"7.3.2. Serology",level:"3"},{id:"sec_22",title:"8. Factors influencing clinical course of acute disease and/or long‐term outcome",level:"1"},{id:"sec_22_2",title:"8.1. Subtype of TBEV",level:"2"},{id:"sec_23_2",title:"8.2. Age of patients",level:"2"},{id:"sec_24_2",title:"8.3. Other factors associated with severe acute disease",level:"2"},{id:"sec_25_2",title:"8.4. Severity of acute illness and other risk factors for unfavorable outcome",level:"2"},{id:"sec_26_2",title:"8.5. Genetic factors",level:"2"},{id:"sec_28",title:"9. Differential diagnosis",level:"1"},{id:"sec_29",title:"10. Treatment",level:"1"},{id:"sec_30",title:"11. Prevention",level:"1"},{id:"sec_30_2",title:"11.1. Nonspecific preventive measures",level:"2"},{id:"sec_31_2",title:"11.2. Prevention with immunoglobulins (passive immunization)",level:"2"},{id:"sec_32_2",title:"11.3. Vaccination",level:"2"},{id:"sec_32_3",title:"11.3.1. Recommendations for TBE vaccination",level:"3"},{id:"sec_33_3",title:"11.3.2. Vaccines",level:"3"},{id:"sec_34_3",title:"11.3.3. Vaccination schedule",level:"3"},{id:"sec_35_3",title:"11.3.4. Mode of application and dosages",level:"3"},{id:"sec_36_3",title:"11.3.5. Efficacy and safety",level:"3"},{id:"sec_37_3",title:"11.3.6. Contraindications and limitations",level:"3"},{id:"sec_37_4",title:"11.3.6.1. Contraindications",level:"4"},{id:"sec_38_4",title:"11.3.6.2. Limitations",level:"4"},{id:"sec_40_3",title:"11.3.7. Storage",level:"3"},{id:"sec_43",title:"12. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Mansfield KL, Johnson N, Phipps LP, Stephenson JR, Fooks AR, Solomon T. 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Clinical Infectious Diseases. 1993;16:392–396. DOI: 10.1093/clind/16.3.392'},{id:"B122",body:'Lotric‐Furlan S, Petrovec M, Avsic‐Zupanc T, Strle F. Concomitant tick‐borne encephalitis and human granulocytic ehrlichiosis. Emerging Infectious Diseases. 2005;11:485–488. DOI: 10.3201/eid1103.040776'},{id:"B123",body:'Kneen R, Solomon T, Appleton R. The role of lumbar puncture in suspected CNS infection – A disappearing skill? Archives of Disease in Childhood. 2002;87:181–183'},{id:"B124",body:'Kramer AH. Viral encephalitis in the ICU. Critical Care Clinics. 2013;29:621–649. DOI: 10.1016/j.ccc.2013.03.011'},{id:"B125",body:'Lani R, Moghaddam E, Haghani A, Chang LY, AbuBakar S, Zandi K. Tick‐borne viruses: A review from the perspective of therapeutic approaches. Ticks and Tick‐Borne Diseases. 2014;5:457–465. DOI: 10.1016/j.ttbdis.2014.04.001'},{id:"B126",body:'Czupryna P, Moniuszko A, Pancewicz SA, Grygorczuk S, Kondrusik M, Zajkowska J. Tick‐borne encephalitis in Poland in years 1993‐2008 – Epidemiology and clinical presentation. A retrospective study of 687 patients. European Journal of Neurology. 2011;18:673–679. DOI: 10.1111/j.1468‐1331.2010.03278.x'},{id:"B127",body:'Vazquez M, Muehlenbein C, Cartter M, Hayes EB, Ertel S, Shapiro ED. Effectiveness of personal protective measures to prevent Lyme disease. Emerging Infectious Diseases. 2008;14:210–216. DOI: 10.3201/eid1402.070725'},{id:"B128",body:'Corapi KM, White MI, Phillips CB, Daltroy LH, Shadick NA, Liang MH. Strategies for primary and secondary prevention of Lyme disease. Nature Clinical Practice Rheumatology. 2007;3:20–25. DOI: 10.1038/ncprheum0374'},{id:"B129",body:'Kluger G, Schöttler A, Waldvogel K, Nadal D, Hinrichs W, Wündisch GF, Laub MC. Tick‐borne encephalitis despite specific immunoglobulin prophylaxis. Lancet. 1995;346:1502. DOI: 10.1016/S0140‐6736(95)92527‐9'},{id:"B130",body:'Bröker M, Kollaritsch H. After a tick bite in a tick‐borne encephalitis virus endemic area: Current positions about post‐exposure treatment. Vaccine. 2008;26:863–868. DOI: 10.1016/j.vaccine.2007.11.046'},{id:"B131",body:'Barrett PN, Porthsmouth D, Ehrlich HJ. Tick‐borne encephalitis virus vaccines. In: Plotkin SA, Orenstein W, Offit PA, editors. Vaccines. 6th ed. Elsevier; Philadelphia, PA 2013. pp. 773–788'},{id:"B132",body:'Pen’evskaia NA, Rudakov NV. Efficiency of use of immunoglobulin preparations for the postexposure prevention of tick‐borne encephalitis in Russia (a review of semi‐centennial experience) (in Russian). Meditsinskaia Parazitologiia (Mosk). 2010;1:53–59'},{id:"B133",body:'WHO. Vaccines against tick‐borne encephalitis: WHO position paper. Weekly Epidemiology Record. 2011;86:241–256'},{id:"B134",body:'Haditsch M, Kunze U. Tick‐borne encephalitis: A disease neglected by travel medicine. Travel Medicine and Infectious Disease. 2013;11:295–300. DOI: 10.1016/j.tmaid.2013.07.003'},{id:"B135",body:'Zavadska D, Anca I, André F, Bakir M, Chlibek R, Cižman M, Ivaskeviciene I, Mangarov A, Mészner Z, Pokorn M, Prymula R, Richter D, Salman N, Simurka P, Tamm E, Tešović G, Urbancikova I, Usonis V. Recommendations for tick‐borne encephalitis vaccination from the Central European Vaccination Awareness Group (CEVAG). Human Vaccines & Immunotherapeutics. 2013;9:362–374. DOI: 10.4161/hv.22766'},{id:"B136",body:'Wiedermann U. Tick borne encephalitis TBE – Vaccination in non‐endemic countries. Travel Medicine and Infectious Disease. 2010;8:251–256. DOI: 10.1016/j.tmaid.2010.05.007'},{id:"B137",body:'Schöndorf I, Schönfeld C, Nicolay U, Zent O, Banzhoff A. Response to tick‐borne encephalitis (TBE) booster vaccination after prolonged time intervals to primary immunization with the rapid schedule. International Journal of Medical Microbiology. 2006;296(Suppl 40):S208–S212. DOI: 10.1016/j.ijmm.2006.01.009'},{id:"B138",body:'Heinz FX, Stiasny K, Holzmann H, Grgic‐Vitek M, Kriz B, Essl A, Kundi M. Vaccination and tick‐borne encephalitis, Central Europe. Emerging Infectious Diseases. 2013;19:69–76. DOI: 10.3201/eid1901.120458'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Perta Bogovič",address:null,affiliation:'
Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Mignon",authors:[{id:"74123",title:"Dr.",name:"Regis",middleName:null,surname:"Sodoyer",fullName:"Regis Sodoyer",slug:"regis-sodoyer"},{id:"136424",title:"Dr.",name:"Virginie",middleName:null,surname:"Courtois",fullName:"Virginie Courtois",slug:"virginie-courtois"},{id:"136426",title:"Mrs.",name:"Isabelle",middleName:null,surname:"Peubez",fullName:"Isabelle Peubez",slug:"isabelle-peubez"},{id:"136428",title:"Mrs.",name:"Charlotte",middleName:null,surname:"Mignon",fullName:"Charlotte Mignon",slug:"charlotte-mignon"}]},{id:"34710",title:"Antibiotic Susceptibility of Probiotic Bacteria",slug:"antibiotic-susceptibility-of-probiotic-bacteria",signatures:"Zorica Radulović, Tanja Petrović and Snežana Bulajić",authors:[{id:"75839",title:"Prof.",name:"Zorica",middleName:null,surname:"Radulovic",fullName:"Zorica Radulovic",slug:"zorica-radulovic"},{id:"83598",title:"Dr.",name:"Tanja",middleName:null,surname:"Petrović",fullName:"Tanja Petrović",slug:"tanja-petrovic"},{id:"121575",title:"Dr.",name:"Snezana",middleName:null,surname:"Bulajic",fullName:"Snezana Bulajic",slug:"snezana-bulajic"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"73202",title:"Analytical, Bioanalytical, Stability-Indicating Methods: Key Part of Regulatory Submissions",doi:"10.5772/intechopen.93566",slug:"analytical-bioanalytical-stability-indicating-methods-key-part-of-regulatory-submissions",body:'
1. Introduction
The United States of America (USA), Europe and Japan were developed the Common Technical Document (CTD) which should be implement while applying for registration of pharmaceutical product for human use. For the development of these guidelines International conference for Harmonization (ICH) plays important role and currently these are becoming the part of ICH guidelines [1]. The identity, strength, quality, purity and potency are important points of Investigational new drug application (IND), New drug application (NDA), Abbreviated new drug application (ANDA). The related analytical methods of drug substance and product should be included in NDA and ANDA. A Complete description, total manufacturing process including analytical procedures should ensure compliance with standards and potency should be part of Biologics license application (BLA). It is must to meet all standards of guidelines provided for analytical procedures. All these parameters should be suitable for their purpose wherever applicable. Detail Analytical procedures including detail validation parameters are the important part of Electronic Common Technical Document Specification as per International conference of Harmonization (ICH). The analytical procedure is Food and Drug Approved (FDA) if it a part of Approved NDA, ANDA or BLA. These methods can be generated from FDA recognized sources like U. S. Pharmacopeia/National Formulary (USP/NF) or if anyone submits validated procedure that will be accepted by FDA. The only validation or verification data of FDA approved methods of new products are considered for applications to various drug products (Figure 1).
Figure 1.
Flow chart showing essential requirements of registration of pharmaceutical product.
Every manufacturer must generate large amount of corrected data for safety and efficacy of drug for commercial viewpoint. As it is mandatory to follow Current Good Manufacturing practices (cGMPs) for manufacturing purpose, likewise each analytical activity must follow Good Analytical Practices.
Method Validation, calibrated instrument, and training are three important tasks of Good analytical practices (GAPs). Commercially available dosage form is an outcome of several steps which are systematically carried out during product development. It is very important that all steps should be carried in systematic manner to ensure complete drug development stage. In recent years there is special focus on efficiency and efficacy of drug product and for this clinical study is most important task but apart from this there are various behind the scene activities are associated with drug development process without which pharmaceutical drug development is not possible. Among these behind the scene activities Method Development and Validation has its own uniqueness to ensure the drug development.
2. Noncompendial analytical method validation
The objective and plan of work should be clearly defined prior to start the work. This data is based on scientific findings from the method development and Optimization. The validation of results should be obtained by approved protocol. Then sponsor must follow cGMP’s which includes detail procedure, validation characteristics and acceptance criteria by the use of qualified instrumentation. All the protocols of drug substance and product analytes in respective matrices should be prepared and followed. All the results of validation studies, application should be included.
3. Compendial analytical procedures
The analytical procedure official in pharmacopeias, are cross checked for implementation stage and its suitability should be checked. The verification protocol should include details of data which explains suitable analytical procedure official in USP/NF for drug product or drug substance.
The following points are to be included in the verification protocol
The compendia method which should be verified with acceptance criteria’s.
All parameters related to each aspect of method that is reagent, equipment, validation characteristics that is specificity, Limit of quantitation (LOQ), Precision, accuracy, should be included in validation are covered by procedure and extent of verification. There is no need to include robustness study for compendia assays if there is no deviation. For a BLA, if the methods are already specified in FDA regulations, there is must to take pre-approval from FDA to change in analytical method.
3.1 Statistical analysis
The statistical analysis is important work after finishing the method development and validation. The statistical values of validation are compared with the predetermined acceptance criteria.
The statistical parameters used are based on proper principle and required for evaluation of parameter. The methods like analysis of variance (ANOVA) for analysis of regression analysis, (R2-Correlation coefficient) to measure the linearity are applied for studying validation characteristics. In case of observed data is not distributed then it is transformed normal distribution or distribution free approach. By using validates software or independent verification for correctness the data can be analyzed.
3.2 System suitability requirement for potency assay
Before starting actual analysis of standard sample, it is necessary to check whether system is working properly or not. This important task can be completed by analyzing system suitability. In this all integral system that is equipment, electronics, analytical operations and samples are evaluated. These system suitability parameters are depending on method or procedure under validation.
System suitability can be evaluated according to following points:
The system suitability measures the performance of given system of samples on a given day. 2. The variable parameters like chromatographic columns, column aging, mobile-phase variations, changes in instrumentation are checked whether they are working properly or not.
It is nothing but the part of method validation. The experience and information obtained at the time of method development, which is helpful to determine system suitability of final method.
At every time when system is used for performing the assay there is necessary to use system suitability test. For longer period if it is continuously in use then there is need to reevaluate the system suitability at proper intervals.
The system suitability means criteria and parameters obtained collectively which can explain the system are working properly [2].
The important aspects of pharmaceutical development program are analytical method development, validation method transfer but it is fact that they are less considered in sense of total contribution in development process, time and economy. At the time of drug development phases, all the analytical method related activities are interrelated. In early development stages they are related and occur one after another in coming phases of development. During drug development process the changes may require to be performed in current methods and these changes in methods again requires validation or method transfer treatment.
If one’s objective of method development and validation is achieved, then it can prove that the laboratory facilities are accurate and fit for further development process that is one can say optimized. Method validation is the “process of demonstrating that analytical procedures are suitable for their intended use.” Both method validation and methods transfer have important share in drug development and further changes in methods. To generate supportive data during manufacturing and quality control, these methods provides a valuable data by comparing with specifications including all types stability study, Safety, characterization and drug performance can obtain with these supportive methods.
Method development is the simultaneous process as the gradual development of drug product continues. The system suitability parameters are set of tests to checks the proper working of the system. After performing robustness with proper statistical data collection one can set the criteria for final system suitability of the method.
These methods focus on active pharmaceutical ingredient (API) behavior. As the knowledge about API and drug product goes on progress the analytical methods become more refined. The important aspects of analytical method are that should be robust, simple and meeting the regulatory guidelines. Various trial an error experiments are to be carried out to develop the method. The performance criterion’s to be finalized before the final validation of method. Forced degradation study which is integral part of stability-indicating method and system suitability tests are one of the key points of method development and final validation [3].
3.3 Impurity profiling
The International Conference for Harmonization (ICH) guidances are available that are related to the qualification of impurities in new drug substances that are produced by chemical synthesis. These impurities can be addressed in two perspectives that are chemistry aspects and safety aspects. The chemistry aspects explain the identification and classification of impurities, the various analytical procedures and setting of specifications. In the safety aspects explains the qualification of impurities which are not addressed in clinical trials. In this aspect the threshold limits are defined. This ICH guidance classifies impurities in three classes as Organic, Inorganic and Solvent. Each class of impurities should be properly reported, with all aspects, developed during synthesis, storage of the new drug product. The analytical procedure including validation reports related to impurities should be properly reported [4]. In concern with the above discussed guidelines related to qualification of impurities in new drug substances produced by chemical synthesis, impurities which are classified as degradation product developed with the reaction with excipients or container closure system may termed as reaction products. All the observed degradants during manufacturing and stability study should be reported. All the data related to their identification, specification, analytical procedures for quantification, their limits of detection and quantification should be reported [5].
4. Stability-indicating method
To ensure safety, efficacy and quality of drug product there are need of stability indicating methods. The Food and Drug Administration (FDA) defines the stability indicating method as a validated analytical procedure that accurate and precisely measure active ingredients (drug substance or drug product) free from process impurities, excipients and degradation products [6].
To obtain forced degraded samples for assessing selectivity of method, method development and method validation are three important steps of stability indicating methods.
4.1 Importance of forced degradation
As per guidance document available for stability indicating method does not contain any explanation about extent up to which the degradation should be carried out. There are no certain guidelines regarding stress degradation. Therefore, it is always necessary to keep all experimental conditions of degradation with more reality and deliberate degradation.
The main purpose of forced degradation is to obtain stability of drug. It should provide information about route of degradation and utility towards the stability indicating [6].
Forced degradation can be able to judge excipients or non-drug substances. It also provides information useful for structure elucidation of degradation products. Importantly it gives data related to thermal, hydrolysis, and oxidation and photo degradation behavior of drug substance and drug product. It is very important to know about chemical behavior of drug product and drug substance in formulation development, manufacturing and packaging. The data helps in quality improvement [7].
4.2 Acceptance criteria for forced degradation
There are vast discussions among the various scientists that what should be the limits of stress testing? Generally, values in between 5–20% are proper and acceptable for chromatographic assays. The acceptable stability limit for small molecules are 90% of label claim and generally employed by pharmaceutical scientist that is 10% degradation is optimum for use in analytical validation. There are some experiments in which very little or no degradants are obtained due to exceptional stability of molecule under study in such case accelerated storage 400 c for 6 months should be carried out. If positive result is obtained, then the stability of drug is noted. But overstressing the drug substance may produce false results [7].
According to the recent recommendations of Food and Drug administration (FDA) and ICH guidelines, the stability indicating property of analytical method can be obtained by carrying out forced degradation study. The pathway of decomposition from API, solution and formulation also be determined. The structural information, their characterization and isolation of major degradants are the important part of the new drug approval (NDA). The use of forced degradation study is primary to understand molecular chemistry of drugs, its stability indicating properties and its degradation products and their pathways. In most of the cases the Hydrolysis, Oxidation, Photolysis, Racemization, and Decarboxylation are the type of reactions that are responsible for decomposition of most the drugs. However, the regulatory guidelines do not define the procedures to carry out degradation study. Therefore, there are various approaches to carry out forced degradation study [8].
4.3 Stress conditions
In pharmaceutical industry thermal, hydrolysis, oxidation and photo degradation are generally employed. If one must serve the purpose of degradation, the expected degradation should be achieved. The optimum percentage of degradation should be obtained in all types of conditions or in minimum of one according to FDA guidelines. If no degradation is achieved, then in that case, all reports related degradation experiment carried out should be produced. It is important fact to obtain the degradation as per expected level. The degradation in between 5 and 20% is recommended [9].
4.4 Hydrolysis
By using acid and base the hydrolysis studies are performed. Generally, a chemical reaction is carried out with water to obtain decomposed analyte. The wide pH range that is from 2 to 12 is used for acid and base, which is to be used for hydrolysis purpose. For acid hydrolysis generally Hydrochloric acid (HCl) or Sulfuric acid (H2SO4) is used and for base hydrolysis Sodium or Potassium hydroxide is used. According to stability of molecule, the concentration of acid or base is decided. One can used more than one stress conditions to obtain desired degradation. If the desired degradation is not achieved at room temperature, then higher temperature is used. After the degradation process completed the degraded samples are neutralized by same acid or base so as it can easily injected in HPLC column without any harm to silica stationary phase. For water insoluble samples alcoholic acid or base are used for obtaining degradation [9].
4.5 Oxidation
To carry out oxidation degradation of drug substance or drug product, generally hydrogen peroxide is used. Apart from hydrogen peroxide metal ions, oxygen and radical initiators can also be employed. The oxidizing agent, its quantity requirement, properties are depending on the drug substance under study. If hydrogen peroxide is used as a degradant, in that case combination of stress should not be employed. If elevated temperature is used in case of Hydrogen Peroxide, it leads to hydrolysis instead of oxidation because in Hydrogen Peroxide O-O are not stable and they may decompose at ambient temperature also. Due to heating, these bonds break faster and oxidation occurs. Sodium metabisulfite solution is used for neutralization of oxidation degraded samples [9].
4.6 Heat
Active pharmaceutical ingredients, Dosage form with or without humidity can be undergoing thermal degradation. The sample is exposed to heat. (weather there is humidity or absence of humidity as mentioned earlier) In case of liquid, humidity is completely avoided. While applying stress to liquid samples especially for injections, oral solutions, and syrups as further diluting the samples, the precaution should be taken because these types of samples may loss water and concentration of actual sample. By obtaining multiple time results, the detail information about primary and secondary degradation can collected. If any molecule is so stable that it cannot generate degradation, in such situation the energy analogous to the accelerated stress condition is to be applied to express efforts taken for obtaining degradation [9].
4.7 Photo stability
The exposure to light is one of the important degradation steps to obtain degradation caused by light. This degradation is evaluated by obtaining any unacceptable change due to light. The recommendations related to photo stability are described in ICH guidelines Q1B.The UV–VIS light exposure with not less than 1.2 million hours to achieve degradation of sample. The samples are preferably exposed to cool white fluorescent light and near ultraviolet lamp. The natural light can be used, if specific instrument is not available, but there will be intensity problem as it is varying with time, weather conditions, pollution etc. due to which natural light becomes not suitable for degradation [9].
4.8 Evaluation of results
After generating forced degradation samples obtained by accelerated stress conditions, their evaluation is the important task. For evaluation purpose, each sample should be studied individually. The Chromatographic techniques including High performance liquid chromatography (HPLC), Ultra-performance liquid chromatography (UPLC), UHPLC and Capillary Electrophoresis are commonly used techniques for this important task. The most important work is development and validation of stability-indicating method which can be able to separate every degradation product from each other and from drug. Therefore, peak purity is important in sense of selectivity determinations of the method. One more important parameter is sensitivity, which can be helpful to asses’ impurities at lower level. There are chances that the impurity peak may get depressed at the time of method development which is co-eluted. Many times, it may happen that two unknown impurity get merged due to which false results are appear for stability, therefore it is important to implement such analytical method that can have capacity to resolve each unknown impurity and that is helpful to control out of specification results [9] (Figure 2).
Figure 2.
Important parameters and acceptance criteria for impurity profiling and stability indicating methods.
5. Bioanalytical method development and validation
There were various regulatory agencies had done serious efforts to regulate bioanalytical method development and validation. Almost from last three decades there were large progresses in this area. The various regulatory agencies that were worked can be listed as US FDA, American association of pharmaceutical scientists (AAPS), Health protection Branch HPB, Association of analytical chemists (AOAC), Center for Veterinary medicine (CVM), U. S. Department of Health and Human Services Food and drug Administration, Center for Drug Evaluation and Research (CDER), European Medicine Agency (EMA), China Food and Drug Administration (CFDA), European Bioanalytical forum (EBF), Global CRO Council (GCC), The Brazilian health regulatory agency (ANVISA, Brazil). To regulate and harmonize bioanalytical method development and validation first workshop was held in 3–5 December 1990, report of which was published in pharmaceutical research and in other journals. On basis of the reports of this workshop, the FDA was issued draft guidance on bioanalytical method development and validation in January 1999.The second FDA guidance was published in May 2001 on the basis of workshop which was held in January 2000.The recommendations for bioanalytical method development and validation for macromolecules was published in 2006. The recommendations for regulation and harmonization of bioanalytical methods were again refreshed in 2006. In 2010, a draft guidance was published by EMA for development and validation of bioanalytical methods. As per above discussion this can be concluded that there were serious efforts carried out to regulate bioanalytical method development and validation by the various abovementioned regulatory agencies.
6. Need of bioanalytical method development and validation
The various manufacturers are applying for Investigational new drug application (IND), New drug application (NDA), Abbreviated new drug application (ANDA) to FDA. There was harmonization in this process related to human clinical pharmacology, bioavailability (BA) and Bioequivalence (BE), pharmacokinetic evaluation (PK), non-human pharmacology and toxicology studies and preclinical studies, which should be included in abovementioned applications. To obtain the data related to abovementioned requirements, there is need of development and validation of bioanalytical methods in biological matrices such as blood, serum, plasma or urine [10].
The most recent FDA guidance document on bioanalytical method development and validation was released in May 2018. Before this there was a guidance documents in 2001 and its revision in 2013 were released. The overall previous recommendations remain same, only the following points are revised.
The validation criteria for dilution and carryover
There was clarification on the number of Quality control (QC) samples and replicates
There will be no acceptance criteria for QCs for accuracy and precision
The QCs should have to cover the sample concentration range
The LLOQ should be evaluated for interference for each run
There will be the further acceptance criteria within the different batches
The internal standard (IS) and the drift should be monitored
In this document following clarity regarding Ligand Binding Assay (LBA) was added
The accuracy and precision runs
The control of each sample should be included with clear definition
The consistency in standard calibrator preparations
The significant change in final document, the incurred sample reanalysis section was added which includes endogenous compounds, biomarkers, diagnostic kits, bridging data and dried blood spots [11]. The guidance documents (M10) on Bioanalytical Method Development and Validation was released by International Council for Harmonization of technical requirements for pharmaceuticals for Human Use (ICH), in February 2019. Simultaneously, American association of Pharmaceutical scientists (AAPS), European bioanalysis forum (EBF), Japan Bioanalysis forum (JBF), China Bioanalysis forum (CBF) were organized a workshop of industry, academia, and health authorities to discuss this draft guidance. The objective of these discussions was the M10 guidelines which are for Bioanalytical Method Development and validation which are part of regulatory submissions. This guidance document explains the validation of Bioanalytical Methods form, which the concentration of analyte is determined from biological fluids. The concentration was obtained from pivotal nonclinical pharmacokinetic studies which are useful for taking the decisions over the regulatory submission including all phases of clinical trials [12].
6.1 Key principles of bioanalytical method validation and establishment
Accuracy, precision, selectivity, sensitivity, reproducibility and stability are the fundamental parameters that ensure the acceptability of bioanalytical method.
There should be specific protocol, study plan, report or SOP for bioanalytical method development and validation.
How the analyte is being get affected by environmental, matrix, or procedural variables? Every step, including time of collection of matrix and overall investigation time, should be clarified.
The physiological nature of samples gives variable matrix. When there are Liquid Chromatography-Mass spectrometry-Mass Spectrometry (LC-MS-MS) based procedures, then protocol should be designed to avoid matrix effect, matrix may change during method validation.
It is necessary to validate bioanalytical method for the intended use or application.
There should be written method validation report to claim the results.
The same biological matrix as the matrix in the intended samples should be used for validation purposes. It is necessary in case of limited availability of matrix like bone marrow.
The stability at the time of matrix during collection and storage should be assessed before analysis.
The stability of analyte in matrix from dosed subjects should be finalized in case of potentially labile metabolites.
The parameters like accuracy, precision, reproducibility, response function, and selectivity of method for endogenous substances, metabolites, and known degradation products should be set for biological matrix.
In case of selectivity the evidence should be produced that substance being quantified is the intended analyte.
The concentration range of analyte should be defined on standard samples including their statistical parameter which clears the standard curve.
To define concentration and response relationship an enough sample should be analyzed. This relationship should be continuous and reproducible. For this purpose, the standard used should be from dynamic range and nature of the concentration-response relationship. Generally, six to eight concentrations excluding blank can be used to define standard curve. In case of nonlinear concentrations more standard may be recommended.
There should be proper demonstration to show the ability to dilute samples originally above the upper limit of the standard curve by accuracy and precision parameters in the validation.
In case of high throughput analyses like multiplexing, multicolumn and parallel systems, enough Quality control (QC) samples should be assessed to prove control of the assay. Based on the run size, the number of QC samples should be determined.
There should be proper placement of the QC samples in the run.
There is a need to set a specific acceptance criterion for bioanalytical method to be considered as a valid method. That should be achieved for accuracy and precision for validation of QC samples over the range of standards.
6.2 Specific recommendations for bioanalytical method validation
There should be minimum six standard points for matrix based standard curve excluding blank, which may be single or replicates and should cover the entire range of expected concentrations.
Standard curve should explain the concentration-response relationship with appropriate weighting and statistical tests for goodness of fit.
The Lower limit of quantitation, (LLOQ) should be measured with acceptable accuracy and precision which is the lowest concentration of the standard curve. By using a least five samples independent of standards and its coefficient of variation, the LLOQ can be established. The LLOQ should not be confused with the limit of detection and/or the low-Quality Control (QC) samples. The upper limit of quantification will be defined by highest standard.
The accuracy and precision should be determined by using minimum of five determinations per concentration level excluding blank samples. The average value should be within ±15% of the theoretical value. The LLOQ should be up to ±20%. The coefficient of variance of precision should not exceed 15% and for LLOQ should not exceed 20%. The methods which give the results of accuracy and precision with these above-mentioned values should be acceptable.
There should be proper demonstration of concentration of analyte in biological matrix with which the accuracy and precision is determined. This can be performed by analyzing replicate sets of QC samples from same biological matrix. This QC sample should be representative of entire concentration range selected for standard curve. From which one concentration within LLOQ , one should be middle one that is middle QC (MQC) and last should be upper limit of standard curve that is High QC (HQC).
All outliers should be included in reported method validation data and accuracy and precision data. The values of outliers that are determined statistically can also be reported with the calculations of accuracy and precision.
The storage temperature stability in biological matrix should be determined for analyte. The freeze-thaw stability at minimum of three cycles of two concentrations in triplicates should be studied.
The ambient temperature stability of analyte should be determined over the time period equal to typical sample preparation, sample handling and analytical run times.
In case of instrument failure, reinjection reproducibility should be evaluated to determine an analytical run could be reanalyzed.
For determination of specificity of assay method, a minimum of six concentration of same matrix should be studied. In case of hyphenated techniques like mass-spectrometry based methods, it is not important to study six independent matrices. There should not any compromise to study matrix effect to ensure precision, selectivity and sensitivity in case of Liquid Chromatography-Mass spectrometry (LC-MS) and Liquid Chromatography-Mass spectrometry-Mass Spectrometry (LC-MS-MS) based procedures. The selectivity should be evaluated throughout method development, method validation and it should be continued up to the application of method to actual study samples.
The acceptance/rejection criteria for spiked, matrix-based calibration standards and validation of QC samples should be based on theoretical concentration of analytes. For studying accuracy and precision, the specific criteria should be set in the standard concentration range [13] (Figure 3).
Figure 3.
Sequence showing development and validation of bioanalytical method.
7. Analytical techniques for method development and validation
The various analytical techniques are available for Qualitative and Quantitative analysis, which can be used in above explained types of analytical methods. The chromatographic techniques used as a separation tool and spectroscopic techniques are used for an identification and to obtain structural information. Among all these techniques High performance liquid chromatography, High performance thin layer chromatography, Spectrophotometric techniques and Hyphenated techniques are explained in brief.
7.1 High performance liquid chromatography
When we draw the attention towards the working principle of HPLC, which involves the injection of small sample (Generally in μl) into the stationary phase composed of 3–5-micron tiny particles. The injected components of the sample moved through the abovementioned stationary phase with the mobile phase which is forced through high pressure by the pump.
The HPLC technique is having advantage of High speed, Efficiency, Sensitivity and vastly superior over the simple liquid chromatography. The process of separation of components of sample involves chemical and physical interactions with the stationary phase particles. The separated components are detected at the end of column by the detector in the form of the liquid chromatogram (Figure 4).
Figure 4.
Flow diagram of working principle of HPLC.
The HPLC can be applied for separation of non-volatile compounds like Aspirin, Ibuprofen, Acetaminophen and then for separation of salts like Sodium Chloride, Potassium Phosphate. For the separation of proteins like Egg white and Blood proteins. The HPLC can also be applied for separation of Organic Polymers, Heavy Hydrocarbons, Natural Products, Thermally unstable compounds and Enzymes [14].
For separation of many complex mixtures including biological samples high performance liquid chromatography is the best form of liquid chromatography (HPLC). HPLC is widely used for qualitative and quantitative analysis of different types of pharmaceuticals due to its sensitivity. By using HPLC, one can obtain individual sample with its role in that sample. In 20th century, the HPLC methods were appeared for assay of bulk drugs and later become a principal method of Pharmacopeia. The interaction among the solute molecules and stationary phase, decides the mode of chromatography. HPLC is more versatile technique as various modes are available. By using HPLC, the proper values of precision can obtain with excellent specificity of the methods. Though the specificity, precision and accuracy are obtained with HPLC methods, the system suitability parameters are first analyzed before analyzing these parameters. The more attention should also be providing for high accuracy, precision and specificity. By doing wide literature survey it was observed that HPLC is widely used technique among all chromatographic techniques. One of the reasons for this is detection system of HPLC which can able to detect every component of mixture. The UV detector is most widely used detector for HPLC. The Ultra-violet (UV) detector can analyze various wavelengths simultaneously by giving multiple wavelength programmers on HPLC software. Every component present in mixture which UV can detect that can be obtained by UV detector. A Photodiode array (PDA) detector is one of useful spectroscopic detector. By placing at the image plane of spectrophotometer various wavelength can be scanned simultaneously. For analysis of alcohols, sugars, carbohydrates, fatty acids and polymers, the refractive index detector is used as there is restriction for UV absorption of these compounds. The Refractive Index (RI) detector is one of the lowest sensitivity detectors but it can be applied for trace detection with low noise. For analyzing oxidizable and reducible substances, the electrochemical detector is implemented. In this detector the electrical output obtained by electron flow due to chemical reaction at electrode surface due to presence of above-mentioned compound is used for qualitative and quantitative analysis of these types of samples. Among various detectors available for HPLC, the most sensitive detector is fluorescence detector. The sensitivity of fluorescence detector is 10–1000 times more sensitive as compared with the UV detector. If sample contains any specific fluorescent compound, then it can be easily detected by this detector. For estimation of pharmaceuticals especially fluorescence detector is applied. As most of pharmaceuticals are polar in nature, there analyses are carried out as reverse phase HPLC. In recent years most of the researchers used reverse phase chromatography with UV detection, due to that the results are obtaining with best reliability, analysis, repeatability and sensitivity. Generally, in pharmaceutical industry Octadecyl silyl (ODS) C18 is mostly used stationary phase. Many drugs can be easily obtained in pharmaceutical formulations and biological fluids by using HPLC. Nowadays, HPLC is one of the important tools for solving many problems in pharmaceutical industry. There are certain limitations to HPLC that high price of column, HPLC grade solvents and it is difficult to obtain long term reproducibility due to nature of column packings.
The Liquid Chromatography-Mass spectrometry (LC-MS) is wide choice for quality control and quality assurance in various stages in pharmaceutical industry. The LC-MS can be easily applied for assay of many drugs and pharmaceuticals also applied for analysis of impurities and degradation products. The most hyphenated technique like Liquid Chromatography-Mass spectrometry-Mass spectrometry (LC-MS-MS) is also available for above mentioned work [15].
7.2 High performance thin layer chromatography (HPTLC)
The advancement of Thin layer chromatography (TLC) is the HPTLC that is, High performance thin layer chromatography which an instrumental semi or automatic form of TLC. It is fast working, sensitive and can be able to analyze wide range of samples.
The HPTLC is advantageous to handle a sample with short analysis time for analysis of even complex samples including crude drugs. As automation with the instrument it can be able to analyze entire chromatogram with many parameters without any interruption. The samples can be analyzed simultaneously or independently with standard that shows the reliability of technique. The HPTLC is equipped with high performance adsorbent layers having refined uniform particles, approx. 5 microns in diameter. All processes of experimentation including method development, optimization of various parameters and documentation are performed with standardized methods. The HPTLC can be applied for both qualitative and quantitative analysis of mixtures, as the technique is automated, the quantitative mode is more optimized as compared with the TLC. Also, it can be used for the assay of the compound (Figure 5).
Figure 5.
Diagram showing components of HPTLC.
The advantages of the HPTLC are as follows:
Colored samples can be easily separated
Many samples can be assessed easily on single plate which reduces the cost and time.
Two-dimensional mode is possible
Visualizing agent used which are Specific and Sensitive for detection purpose
Other evaluation technique can be implemented for different samples with different light absorption characteristics.
Radio labeled compounds can be monitored and microbial activity can be assessed.
No regeneration and cleanup are required as the technique is disposable.
Development of plate and evaluation of plate are separate processes therefore both can perform as per time available differently [15].
The important advantages of the HPTLC are fast, inexpensive method of analysis. It can prove over high-performance liquid column chromatography when it is performed by skilled person for quantitative analysis. The qualitative and quantitative analysis by the HPTLC with automated sample application and densitometric scanning shows very sensitive and reliable results. The HPTLC has important advantage of providing chromatographic fingerprints which can be stored as an electronic image [16].
7.3 UV-spectrophotometric methods
For the quantification of components present in solution, the UV absorption spectroscopy works on the principle of Beer-Lambert law [17] (Figure 6).
Figure 6.
Flow diagram of working principle of UV spectrophotometer.
According to Beer-Lambert law,
A=logI0/I=ε.c.lE1
where A = Absorbance.
I0 = intensity of incident light.
I = intensity of emergent light.
ɛ = molar absorptivity.
c = molar concentration of solute.
I = length of sample cell.
The natural Ultra-Violet (UV) absorption methods and chemical reactions spectrophotometric methods are having importance in pharmacopeia. In these methods quantitative data of reflection or transmission by the analyte as function of wavelength is measured. The method is based on the fact, that functional group of analyte absorbs UV radiation at specific wavelength in a solvent system. The λmax is the term used for maximum absorption of wavelength which is independent of concentration. These methods require less time and less labor consumption. The method also gives best precision. The UV-Visible methods are applied for multicomponent analysis of samples [15].
7.4 Brief introduction of other spectroscopic techniques
The Near Infrared spectroscopy (NIRS) is one of the spectroscopic techniques that can be applied for multicomponent analysis of all types of samples and having advantage of non-destructive technique. For the purpose of raw material testing, quality control of finished product and to monitor the process, the NIR spectroscopy plays important role in recent years. The great advantage of NIR is there no requirement of sample pre-treatment, the use of fiber optic probes and both the chemical and physical parameters can be obtained in single spectrum [15].
The Nuclear Magnetic Resonance (NMR) spectroscopy is one of the advantageous techniques over UV and IR spectroscopy that it can detect the intermediate products like ions, reaction complexes, solvents of chemical reaction. The NMR spectroscopy provides unique information on the structure of intermediate due to which there is no need to restore various hypotheses to explain the mechanism of the process [18]. The mass spectrometry is one of the outstanding techniques in all type’s spectroscopies due to its sensitivity, detection limits and its wide range of application. It is widely applied in biochemical problems like proteome, metabolone, drug discovery and metabolism. This technique can also be applied for pollution control, food control, forensic science and natural product or process monitoring. It can also be applied in atomic physics, reaction physics, reaction kinetics, inorganic chemical analysis, ion-molecule reactions and determination of thermodynamic parameters [19].
7.5 Hyphenated techniques
Generally, for the qualitative and quantitative analysis of the samples, the separation technique is combined with the identification technique. In the analysis, chromatographic and electrophoresis are used for separation or isolation of the required components. The quantitative determination or structural information of the sample under study is performed by spectrophotometry. The Hyphenated technique is nothing but the combination of both above said techniques that are separation and spectrophotometric technique. The various hyphenated techniques like Liquid chromatography-Mass spectrometry (LC-MS), Gas chromatography-Mass spectrometry, Liquid Chromatography-Nuclear Magnetic resonance (LC-NMR), Liquid chromatography-Fourier transform infra-red spectroscopy (LC-FTIR), Capillary electrophoresis-Mass spectrometry (CE-MS) are used widely for qualitative and quantitative analysis. There may be a combination of more than one separation or detection technique like Liquid chromatography-Photodiode array-Mass spectrometry (LC-PDA-MS), Liquid chromatography-Mass spectrometry-Mass spectrometry (LC-MS-MS), Liquid chromatography-Nuclear magnetic resonance-mass spectrometry (LC-NMR-MS), Liquid chromatography-photodiode array-nuclear magnetic resonance-Mass spectrometry (LC-PDA-NMR-MS) [20].
\n',keywords:"noncompendial and compendial analytical methods, forced degradation analytical techniques, bioanalytical methods, analytical techniques",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73202.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73202.xml",downloadPdfUrl:"/chapter/pdf-download/73202",previewPdfUrl:"/chapter/pdf-preview/73202",totalDownloads:82,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 28th 2019",dateReviewed:"August 10th 2020",datePrePublished:"September 14th 2020",datePublished:null,dateFinished:null,readingETA:"0",abstract:"According to the International Conference for Harmonization (ICH), the validation and verification data must be included in the Electronic Common Technical Document. The validated analytical procedure gets automatically Food and drug approved (FDA) if it is part of New drug application (NDA), Abbreviated new drug application (ANDA) or Biologic license application (BLA). The analytical, bioanalytical and stability-indicating methods are essential part of all above said regulatory submissions. There are certain ways to generate these analytical methods like U.S. pharmacopeia/National Formulary which are Food and drug approved. The validated analytical method can also be submitted by any researcher or agency which can gets the food and drug approval. It is necessary that the methods which are Food and drug approved can only be applied to the various drugs and drugs products. In the current chapter, the meaning and requirements of analytical methods, procedures, acceptance criteria and evaluation of stability indicating methods, need, recommendations for bioanalytical methods are discussed in detail. The analytical techniques like HPTLC, HPLC, Spectrophotometry and Hyphenated techniques are also discussed as these are playing important role in validation of these methods.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73202",risUrl:"/chapter/ris/73202",signatures:"Mahesh Mukund Deshpande",book:{id:"9932",title:"Analytical Chemistry - Advancement, Perspectives and Applications",subtitle:null,fullTitle:"Analytical Chemistry - Advancement, Perspectives and Applications",slug:null,publishedDate:null,bookSignature:"Dr. Abhay Nanda Nanda Srivastva",coverURL:"https://cdn.intechopen.com/books/images_new/9932.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"293623",title:"Dr.",name:"Abhay Nanda",middleName:"Nanda",surname:"Srivastva",slug:"abhay-nanda-srivastva",fullName:"Abhay Nanda Srivastva"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"270956",title:"Mr.",name:"Mahesh",middleName:null,surname:"Deshpande",fullName:"Mahesh Deshpande",slug:"mahesh-deshpande",email:"mahesh_deshpande11@rediffmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Noncompendial analytical method validation",level:"1"},{id:"sec_3",title:"3. Compendial analytical procedures",level:"1"},{id:"sec_3_2",title:"3.1 Statistical analysis",level:"2"},{id:"sec_4_2",title:"3.2 System suitability requirement for potency assay",level:"2"},{id:"sec_5_2",title:"3.3 Impurity profiling",level:"2"},{id:"sec_7",title:"4. Stability-indicating method",level:"1"},{id:"sec_7_2",title:"4.1 Importance of forced degradation",level:"2"},{id:"sec_8_2",title:"4.2 Acceptance criteria for forced degradation",level:"2"},{id:"sec_9_2",title:"4.3 Stress conditions",level:"2"},{id:"sec_10_2",title:"4.4 Hydrolysis",level:"2"},{id:"sec_11_2",title:"4.5 Oxidation",level:"2"},{id:"sec_12_2",title:"4.6 Heat",level:"2"},{id:"sec_13_2",title:"4.7 Photo stability",level:"2"},{id:"sec_14_2",title:"4.8 Evaluation of results",level:"2"},{id:"sec_16",title:"5. Bioanalytical method development and validation",level:"1"},{id:"sec_17",title:"6. Need of bioanalytical method development and validation",level:"1"},{id:"sec_17_2",title:"6.1 Key principles of bioanalytical method validation and establishment",level:"2"},{id:"sec_18_2",title:"6.2 Specific recommendations for bioanalytical method validation",level:"2"},{id:"sec_20",title:"7. Analytical techniques for method development and validation",level:"1"},{id:"sec_20_2",title:"7.1 High performance liquid chromatography",level:"2"},{id:"sec_21_2",title:"7.2 High performance thin layer chromatography (HPTLC)",level:"2"},{id:"sec_22_2",title:"7.3 UV-spectrophotometric methods",level:"2"},{id:"sec_23_2",title:"7.4 Brief introduction of other spectroscopic techniques",level:"2"},{id:"sec_24_2",title:"7.5 Hyphenated techniques",level:"2"}],chapterReferences:[{id:"B1",body:'Jordan D. An overview of the common technical document (CTD) regulatory dossier. Medical Writing. 2014;23(101):101-105. DOI: 10.1179/2047480614Z.000000000207'},{id:"B2",body:'Analytical procedures and methods Validation for drugs and Biologics, Guidance or Industry, U.S. Department of Health and Human Services, Food and Drug Administration, center for Drug Evaluation and Research (CDER), Centre for Biologics Evaluation and Research (CBER); 2015. pp. 1-15'},{id:"B3",body:'Robert WL, Laurie G. The Central Role of Analytic Method Development and Validation in Pharmaceutical Development, Life Science Connect 5340 Fryling Road, Suite 300, Erie, PA 165101, 814.897.7700. pp. 1-3. Available from: www.lifescienceconnect.com'},{id:"B4",body:'ICH Topic Q3A Impurities testing guideline: impurities in new drug substances. The European agency for evaluation of Medical product, Human Medicines Evaluation Unit, CPMP/ICH/142/95. pp. 1-11'},{id:"B5",body:'ICH topic Q3B (R2) impurities in new drug product, European Medicine Agency CPMP/ICH/2738/99; June 2006. pp. 1-14'},{id:"B6",body:'Cione AP, Tonhi E, Silva P. Stability Indicating Methods. Brazil: Bioagri Laboratories; 2011. pp. 27-36. DOI: 10.5772/19940'},{id:"B7",body:'Ngwa G. Forced degradation studies, forced degradation as an integral part of HPLC stability-indicating method development. Drug Development & Delivery. 2010;10(5):1-4'},{id:"B8",body:'Sengupta P, Chatterjee B, Tekade RK. Current regulatory requirements and practical approaches for stability analysis of pharmaceutical products: A comprehensive review. International Journal of Pharmaceutics. 30 May 2018;543(1-2):328-344. DOI: 10.1016/j.ijpharm.2018.04.007'},{id:"B9",body:'Sharma MK, Murugesan M. Forced degradation study: An essential approach to develop stability indicating method. Journal of Chromatography. 2017;801:1-3'},{id:"B10",body:'Deshpande MM, Kasture VS, Mohan M, Chaudhari SR. Practical approach for development and validation of bioanalytical method: A review. Inventi Rapid/Impact: Pharm Analysis & Quality Assurance. 2017;2017(1):1-8'},{id:"B11",body:'Booth B, Stevenson L, Pillutla R, Buonarati M, Beaver C, et al. White paper on recent issues in bionalysis: FDA BMV guidance, ICH M10BMV guidance and regulatory inputs (part 2-recommendations on 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guidance and regulatory agencies input on bioanalysis, biomarkers and immunogenicity). Bioanalysis. 2019;11(23):2099-2132'},{id:"B12",body:'Booth B, Vazvaei F, Fluhler E, Myler H, Woolf E. AAPS, workshop report on ICH M10. The AAPS Journal. 2020;22:10. DOI: 10.1208/s12248-019-0398-7'},{id:"B13",body:'Guidance for Industry Bioanalytical Method Validation, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM). BP; May 2001. pp. 8-11'},{id:"B14",body:'HPLC Basics. Fundamentals of liquid chromatography (HPLC). Courtesy of Agilent Technologies, Inc.; 2007'},{id:"B15",body:'Siddiqui MR, Alothman ZA, Rahman N. Analytical techniques in pharmaceutical analysis: A review. Arabian Journal of Chemistry. 2017;10:S1409-S1421'},{id:"B16",body:'Srivastava MM. High-Performance Thin Layer Chromatography (HPTLC). Heidelberg Dordrecht London, New York: Springer. 2011. pp. 9-10. DOI: 10.1007/978-3-642-14025-9'},{id:"B17",body:'Stauffer E, Newman R. Other Techniques of Analysis and the Future of Fire Debris Analysis. ScienceDirect. Amsterdam: Global Business; 2008'},{id:"B18",body:'Ionin BI, Erhoy BA. Application of NMR spectroscopy in various fields of organic chemistry. In: NMR Spectroscopy in Organic Chemistry. Physical Methods in Organic Chemistry. Boston, MA: Springer; 1970'},{id:"B19",body:'Hoffmann ED, Stroobant V. Mass Spectrometry Principles and Applications. 3rd ed. Hoboken, New Jersey: John Wiley and Sons, Ltd. 2007. p. 1'},{id:"B20",body:'Patel KN, Patel JK, Patel MP, Rajput GC, Patel HA. Introduction to hyphenated techniques and their applications in pharmacy. Pharmaceutical Methods. 2010;1(1):2-13'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mahesh Mukund Deshpande",address:"mahesh_deshpande11@rediffmail.com;, maheshdeshpande83@gmail.com",affiliation:'
Department of Pharmaceutical Chemistry, Amrutvahini College of Pharmacy, Sangamner, M.S., India
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This chapter presents the biology of these two pathways, their genes and cascading proteins, and then, it looks at the research that has connected these molecules to autism. Finally, it imparts current and future therapeutic modalities that might exploit abnormalities in these genes and proteins, change them and ultimately alter aberrant autistic behaviors.",signatures:"Anthony J. Russo",authors:[{id:"191116",title:"Ph.D.",name:"Aj",surname:"Russo",fullName:"Aj Russo",slug:"aj-russo",email:"dr.a.j.russo@gmail.com"}],book:{title:"Autism",slug:"autism-paradigms-recent-research-and-clinical-applications",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"190422",title:"Ph.D. Student",name:"Renee",surname:"Cachia",slug:"renee-cachia",fullName:"Renee Cachia",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Monash University",institutionURL:null,country:{name:"Australia"}}},{id:"190954",title:"Dr.",name:"Timo",surname:"Lorenz",slug:"timo-lorenz",fullName:"Timo Lorenz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190954/images/4729_n.jpg",biography:null,institutionString:null,institution:{name:"Freie Universität Berlin",institutionURL:null,country:{name:"Germany"}}},{id:"190980",title:"Prof.",name:"Marwa",surname:"Saleh",slug:"marwa-saleh",fullName:"Marwa Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",institutionURL:null,country:{name:"Egypt"}}},{id:"191006",title:"Dr.",name:"Alina",surname:"Rusu",slug:"alina-rusu",fullName:"Alina Rusu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Babeș-Bolyai University",institutionURL:null,country:{name:"Romania"}}},{id:"191313",title:"Dr.",name:"Michael",surname:"Fitzgerald",slug:"michael-fitzgerald",fullName:"Michael Fitzgerald",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:"Professor Michael Fitzgerald was the first Professor of Child and Adolescent Psychiatry in Ireland, specialising in Autism Spectrum Disorders. He trained at the Chicago Medical School, the Maudsley Hospital, London, Kings College Hospital London and the National Hospital for Nervous Diseases, London. He has a Doctorate in Autism. He has a large number of peer-reviewed publications and thirty books written, co-written or co-edited, including Japanese and Polish translations of some books. Professor Simon Baron-Cohen of the University of Cambridge described one of his books on Autism as “the best book I have read on Autism”. He also described him as an “exceptional scholar”. He has diagnosed just under 4,000 persons with Autism Spectrum Disorder since 1973. He has lectured extensively throughout the world including The Royal Society/British Academy, The British Library in London and also in New York, Buenos Aires, Tbilisi, Melbourne and many European countries as well as China, Malaysia and Hawaii.",institutionString:null,institution:{name:"Trinity College Dublin",institutionURL:null,country:{name:"Ireland"}}},{id:"195124",title:"Ms.",name:"Nomi",surname:"Reznik",slug:"nomi-reznik",fullName:"Nomi Reznik",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"195125",title:"Prof.",name:"Kathrin",surname:"Heinitz",slug:"kathrin-heinitz",fullName:"Kathrin Heinitz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"195136",title:"Dr.",name:"Aya",surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",institutionURL:null,country:{name:"Egypt"}}},{id:"195244",title:"Ph.D. Student",name:"Elizabeth",surname:"Hughes Fong",slug:"elizabeth-hughes-fong",fullName:"Elizabeth Hughes Fong",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"195269",title:"Dr.",name:"Helen",surname:"Lee",slug:"helen-lee",fullName:"Helen Lee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"open-access-funding",title:"Open Access Funding",intro:"
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\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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