\r\n\tThe main idea for any data or information processing system for those aspects of aggregating the data or computing the hierarchy of various process elements is that they should not only be machine-readable but also machine-understandable. Moreover, an adequate knowledge-based system is perceived to be, on the one hand, understandable by people, and on the other hand understandable by the machines. \r\n\tAs devices become smarter and produce data about themselves, it will become increasingly important for scientists to take advantage of more powerful tools and/or data integration techniques to help provide a common standard for information dissemination across the different platforms. To this end, the content of this book shows that technologies such as the semantic web, machine learning, deep learning, natural language processing, and learning analytics which encompasses the wider spectrum of the Linked Open Data (LOD) are of paramount. Therefore, the work presents two main drivers for the Linked Open Data technologies: (i) encoding knowledge about specific data and process domains, and (ii) advanced reasoning and analysis of the big data at a more conceptual level. \r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art within the Linked Open Data and the benefits of the methods – ranging from the semantics-aware techniques that exploit knowledge kept in (big) data to improve data reasoning (big analysis) beyond the possibilities offered by most traditional data mining techniques.
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He also completed a Master\\'s degree in Technology Management in 2011 and a Bachelors degree in Computer Science in 2007. He is a MIET member at the Institution of Engineering and Technology, UK. and a Graduate Member in the Institute of Electrical and Electronics Engineers, IEEE. He is a devoted researcher to Industry and Academia in operational, hardware and software fields of computing in areas such as Data Science, Machine Learning, Artificial Intelligence, Big Data and Advanced Analytics, Software Development and Programming, and Business Process Management. Therefore, Kingsley has had the opportunity to do case studies and work in interdisciplinary and cross-cultural teams of various business and academic units that serve multiple industries. This includes serving as a software programming lab tutor for undergraduate students. 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1. Introduction
Miscarriage also known as spontaneous abortion is the termination of pregnancy before the age of fetal viability or expulsion of fetus or embryo weighing less than 500g. It occurs naturally without any human intervention and complicates about 15–20% pregnancies globally. The age of fetal viability varies from country to country depending on the level of technological development and fetal salvage rate. The age of fetal viability in Norway is 16 weeks, in Australia its 20 weeks, 24 weeks in the UK, 26 weeks in Spain and Italy while in Nigeria the age of fetal viability is 28 weeks of gestation. Causes of miscarriage include morphologic/genetic/chromosomal abnormalities, immunological and endocrine factors, structural uterine anomalies, cervical incompetence, maternal infections and toxins. Miscarriage can be classified into threatened miscarriage, inevitable miscarriage, incomplete miscarriage, septic miscarriage, missed miscarriage, complete miscarriage and recurrent miscarriage. It profoundly affects the women. This chapter methodology derives from a synthesis of the available literature under the MESH search term miscarriage and focus group discussion of women attending a tertiary health facility in Southern Nigeria.
2. Miscarriage and maternal morbidity
Miscarriage can profoundly affect the health and wellbeing of the mother, either from the complications of the process itself or from the complications arising from the treatment and management of the condition or both depending on the stage of the pregnancy, the abortion type, the management instituted, the facility, the skill/expertise and quality of the care giver and the mother’s pre-pregnancy/pre-miscarriage health condition.
The complications can arise early, during or just after the process or manifest much later following the abortion process, also depending on several factors.
2.1 Early morbidities
2.1.1 Hemorrhage
Genital bleeding during or following miscarriage may be slight especially in early 1st trimester, but can also be severe and torrential with disastrous consequences in the second trimester when there is increased risk of placenta retention. This may occur more commonly in the developing countries like Nigeria where mothers may not present to health facilities for optimal management due to ignorance, illiteracy, poverty, non-availability or poor accessibility to health care facilities especially women in remote areas. Even when they do, they may present late to the health facility, at that further complications including severe anemia, sepsis, shock etc. may have set in, worsening maternal health and making management difficult in resource poor setting.
Management entails controlling the bleeding with use of oxytocics and delivery of the placenta by skilled and experienced care provider either by careful controlled cord traction or piece meal removal with sponge holding forceps and antibiotic therapy.
2.1.2 Anemia
Anemia may occur more commonly from hemorrhage or occasionally from sepsis due to hemolysis or both. Management of anemia in developing countries, especially when severe, may be particularly difficult because of the problems enumerated earlier. Even when mothers access health facility, there may not be blood banking services or when available may not be functioning optimally because of endemic problems of electricity and corruption with its negative multiplier effects in sub-Saharan Africa.
2.1.3 Septic incomplete abortion
Incomplete miscarriage occurs when some of the products of conception have been expelled while some are still retained in the uterus. This may cause bleeding which may range from mild to severe, causing blood loss anemia that may require blood transfusion. When bleeding is severe and not properly managed in time, post abortal pituitary necrosis resulting in Sheehan’s syndrome may occur, which later causes infertility which causes infertility later.
When some of the products of conception have been expelled and some retained, as may happen at gestational age 10 and above, this becomes substrate for microbial colonization and eventual infection. This infection may become severe causing systemic effects like fever, vomiting and prostration. Long term complications will include Asherman’s syndrome, chronic pelvic inflammatory disease, frozen pelvis and infertility as discussed in late maternal morbidities. Septicemia may occur and if not properly managed may result in multiple organ injury with sequelae.
2.1.4 Post-abortal sepsis
Post abortal sepsis usually results from complete miscarriage managed with inadequate or without prophylactic antibiotics. It may also occur if incomplete miscarriage is evacuated in an unhygienic environment or by unskilled care provider.
Mothers may present days, weeks or even months following miscarriage with varying degrees of abdominal pain, vaginal discharge or subfertility. These can be distressing and negatively affected maternal health. This can lead to loss of man hours in work place, school resulting in economic loss. Marital disharmony may also arise from infertility especially in sub-Saharan Africa where high premium is placed on child bearing. There is also a huge burden on health care delivery occasioned by these health challenges.
2.1.5 Shock
Shock could be hypovolemic or cardiogenic from massive hemorrhage or even septic from Gram negative sepsis with its very high mortality rate.
2.1.6 Organ injury
Though more common with induced abortion, uterine perforation can also occur following curettage or manual vacuum aspiration in the management of incomplete miscarriage. In acute state this can cause acute abdomen and may require hospitalization and even laparotomy. This affects maternal health in the short run and even in the long run depending on the nature and severity of the injury.
Bladder and injury to the intestinal injuries have also been reported. A couple times in the Accident and Emergency department of the University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria, patients have presented with large intestine protruding from the introitus through the uterus following manual vacuum aspiration for incomplete miscarriage done by unskilled health care provider.
More often, these will require laparotomy, repair of uterine perforation, bowel resection and anastomosis.
Bladder injury may even be more devastating when genito-urinary fistula manifest with continuous leakage of urine, with its accompanying morbidities- vulva excoriations/ itching, disgusting and nauseating offensive ammoniacal smell, social stigma, subfertility and sometimes marital disharmony and divorce. The emotional and psychological trauma is unparalleled.
2.2 Late morbidities
Some morbidities may not manifest immediately or early but become apparent months or even years following miscarriage or treatment of miscarriage.
2.2.1 PID/frozen pelvis
Pelvic inflammatory disease may complicate poorly treated incomplete miscarriage. This may subsequently lead to chronic PID especially in resource poor settings where people resort to self-management of the condition using sometimes unorthodox methods. They may present with chronic pelvic pain, dysmenorrhea or even amenorrhea depending on the severity, dyspareunia, chronic vaginal discharge and or low back pain. In some instances they may develop tubo-ovarian mass or abscess resulting in frozen pelvis. All these no doubt will negatively impact maternal health.
2.2.2 Asherman’s syndrome/infertility
Oligomenorrhea, amenorrhea and subfertility constitute Asherman’s syndrome. This results from scarring occasioned by healing from endometritis or healing from overzealous curettage in management of incomplete miscarriage.
2.3 Psychological/emotional morbidities
Prior miscarriage or even just perception of miscarriage can have profound and tremendous psychologic and emotional effects on mothers before or during subsequent gestations.
Studies have shown that compared to women without prior miscarriage, women with previous history of miscarriage had greater state anxiety in the second and third trimesters. Having a living child did not buffer state anxiety in women with a prior miscarriage. Attention to patterns of distress can contribute to delivery of appropriate support resources to women experiencing pregnancy after miscarriage and may help reduce risk for stress-related outcomes.
Just like other stressful experiences, the effects of miscarriage vary considerably across individuals [1], but for many women, miscarriage can be a tragic, and life-altering experience [2] and results in significant suffering [3, 4]. In the last 20 years, research on the emotional and psychological impact of miscarriage has grown, including studies of women who have experienced miscarriage exclusively and mixed-sample studies of various types of perinatal loss including miscarriage, stillbirth, and neonatal death, establishing an empirical foundation for understanding the livid experiences of miscarriage. Women who experience miscarriage worry about future pregnancies [4] and may perceive a subsequent pregnancy as especially precious and very desirable [5]. Pregnancy after miscarriage can be experienced as emotionally and psychologically distressing [4, 6]. According to descriptive studies of pregnancy following miscarriage, for some women the subsequent pregnancy is perceived as threatening [7] and involves tremendous vulnerability and anxiety related to uncertainty about its outcome [8].
Researchers who included comparison groups of mothers without a prior history of miscarriage have found that women with a history of miscarriage, experience significantly higher state anxiety, pregnancy-specific anxiety, worry, depression, and less attachment to the subsequent pregnancy than women without prior miscarriage [9, 10].
The most prevalent finding is that pregnancy-specific anxiety is higher in those with prior loss [10, 11], but more generalized distress does not differ significantly between the groups [10, 12] of perinatal loss. It has been demonstrated that pregnancy anxiety decreased significantly over the course of pregnancy [7]. focus group discussion with parturients attending antenatal care in Port Harcourt, Nigeria, revealed similar findings. The psychosomatic stress experienced by women who have had a prior miscarriage is better imagined then experienced. The feeling of being responsible for the loss coupled with the premium placed on childbirth leads to profound anxiety, sadness and depression. Understanding and empathy from healthcare providers and family members aided the recovery process.
3. Conclusion
Miscarriage or even just perception of miscarriage can have profound and tremendous psychologic and emotional effects on mothers before or during subsequent gestations. The associated early and long term complications are devastating for women. Every effort must be made to show understanding and empathy.
\n',keywords:"pregnancy loss, maternal health, miscarriage, women’s health, introduction",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65996.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65996.xml",downloadPdfUrl:"/chapter/pdf-download/65996",previewPdfUrl:"/chapter/pdf-preview/65996",totalDownloads:259,totalViews:161,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"June 5th 2018",dateReviewed:"October 18th 2018",datePrePublished:"March 6th 2019",datePublished:"June 12th 2019",readingETA:"0",abstract:"Miscarriage also known as spontaneous abortion is the termination of pregnancy before the age of fetal viability or expulsion of fetus or embryo weighing less than 500g. It occurs naturally without any human intervention and complicates about 15–20% pregnancies globally. The age of fetal viability varies from country to country depending on the level of technological development and fetal salvage rate. The age of fetal viability in Norway is 16 weeks, in Australia its 20 weeks, 24 weeks in the UK, 26 weeks in Spain and Italy while in Nigeria the age of fetal viability is 28 weeks of gestation. Causes of miscarriage include morphologic/genetic/chromosomal abnormalities, immunological and endocrine factors, structural uterine anomalies, cervical incompetence, maternal infections and toxins. It is classified into threatened miscarriage, inevitable miscarriage, incomplete miscarriage, septic miscarriage, missed miscarriage and complete miscarriage. Miscarriage has profound and tremendous psychologic and emotional effects on mothers before or during subsequent gestations. Every effort must be made to show understanding and empathy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65996",risUrl:"/chapter/ris/65996",book:{slug:"complications-of-pregnancy"},signatures:"John D. Ojule and Rosemary N. Ogu",authors:[{id:"213063",title:"Prof.",name:"Rosemary",middleName:null,surname:"Ogu",fullName:"Rosemary Ogu",slug:"rosemary-ogu",email:"rosemary.ogu@uniport.edu.ng",position:null,institution:{name:"University of Benin",institutionURL:null,country:{name:"Nigeria"}}},{id:"262641",title:"Dr.",name:"John",middleName:null,surname:"Ojule",fullName:"John Ojule",slug:"john-ojule",email:"ojulejohn@yahoo.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Miscarriage and maternal morbidity",level:"1"},{id:"sec_2_2",title:"2.1 Early morbidities",level:"2"},{id:"sec_2_3",title:"2.1.1 Hemorrhage",level:"3"},{id:"sec_3_3",title:"2.1.2 Anemia",level:"3"},{id:"sec_4_3",title:"2.1.3 Septic incomplete abortion",level:"3"},{id:"sec_5_3",title:"2.1.4 Post-abortal sepsis",level:"3"},{id:"sec_6_3",title:"2.1.5 Shock",level:"3"},{id:"sec_7_3",title:"2.1.6 Organ injury",level:"3"},{id:"sec_9_2",title:"2.2 Late morbidities",level:"2"},{id:"sec_9_3",title:"2.2.1 PID/frozen pelvis",level:"3"},{id:"sec_10_3",title:"2.2.2 Asherman’s syndrome/infertility",level:"3"},{id:"sec_12_2",title:"2.3 Psychological/emotional morbidities",level:"2"},{id:"sec_14",title:"3. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Huffman CS, Schwartz TA, Swanson KM. Couples and miscarriage: The influence of gender and reproductive factors on the impact of miscarriage. Women’s Health Issues. 2015;25(5):570-578'},{id:"B2",body:'Radford EJ, Hughes M. Women’s experiences of early miscarriage: Implications for nursing care. Journal of Clinical Nursing. 2015;24(11-12):1457-1465'},{id:"B3",body:'San Lazaro Campillo I, Meaney S, McNamara K, O’Donoghue K. Psychological and support interventions to reduce levels of stress, anxiety or depression on women’s subsequent pregnancy with a history of miscarriage: An empty systematic review. BMJ Open. 2017;7(9):e017802'},{id:"B4",body:'Geller PA, Kerns D, Klier CM. Anxiety following miscarriage and the subsequent pregnancy. A review of literature and future directions. Journal of Psychosomatic Research. 2004;56:35-45'},{id:"B5",body:'Cannella BL, Yarcheski A, Mahon NE. Meta-analyses of predictors of health practices in pregnant women. Western Journal of Nursing Research;40(3):425-446'},{id:"B6",body:'Bhat A, Infertility BN. Perinatal loss: When the bough breaks. Current Psychiatry Reports. 2016;18(3):31'},{id:"B7",body:'Cote-Arsenault D. Threat appraisal, coping, and emotions across pregnancy subsequent to perinatal loss. Nursing Research. 2007;56:108-116'},{id:"B8",body:'Côté-Arsenault D, Schwartz K, Krowchuk H, McCoy TP. Evidence-based intervention with women pregnant after perinatal loss. MCN: The American Journal of Maternal/Child Nursing. 2014;39(3):177'},{id:"B9",body:'Moore T, Parrish H, Black BP. Interconception care for couples after perinatal loss: A comprehensive review of the literature. The Journal of Perinatal & Neonatal Nursing. 2011;25(1):44-51'},{id:"B10",body:'Cote-Arsenault D. The influence of perinatal loss on anxiety in multigravidas. Journal of Obstetrics, Gynaecologic and Neonatal Nursing. 2003;32:623-629'},{id:"B11",body:'Armstrong D, Hutti M. Pregnancy after perinatal loss: The relationship between anxiety and prenatal attachment. Journal of Obstetrics, Gynecologic and Neonatal Nursing. 1998;27:183-189'},{id:"B12",body:'Franche RI, Mikail SF. The impact of perinatal loss on adjustment to subsequent pregnancy. Social Science and Medicine. 1999;48:1613-1623'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"John D. Ojule",address:null,affiliation:'
Department of Obstetrics and Gynaecology University of Port Harcourt, Port Harcourt, Nigeria
'},{corresp:"yes",contributorFullName:"Rosemary N. Ogu",address:"rosemary.ogu@uniport.edu.ng",affiliation:'
Department of Obstetrics and Gynaecology University of Port Harcourt, Port Harcourt, Nigeria
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Lusher, Paolo Conti, Wim Dokter, Pedro H. Hermkens and Jacob de Vlieg",authors:[{id:"72825",title:"Mr.",name:"Scott",middleName:null,surname:"Lusher",fullName:"Scott Lusher",slug:"scott-lusher"},{id:"72956",title:"Prof.",name:"Jacob",middleName:null,surname:"De Vlieg",fullName:"Jacob De Vlieg",slug:"jacob-de-vlieg"},{id:"125974",title:"Dr.",name:"Wim",middleName:null,surname:"Dokter",fullName:"Wim Dokter",slug:"wim-dokter"},{id:"125975",title:"Mr.",name:"Paolo",middleName:null,surname:"Conti",fullName:"Paolo Conti",slug:"paolo-conti"},{id:"125977",title:"Prof.",name:"Pedro",middleName:null,surname:"Hermkens",fullName:"Pedro Hermkens",slug:"pedro-hermkens"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"65069",title:"What Is Limulus Amebocyte Lysate (LAL) and Its Applicability in Endotoxin Quantification of Pharma Products",doi:"10.5772/intechopen.81331",slug:"what-is-limulus-amebocyte-lysate-lal-and-its-applicability-in-endotoxin-quantification-of-pharma-pro",body:'
1. Introduction
Endotoxins, a type of pyrogen, are natural compounds found in the outer cell membrane of Gram-negative bacteria and can impact over 30 biological activities. Endotoxin can lead to cell death by initiating complement activation. The Limulus amebocyte lysate (LAL) test was commercially introduced in the 1970s. LAL is derived from the blood cells, or amebocytes, of the horseshoe crab, Limulus polyphemus. Frederick Bang and Jack Levin observed that blood cells from horseshoe crabs were found to clot in the presence of endotoxin, and this technology was used in the development of endotoxin detection assays. Today, endotoxin tests are performed on raw and in-process materials, and for the final release of products in the pharmaceutical and medical device industries.
Limulus amebocyte lysate test is an aqueous extract of blood cells (amoebocytes) which obtain from the horseshoe crab (Limulus polyphemus). LAL reagent reacts with the bacterial endotoxins or lipopolysaccharide (LPS). LAL test is recommended in all international pharmacopeias as the method for finding bacterial endotoxins. Gram-negative bacteria produce endotoxins (pyrogen). Exceptionally Bacillus thuringiensis, a Gram-positive bacteria produce delta toxin as endotoxins [1] (Figures 1 and 2).
Figure 1.
Activation of inflammation in body [1]. Note: LPS, lipoglycan. LAL test used according to the U.S. Food and Drug Administration (FDA) [2] guidelines Substituted for the U.S. Pharmacopeia (USP) pyrogen test (rabbit fever test) European Pharmacopeia (EP) Japanese Pharmacopeia (JP) [3]. LAL is used for human injectable drugs, animal injectable drug, medical devices, raw materials used in production, in process quality control.
Figure 2.
Horseshoe crab [1].
2. Applications of the LAL test in the pharmaceutical industry
Among the most well-known and important applications of the LAL test are the ones related to the pharmaceutical industry. It can be said that the most common pyrogens in pharmaceutical products are endotoxins, which is why the pyrogen tests on rabbits have been replaced by the LAL test according to the recommendations of the international pharmacopeia. One of the reasons that has made the LAL test prevail in the pharmaceutical industry is the careful avoidance by the LAL manufacturers of bringing harm to live animals during both production and testing. It is important to clarify that the crabs, from which part of the hemolymph used for the LAL test was extracted, are returned to alive to their natural habitat with no lasting problems after the extraction.
3. Methods to determine the pyrogen in pharma products
Chromogenic method: based on the producing color after cleavage of a synthetic peptide-chromogen complex.
Turbidimetric method: based on forming turbidity after cleavage of an endogenous substrate.
End point method: 0.005 endotoxins units (EU) per ml.
Kinetic method: 0.001 endotoxins units (EU) per ml.
Kinetic method: time taken to reach a specific absorbance at 405 nm (onset time) is determined. The assay requires specialized instrumentation. Take optical density readings at regular intervals. The greatest sensitivity, λ, of lysate is 0.001 EU/ml.
Endpoint chromogenic method [5]: the released amount of pNA can be calculated after a fixed incubation period. A standard curve, consisting of measured optical density plotted against known standard endotoxin concentration. Later used to determine concentrations in the product. The greatest sensitivity, λ, is 0.005 EU/ml UV/visible spectrophotometers.
4. Test performance
Add volume of lysate to a volume of product dilution. Incubating the reaction mixture at 37.5°C. Endotoxin in the reaction would activate the LAL reagent. Cleave small chromogenic peptides and liberates pNA. pNA, color is yellow and absorbs light at 405 nm. For samples that absorb at 405–410 nm, Diazo-coupling agent modification may be used. In this method, pNA reacted with nitrite in hydrochloric acid, ammonium sulfamate and N-(1-naphthyl)-ethylenediamine (NEDA). Absorbs at a range between 540 and 550 nm. A standard curve is used to establish concentrations in product specimens.
5. Materials and equipment
10 × 75 mm fully depyrogenated borosilicate glass culture tubes (Associates of Cape Cod, Inc. catalog numbers TB050).
Optical reader is capable of reading at 405 nm, or at 540–550 nm for the diazo method. Incubator is able to maintaining 37 ± 1°C. A water bath can be used for the endpoint test tube method. Both devices should have a uniform heat distribution. Test tube racks to hold the tubes and/or incubate dilution and reaction tubes. Micropipettes or disposable pipette tips free of interfering endotoxins and glucans are recommended. Vortex-type mixer, Para film (American National Can™) and hot-air oven with the capacity to heat to at least 250°C for depyrogenation of glassware.
6. Chemicals and reagents
Limulus amebocyte lysate (LAL), LAL reconstitution buffer, control standard endotoxins (CSE), solution 1 (nitrite), solution 1A (0.1 N hydrochloric acid), solution 2 (ammonium sulfamate), solution 3 (N-(1-naphthyl)-ethylenediamine (NEDA)), LRW.
The endotoxins limit for USP/BP sterile WFI is only 0.25 EU/ml; therefore, sterile WFI may contain detectable endotoxins and be unsuitable for use. Use certified LRW to make dilutions of standards, and to prepare positive controls.
7. Quality control steps or test procedure
7.1 Specimen collection and preparation
Collect aseptically containers that are free of detectable endotoxins in depyrogenated glassware apparatus.
7.2 pH of the specimen
The pH must be 6–8. Adjust the pH of the product specimen with dilute HCl, NaOH, or buffer (free of endotoxins). Dilute concentrated HCl or NaOH with LRW. Use a volume that will not lead to significant dilution of the test specimen. Dilution (LRW) alone can overcome the issue sometimes.
7.3 Method of lysate reconstitution
Gently tap the vial of lysate. Loose material fall to the bottom. Break the vacuum by lifting the gray stopper. Do not contaminate the mouth of the vial. Remove and discard the stopper. Start the reconstituted lysate with 3.2 ml buffer. Avoid vigorous mixing that may cause excessive foaming and a loss of sensitivity. Wrap the vials with parafilm and store in a cold place (2–8°C) when not in use and use within 8 h of reconstitution.
7.4 Lysate storage conditions
7.4.1 Lyophilized lysate
This is relatively well stable and, if stored properly, will retain full activity through the expiration date on the label. Store the product at 2–8°C. Excess temperature over 37°C cause rapid deterioration, loss of sensitivity and distinct yellowing.
7.5 Control standard endotoxins (CSE)
Each vial of control standard endotoxins (CSE) contains 10 ng of endotoxins. Reconstitute CSE with the volume mentioned on the Certificate of Analysis (CA, which gives the potency of the CSE). Gently knocks the vial of control standard endotoxins (CSE) to cause loose material to fall to the bottom. Break the vacuum by lifting the gray stopper. Do not contaminate the mouth of the vial. Remove the stopper and place it in a cold place aseptically for reuse.
Reconstitute CSE with the volume specified on the Certificate of Analysis (CA, which gives the potency of the CSE) and as directed in the package insert. Place the stopper. Vortex the vial for 40–60 s to form a homogenous mixture. Discard solution if not used immediately, vortex the vial for 30 s prior to use.
7.5.1 Mixing and incubation
Read the tubes UV/visible spectrophotometers (Table 1).
CSE + lysate
Incubation time (min)
50 μl of 0.50 EU/ml + 50 μl
30
50 μl of 0.250 EU/ml + 50 μl
30
50 μl of 0.125 EU/ml + 50 μl
30
50 μl of 0.0625 EU/ml + 50 μl
30
Table 1.
Dilution mixing and incubation time.
Sample + lysate
Incubation (min)
50 μl of sample + 50 μl
30
7.5.2 Mixing and incubation
Stop the reaction by adding 50% acetic acid. Add 0.025 ml (25 μl) read the optical density (OD) at 405 nm read the test.
7.6 Stop reaction solution preparation
7.6.1 Read the test
Reconstitute vial 1 with entire contents of vial, reconstitute vial 2 with 4 ml of water, reconstitute vial 3 with 4 ml of water. Add 0.05 ml (50 μl) of solution 1 (sodium nitrite reconstituted with dilute HCL). Add 0.05 ml (50 μl) of solution 2 (ammonium sulfamate). Add 0.05 ml (50 μl) of solution 3 (NEDA) use new pipette tip agitate the plate to mix. Full color (magenta) should develop immediately. Read the test at 540–550 nm.
7.6.2 Positive control
7.6.2.1 Make standard curve
Positive control must be included to verify that it is appropriate to use the parameters of a previous (archived) standard curve to calculate endotoxin concentrations.
7.6.3 Negative controls
LRW negative controls should be included with each test
1: Equation of straight line (results)
y = mx + c
m = slop
x = endotoxin concentration,
c = y-intercept and
y = mean absorbance
X = y-c/m
Example calculation
7.6.4 Sample preparation
Prepare sample solutions by dissolving or diluting drugs (pH 6.0–8.0). The pH may be adjusted by the use of acid, base, or suitable buffers as recommended. Do not exceed the MVD or MCV while making dilutions and adjusting the pH.
7.6.5 Maximum valid dilution (MVD)
MVD = (endotoxin limit × concentration of sample solution)/(λ)
Endotoxin limit given in USP, concentration of a sample of the label, λ: the labeled lysate sensitivity in the gel-clot technique (IU/ml) or the lowest concentration used in the standard curve for the turbidimetric or chromogenic techniques.
7.6.6 Minimum valid concentration (MVC)
MVC = λ/endotoxin limit
λ: the labeled lysate sensitivity in the gel-clot technique (IU/ml) or the lowest concentration used in the standard curve for the turbidimetric or chromogenic techniques.
Sample 1
Endotoxin limit: 0.5 EU/ml
Concentration of sample: 100 mg/ml
λ: 0.06 EU/ml
MVD = 0.5 EU/ml × 100 mg/ml/0.06 EU/ml
MVD = 833
Add 1 ml of sample 1 in to 832 ml of LRW. Prepare sample 2 in using the same method.
7.6.7 Preparation of CSE dilutions
Using 10-fold and 2-fold dilution methods prepare the following dilutions of control standard endotoxins (CSE)
0.5 EU/ml
0.25 EU/ml
0.125 EU/ml
0.0625 EU/ml
Reconstitute the lysate with 3.2 ml of buffer provided with it. Follow the standard procedure for reconstitution.
7.6.7.1 Mixing and incubation
Stop reaction.
For sample 1 and sample 2:
Stop the reaction by adding 50% acetic acid. Add 0.025 ml (25 μl) (Tables 2 and 3).
CSE + lysate
Incubation (min)
50 μl of 0.50 EU/ml + 50 μl
30
50 μl of 0.250 EU/ml + 50 μl
30
50 μl of 0.125 EU/ml + 50 μl
30
50 μl of 0.0625 EU/ml + 50 μl
30
50 μl of sample 1 + 50 μl
30
50 μl of sample 2 + 50 μl
30
Table 2.
Different dilution of CSE and lysate.
Table 3.
Make two replicates of each CSE and sample preparation to reduce any errors.
8. Results
Use Microsoft word for further calculations and results. Make standard curve and endotoxin concentration (Figure 3).
Figure 3.
Validation of standard curve.
R2 = coefficient of determination
R = correlation coefficient
R ≥ 0.98
R2 = 0.99
R = √R2 = 0.99
Equation of straight line
y = mx + c
m = slop
x = endotoxin concentration
c = y intercept
y = mean absorbance
Equation of straight line
Y = 1.019X − 0.026
8.1 Rearranging the equation
X = Y + 0.026/1.019
m = slop = 1.019,
C = y intercept = 0.026,
Y = mean absorbance,
X = endotoxin concentration
8.2 Sample 1
X = Y + 0.026/1.019
Y = 0.300, X = 0.300 + 0.026/1.019, X = 0.319EU/ml
8.3 Sample 2
X = Y + 0.026/1.019
Y = 0.335, X = 0.335 + 0.026/1.019, X = 0.354 EU/ml
8.4 Advantages of Gel Clot method
Gel Clot LAL provides a simple positive/negative result and is most often mentioned in pharmacopeial monographs as the official referee test.
This is very easy to perform.
This is not time consuming.
Accuracy is 100 percent.
The LAL Gel-Clot assay, gives a more quantitative measurement of endotoxin over a range of concentrations.
8.5 Standard operating procedure
8.5.1 Material
Gel Clot lysate for 20 test, Gel Clot standard 0.5 EU/Vial, LAL reagent water (LRW 50 ml).
8.5.2 Reconstitution
Lysate: add 2 mL LRW and mix it slowly. Do not shake and avoid foaming. Transfer 0.1 ml in 20 test tubes. Store it at –degree (in freezer).
Standard: Add 2 mL of LRW in the vial and mix it well for 15 min. Store the vial at 2–8°C. Storage life is 15 days.
8.5.3 Procedure
Take three test tubes and mark them as test, positive control and negative control [1].
Add your sample in test tube marked as sample. Add standard in test tube marked as Positive control. Add LRW in test tube marked as negative control. Incubate the test tubes at 37 + 2°C for 60 min. After an incubation, check for the gel by inverting the test tube. If the material remains firm in the bottom of the test tube, it means gel has formed. This positive if the material gets the flow down, it means gel has not formed. This means negative.
8.5.4 For water for injection
Take similarly three test tubes as above and add water for injection (WFI) in test tube marked as sample. And proceed as above. The results should be as follows (Table 4):
Sample
Positive control
Negative control
Result
−ve (gel not formed)
+ve
−ve
Pass
Sample
Positive control
Negative control
Result
+ve (gel formed)
+ve
−ve
Fail
Table 4.
Results shown sample pass or not.
8.5.5 For product
We have to make dilution.
Example: If the product endotoxin limit is 1 EU/ml, then we have to make the dilution as follows:
Since we are using 0.25 EU/ml, this is called lambda. Divide the endotoxin limit of product with lambda
Note: All reagents must be stored in refrigerator at 2–8°C.
8.5.7 Preparation of acetic acid 0.8 m
Dissolve 45.6 ml of acetic acid in 1 liter of distilled water. The final concentration of acetic acid is 0.8 M. This solution can be stored for 3 months.
Remove the plastic cover. Wipe off with 70% alcohol around the rubber cap and top portion of every vial. Remove the aluminum cap with sterile and pyrogen free forceps and then cover with depyrogenated aluminum foil to avoid any Endotoxin contamination. (2.8 ml LAL water vial is provided with Endotoxin vial, concentration is mentioned on the label). Pour whole quantity of LAL water into the ET vial and cover with foil. Mix vigorously for at least 10 s by vortexer. During stirring solution must not touch the foil.
Storage: Store reconstituted Endotoxins solution at 4°C in a refrigerator for 14 days. The solution can also be stored at –20°C for a month. Avoid freezing during storage.
Note: Stir every time vigorously before use.
Toxicolor lysate
(Buffer vial 0.35 ml and LAL water are provided with Lysate. Sensitivity is mentioned on the certificate). After taking from the refrigerator, pour whole quantity of buffer and 0.35 ml LAL water into the lysate vial as soon as possible, covers with foil. Then quickly stir to dissolve. Avoid air bubbling during stirring. Place the vial in ice water bath for 2–3 min before use.
Note: Be sure that the reagent is completely dissolved. This reagent must be reconstituted just before use. The reagent is extremely sensitive and must be consumed at one time. Storage should be avoided, but can be stored at −20°C in 0.1 ml dispensed quantities in small test tubes. Use stored lysate if the color is not changed. Reconstituted lysate may only be deep frozen once.
8.5.8 Diazo coupling reagent
Four bottles are provided with one set, marked as 7, 8, 9 and 10s respectively. Transfer whole quantity of bottle no. 7 s into bottle no. 8 s. Then add 12 ml distilled water into each of bottle no. 9 s and 10s. Ultimately, we will have three bottles 8, 9, and 10 s, which are used stepwise to block the reaction.
9. Pre-test preparations
9.1 pH of the sample
The pH of the sample is adjusted by pyrogen free 0.1 N NaOH or 0.1 N HCl. The pH of the sample should be between 6.0 and 8.0.
9.2 Test tubes settings
Arrange test tubes in two stands as under; stand 1—test tubes for sample and standard dilutions; stand 2—test tubes for reaction.
10. Procedure
10.1 Sample preparations
Take 0.05 ml well-mixed sample into small test tubes. If required, make 1/10 dilution of the sample with Pyrogen free water as Below, Take 4.5 ml of pyrogen free water in the test tube. Then add 0.5 ml of well-mixed sample. Vortex mixing for a few seconds.
Take 0.1 ml into a small test tube for further process.
10.2 Standard preparation
Make a dilution of the endotoxin (concentration 0.470 EU/ml) according to the product limit. For making 0.235 EU/ml (if the product limit is 0.25) proceed as follows;
Take 0.05 ml of the reconstituted endotoxin in the test tube after stirring. Add 0.05 ml of pyrogen free water and vortex to mix. Now the final dilution is 0.235 EU/ml.
Take 0.05 ml of step 2 into a small test tube for further process.
10.3 Blank preparation
Pour 0.05 ml of pyrogen free water (being used in the test) in small test tube as a blank for further process.
Lysate addition
Place the tube stand for small test tubes (containing the tubes of blank, standard and diluted samples) in ice water bath or suitable ice water container. Add 0.05 ml of lysate to all of the tubes as soon as possible. Stir the contents of every tube soon after the addition of lysate for a few seconds. Avoid foaming.
10.4 Incubation
Soon after the addition of lysate, place the test tube rack in the incubator set at 32.5 + 2.5°C for 30 min. The tube rack can be placed in the water container placed in the incubator.
10.5 Blocking the reaction
After completion of the incubation period, place tube rack in ice water bath, then blocks the reaction immediately from one of the two methods mentioned below:
By acetic acid
Add 0.4 ml of 0.8 M acetic acid into each tube and stir to mix.
By diazo coupling reagent
Three bottles of the reagent are used as under;
Add 0.5 ml from bottle no 8 s to each tube and stir to mix.
Add 0.5 ml from bottle no 9 s to each tube and stir to mix.
Add 0.5 ml from bottle no 10s to each tube and stir to mix.
Absorbance reading (using spectrophotometer) measurement at 405 nm
If 0.8 M acetic acid is used to block the reaction, then absorbance reading is taken at 405 nm.
Note: The readings. Glass photocell is used for reading at 405 nm. Because the volume of the tube content is not sufficient, the distilled water is added to each tube and is stirred to mix.
10.6 Measurement at 545 nm
When Diazo coupling reagent is used for blockage of the reaction then the reading is taken at 545 nm. Note all the readings.
Note: Distilled water is used for reference in both cases.
11. Results from software
All the absorbance readings are fed in the “Software reader for window version 1.51” to collect the results.
11.1 Manual measurement of endotoxin
Following Formula is used to calculate the results
Where the lowest sensitivity of lysate, M is the maximum dose/kg body weight and K is constant having value equal to 5.
MVD=concentration of product in1ml/MVC
ELC=XMVD
Conflict of interest
The author(s) confirm that this chapter content has no conflict of interest.
\n',keywords:"Limulus amebocyte lysate, lipopolysaccharide, endotoxin, blood, bacteria, detection, horseshoe crab, pharmacopeias, delta, toxin, gel, chromogenic, acetic acid, Gram-negative",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65069.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65069.xml",downloadPdfUrl:"/chapter/pdf-download/65069",previewPdfUrl:"/chapter/pdf-preview/65069",totalDownloads:887,totalViews:0,totalCrossrefCites:1,dateSubmitted:"March 8th 2018",dateReviewed:"September 5th 2018",datePrePublished:"January 8th 2019",datePublished:null,readingETA:"0",abstract:"Limulus amebocyte lysate (LAL) is an aqueous extract of blood cells (amoebocytes) from the horseshoe crab, Limulus polyphemus. LAL reagent reacts with bacterial endotoxin and lipopolysaccharide (LPS), which is a membrane constituent of Gram-negative bacteria. This reaction is the base on the LAL reagent, which is then used for the finding and quantification of bacterial endotoxins. The Gel Clot LAL test provides very simple positive or negative result and is most often mentioned in international pharmacopeia monographs as the official test. Gel Clot assay is a qualitative LAL test for detection of Gram-negative bacteria endotoxins. The Gel Clot assay is run in tubes that are placed in a water bath or in dry heated oven at 37°C. After a one-hour incubation period, the tubes are flipped 180°. A firm clot that stays in the bottom of the tube indicates a positive reaction. If the liquid flows down the side of the tube, the result is negative for endotoxins.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65069",risUrl:"/chapter/ris/65069",signatures:"Yasir Mehmood",book:{id:"7240",title:"Growing and Handling of Bacterial Cultures",subtitle:null,fullTitle:"Growing and Handling of Bacterial Cultures",slug:"growing-and-handling-of-bacterial-cultures",publishedDate:"December 4th 2019",bookSignature:"Madhusmita Mishra",coverURL:"https://cdn.intechopen.com/books/images_new/7240.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"204267",title:"Dr.",name:"Madhusmita",middleName:null,surname:"Mishra",slug:"madhusmita-mishra",fullName:"Madhusmita Mishra"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Applications of the LAL test in the pharmaceutical industry",level:"1"},{id:"sec_2_2",title:"2.1 Limulus amebocyte lysate (LAL) test types",level:"2"},{id:"sec_4",title:"3. Methods to determine the pyrogen in pharma products",level:"1"},{id:"sec_5",title:"4. Test performance",level:"1"},{id:"sec_6",title:"5. Materials and equipment",level:"1"},{id:"sec_7",title:"6. Chemicals and reagents",level:"1"},{id:"sec_8",title:"7. Quality control steps or test procedure",level:"1"},{id:"sec_8_2",title:"7.1 Specimen collection and preparation",level:"2"},{id:"sec_9_2",title:"7.2 pH of the specimen",level:"2"},{id:"sec_10_2",title:"7.3 Method of lysate reconstitution",level:"2"},{id:"sec_11_2",title:"7.4 Lysate storage conditions",level:"2"},{id:"sec_11_3",title:"7.4.1 Lyophilized lysate",level:"3"},{id:"sec_13_2",title:"7.5 Control standard endotoxins (CSE)",level:"2"},{id:"sec_13_3",title:"Table 1.",level:"3"},{id:"sec_14_3",title:"7.5.2 Mixing and incubation",level:"3"},{id:"sec_16_2",title:"7.6 Stop reaction solution preparation",level:"2"},{id:"sec_16_3",title:"7.6.1 Read the test",level:"3"},{id:"sec_17_3",title:"7.6.2 Positive control",level:"3"},{id:"sec_17_4",title:"7.6.2.1 Make standard curve",level:"4"},{id:"sec_19_3",title:"7.6.3 Negative controls",level:"3"},{id:"sec_20_3",title:"7.6.4 Sample preparation",level:"3"},{id:"sec_21_3",title:"7.6.5 Maximum valid dilution (MVD)",level:"3"},{id:"sec_22_3",title:"7.6.6 Minimum valid concentration (MVC)",level:"3"},{id:"sec_23_3",title:"Table 2.",level:"3"},{id:"sec_23_4",title:"Table 2.",level:"4"},{id:"sec_27",title:"8. Results",level:"1"},{id:"sec_27_2",title:"8.1 Rearranging the equation",level:"2"},{id:"sec_28_2",title:"8.2 Sample 1",level:"2"},{id:"sec_29_2",title:"8.3 Sample 2",level:"2"},{id:"sec_30_2",title:"8.4 Advantages of Gel Clot method",level:"2"},{id:"sec_31_2",title:"8.5 Standard operating procedure",level:"2"},{id:"sec_31_3",title:"8.5.1 Material",level:"3"},{id:"sec_32_3",title:"8.5.2 Reconstitution",level:"3"},{id:"sec_33_3",title:"8.5.3 Procedure",level:"3"},{id:"sec_34_3",title:"Table 4.",level:"3"},{id:"sec_35_3",title:"8.5.5 For product",level:"3"},{id:"sec_36_3",title:"8.5.6 LAL test reagents (chromogenic method)",level:"3"},{id:"sec_37_3",title:"8.5.7 Preparation of acetic acid 0.8 m",level:"3"},{id:"sec_38_3",title:"8.5.8 Diazo coupling reagent",level:"3"},{id:"sec_41",title:"9. Pre-test preparations",level:"1"},{id:"sec_41_2",title:"9.1 pH of the sample",level:"2"},{id:"sec_42_2",title:"9.2 Test tubes settings",level:"2"},{id:"sec_44",title:"10. Procedure",level:"1"},{id:"sec_44_2",title:"10.1 Sample preparations",level:"2"},{id:"sec_45_2",title:"10.2 Standard preparation",level:"2"},{id:"sec_46_2",title:"10.3 Blank preparation",level:"2"},{id:"sec_47_2",title:"10.4 Incubation",level:"2"},{id:"sec_48_2",title:"10.5 Blocking the reaction",level:"2"},{id:"sec_49_2",title:"10.6 Measurement at 545 nm",level:"2"},{id:"sec_51",title:"11. Results from software",level:"1"},{id:"sec_51_2",title:"11.1 Manual measurement of endotoxin",level:"2"},{id:"sec_56",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Devleeschouwer M, Cornil M, Dony J. Studies on the sensitivity and specificity of the Limulus amebocyte lysate test and rabbit pyrogen assays. Applied and Environmental Microbiology. 1985;50(6):1509-1511'},{id:"B2",body:'Food, Administration D. Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices. Center for Drug Evaluation and Research. Rockville, MD, USA: Food and Drug Administration; 1987'},{id:"B3",body:'Committee JPE. The Japanese Pharmacopoeia. Tokyo, Japan: The Society of Japanese Pharmacopoeia; 2006. p. 15'},{id:"B4",body:'Ong KG, Leland JM, Zeng K, Barrett G, Zourob M, Grimes CA. A rapid highly-sensitive endotoxin detection system. Biosensors and Bioelectronics. 2006;21(12):2270-2274'},{id:"B5",body:'Scully M, Newman Y, Clark S, Kakkar V. Evaluation of a chromogenic method for endotoxin measurement. Thrombosis Research. 1980;20(2):263-270'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Yasir Mehmood",address:"yasir_dpharm@hotmail.com",affiliation:'
Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Pakistan
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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. 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