Bioanalysis in the NHS and industry

  • Created by: LBCW0502
  • Created on: 10-11-18 14:30
What is bioanalysis?
Studying samples obtained from living organisms. Physical/chemical/biochemical or a combination of methods applied to the study of the composition (drugs, metabolites) of biological samples (body fluids and tissues). Can be quantitative/qualitative
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What is an assay?
The overall method used for measurement of an analyte or a group of analytes in a sample
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Give examples of how bioanalysis is used in the NHS
Diagnosis, monitoring treatment, screening, prognosis, research
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Give examples of how bioanalysis is used in industry
Research, clinical trials, quality control and regulatory approval
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What are the tasks of a pharmaceutical analytical chemist?
Understand level of measurement/analysis required (physical size/shape, m.p, pKa/solubility, Mwt, molecular structure, higher level structure (1/2/3/4), biological sequences), complex system. Balance: cost/speed/sensitivity/selectivity/specificity
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Outline features of concentration range in blood
Wide range of substances can be identified in a blood sample. E.g. albumin 40-50 mg/mL, samples 1 ng/mL, samples in 1 mg/mL.
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Describe features of therapeutic drug concentration
Depends on the drug (generally ranges from ng/mL to micrograms/mL. E.g. digoxin (0.8-2.0 ng/mL), gentamicin (5-10 micrograms/mL). Peak often not measured. Trough (<1 microgram/mL). If trough remains high - toxicity
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How are components quantified in biological samples?
Biochemical methods (separation techniques, immunoassays). Physical methods (separation techniques, spectroscopy). A combination of techniques (depends what you are looking for, concentration range and what the matrix is)
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State features of a typical BP monograph
Tests for: identification, quantification and impurity limits e.g. spectroscopy, HPLC etc.
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What are the main methods in analysing the samples?
Automated analyser (highest level of expertise, better precision, high start up cost, low running cost per sample, larger volume of samples), kit analyser, manual methods (need trained person, low start-up cost, high running cost/sample, small size)
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Outline the process of biochemical analysis for a patient
Clinical question - request form - patient sampled - transit to laboratory - reception/identification - analysis - QC - data collection - interpretation - report - biochemical answer
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Give examples of sampling errors
Haemolysis or plasma water diffuses into the interstitial space during blood sampling (small needle), not enough specimen, error in timing, wrong container (clot/no clot), wrong sampling size, incorrect storage
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Describe the requirements for the specimen needed for bioanalysis? (1)
Correct specimen (request form should have all information clearly stated, collected from right area, use correct specimen tube). Must not be contaminated, must be stored/analysed in timely manner
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Describe the requirements for the specimen needed for bioanalysis? (2)
From patients with dangerous infections (e.g. hepaptitis B and HIV) must be labelled with a yellow 'dangerous specimen' sticker
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Give an example of a case history involving bioanalysis (1)
Blood specimen from female has higher levels of serum potassium concentration (indicates hyperkalaemia). Unknown information about storage (affects sample, unreliable, potential errors - wrong container, haemolysis of cells)
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Give an example of a case history involving bioanalysis (2)
Need to correctly identify sample, analytical procedures need to be quality controlled
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State features of quality control
Diagnosis - monitoring treatment, screening. Prognosis - all depends on laboratory results. Variables - analytical, biological
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Describe features of analytical methods
Performance of analytical method needs to be determined first. Precision, accuracy, sensitivity, specificity, intervals, quality assurance, range and linearity
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What is the difference between precision and accuracy?
Precision is the reproducibility of an analytical method. Accuracy is how close the measured value is to the actual value
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What is analytical sensitivity?
The ability to distinguish the differences in analyte concentration in a sample
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What is analytic specificity?
The ability to distinguish between different analytes
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State different analytical techniques throughout time
Distillation, precipitation, electrophoresis, column chromatography, paper chromatography, TLC, RIA, GLC, GC-MS, ELISA, HPLC, ion-pair extraction, capillary electrophoresis, LC-MS, UPLC (more sensitivity from grams to yg)
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Outline features of analytical specificity
Highly specific assays (immunoassays), highly specific analytical technologies (NMR/MS). Separating analytes before analysis (electrophoresis/chromatography). Combination of techniques increases specificity
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How can valid results to achieved? (1)
Poor precision results in low sensitivity/large number of repeats. Automation of analysis improves precision (removes scattered data/human errors). Sensitivity improved by averaging repeated measurements
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How can valid results to achieved? (2)
Accuracy improved by having good standard/frequent calibration of instrument. Specificity improved by use of a combination of measurements. Range of values within which the precision/accuracy of analytical technique is acceptable
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Describe features of quality assurance
Ensuring analysis is reliable. Achieved by regular measurement of quality control samples (measurements of known standards). External QA programmes involved measurement of identical samples from several laboratories to ensure results are the same
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What are the biological variations in results?
Sex, age, diet, timing, location/position of subject, stress/anxiety, effect of exercise, medical history, pregnancy, menstrual cycle, drug history
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What are the challenges in measuring pharmaceutical efficiency in human?
Small biological variations (good control), large biological variations (little control). E.g. high creatinine is a sign of renal dysfunction but it is proportionate to muscle mass (will elevate if ingested high protein diet)
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What are the ideal results for bioanalysis?
Values in test distinct from values in diagnostic test with 100% specificity and sensitivity. Not ideal to have overlapping of results from control (placebo) and test
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What is specificity?
How common positive results are correct. High specificity - low chance of false positive result
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What is sensitivity?
How common negative results are correct. High sensitivity - low chance of false negative result
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What is a false negative result?
When values in test overlap with values in control, located before diagnostic cut off
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What is a false positive result?
When values in control overlap with values in test, located after diagnostic cut off
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What is sensitivity and specificity dependent on?
Diagnostic cut off. If the diagnostic cut off is within the values in test, there is high specificity and low sensitivity. If the diagnostic cut off is within the values in control, there is low specificity and high sensitivity
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Outline features of interval (reference interval)
An arbitrary interval to define the 'normal range' e.g. 95% of data. 68-95-99.7 rule (+ or - 1,2,3). Can be useful in setting action limits
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Summarise interpretation of results (1)
Appreciate characteristics of test. Variability in results due to analytical/biological factors. Reference interval is a guide to probability of being normal/abnormal. Different reference interval depends on subject (age, gender)
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Summarise interpretation of results (2)
Odd results should be repeated. Need to look at results placed in clinical context as important as the numbers - must understand statistics
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“Cholestasis, even of short duration, results in an increased enzyme activity to at least twice the upper end of the ALP reference interval (80- 280 U/L).”
Cholestasis, even of short duration, results in an increased enzyme activity to at least 560 U/L
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“For historical reasons many occupational and other health checks include urine glucose testing, which may reveal unsuspected diabetes. However, the false-negative rate for this test is unacceptably high...”
Test has low sensitivity but does not mention specificity
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Patient in treatment where 1% experienced side effects. Diagnostic test has 90% sensitivity and 91% specificity. Test result came out positive. What is the chance of the patient developing side effects?
1 in 10. Out of 1000, 10 and 990, out of 10, 1 and 9, out of 990, 89 and 901. 9/89 approximately 1 in 10
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Describe features of point of care analysis
For robust and simple to use tests. Convenience, can get results quickly (remove unnecessary anxiety). Can be used in hospital theatres, clinics, homes and shopping centres. Diabetic patients monitoring blood sugar level. Pregnancy test
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What are the disadvantages point of care analysis?
Relatively more expensive. Operator errors. Need comprehensive instructions. Need training sessions (ward-based blood gas analyser). Errors (instrument calibration/cleaning, misuse of QC samples, incorrect storage. Vary quality of instrument
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Outline a case history which involves analysis of a blood sample
High blood glucose levels indicating diabetes. Timing of test was inappropriate (patient consumed large amounts of refined carbohydrate). More appropriate to do a fasting glucose test
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Describe features of bioanalysis in industry
Research for new compounds. Exposure-response relationship for efficacy, safety, quality. Measure drug and metabolites for bioanalysis in industry
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Describe features of regulatory requirements
Need to have evidence for efficacy, safety and quality for application of licenses. Most evidences (data) come from bioanalysis and tests. Example of important guidelines - ICH (international council harmonisation)
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Give an example of bioanalysis in industry - antibody drug conjugates (1)
Antibody drug conjugate as a targeted drug delivery. Consists of antibody, linked and payload. ADC binds to tumour specific antigen. Endocytosis occurs. Enzymatic linker cleavage in lysosome. Release of cytotoxin into cell
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Give an example of bioanalysis in industry - antibody drug conjugates (2)
Measure PK of ADC dependent on antibody, linker and payload. Inject into subject - analyse plasma/tumour
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What are the challenges with bioanalysis in industry?
One species might be responsible for efficacy, another might be for toxicity. Amount of sample available. Drug may be released through freezing and thawing cycles. Cytotoxin stability issues. Samples - plasma, tumour tissue
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Describe features of bioanalysis methods developed
Drug (free drug/unconjugated, antibody conjugated). Antibody (drug conjugated antibody, total antibody, naked antibody). Small molecule catabolites. Antibody conjugated. Drug: antibody ratio
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Give examples of bioanalysis methods developed
Ligand-binding assay (conjugated antibody, total antibody, anti-therapeutic antibody). LC-MS/MS (free drug/unconjugated, antibody conjugated)
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