Quality control & Assurance in Analytical Chemistry

1. Quality control in Analytical Chemistry 1September 29, 2015 Andhra university

2. Quality • In manufacturing, a measure of excellence or a state of being free from defects, deficiencies and significant variations. It is brought about by strict and consistent commitment to certain standards that achieve uniformity of a product in order to satisfy specific customer or user requirements. • ISO 8402-1986 standard defines quality as "the totality of features and characteristics of a product or service that bears its ability to satisfy stated or implied needs." • If an automobile company finds a defect in one of their cars and makes a product recall, customer reliability and therefore production will decrease because trust will be lost in the car's quality. 2September 29, 2015 Andhra university

3. • Quality control is an essential operation of the pharmaceutical industry. Drugs must be marketed as safe and therapeutically active formulations whose performance is consistent and predictable. New and better medicinal agents are being produced at an accelerated rate. At the same time more exacting and sophisticated analytical methods are being developed for their evaluation. Dictionary definition of QC: Quality control means checking and directing the degree or grade of excellence of processes and products ISO-Quality The totality of features and characteristics of a product, process or service that bear on its ability to satisfy stated or implied needs ISO-QA All those planned and systematic actions necessary to provide adequate confidence that a product, process or service will satisfy given quality requirements 3September 29, 2015 Andhra university

4. DEFINITIONS True Value The known, accepted value of a quantifiable property Measured Value The result of an individual’s measurement of a quantifiable property Accuracy How well a measurement agrees with an accepted value Precision How well a series of measurements agree with each other Systematic Error Avoidable error due to controllable variables in a measurement Random Errors Unavoidable errors that are always present in any measurement. Impossible to eliminate • An analysis provides chemical or physical information about a sample. The component of interest in the sample is called the analyte, and the remainder of the sample is the matrix. • In an analysis we determine the identity, concentration, or properties of an analyte. To make this determination we measure one or more of the analyte’s chemical or physical properties • Analysis, a determination and a measurement 4September 29, 2015 Andhra university

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11. Techniques, Methods, Procedures, and Protocols 11September 29, 2015 Andhra university

14. Quality control 14September 29, 2015 Andhra university

16. For Drug 1.The identifying name or mark of the new drug, along with its accepted chemical name, as well as any code names, synonyms, non-proprietary and brand names which may be known. 2. The chemical structure or other specific identification of the composition of the new drug, such as its molecular formula and molecular weight. 3. The source of the new drug, along with information concerning the role of the manufacturer in its production, packaging and distribution, relevant data showing whether the drug is of domestic or foreign origin, and whether or not it is a product of private formula or custom manufacture. 4. The tests applied to control the potency, purity and safety of the new drug, and 5. The methods, equipment, plant and controls used in the manufacture, processing and packaging of the new drug. 16September 29, 2015 Andhra university

17. Quality assurance 17September 29, 2015 Andhra university

18. Accreditation system 18September 29, 2015 Andhra university

19. Limit of detection 19September 29, 2015 Andhra university

23. Sensitivity • The ability to demonstrate that two samples have different amounts of analyte is an essential part of many analyses. A method’s sensitivity is a measure of its ability to establish that such differences are significant. Sensitivity is often confused with a method’s detection limit, which is the smallest amount of analyte that we can determine with confidence. • Usually regarded as detection limit • Capability of a method or instrument to discriminate between measurement responses – but this term is often used without defining what is intended (minimum detection or quantitation) • A sensitivity QC describes the capability of measuring a constituent at low levels – a Practical Quantitation Level describes the ability to quantify a constituent with known certainty 23September 29, 2015 Andhra university

24. Bias • Bias is systematic or persistent distortion of a measurement process that causes error in one direction • A bias can result from: – biased sampling design – calibration errors – response factor shifts – unaccounted -for interferences – chronic sample contamination 24September 29, 2015 Andhra university

25. Safety • Materials - High quality raw materials. This includes defining specifications for the materials • Preparation - Preventing foreign bodies from entering products, enabling the management of allergens, and controlling pests - a clean and safe water supply, for air filtration, and for any material that will come into contact with our product, to guarantee that the materials, equipment and manufacturing environment are all designed to produce safe products. - We follow certified cleaning and sanitation practices at every step of production • Processing - We prepare products in quantities that provide an appropriate and consistent dosage of any nutrient, to avoid any harm linked to over- or under-dosage. And we process at optimum temperatures to retain its nutritious value, while removing dangerous microorganisms and preventing the formation of chemical contaminants • Testing • Packaging and transportation 25September 29, 2015 Andhra university

26. Specificity & Selectivity • Selectivity of a method refers to the extent to which it can determine particular analytes under given conditions in mixtures or matrices, simple or complex, without interferences from other components in the mixture. “Specificity is the ultimate of Selectivity” • Selectivity is very often expressed in combination with words such as adjustment ,tuning ,optimization ,predetermined ,enhancement ,and coefficients ,as well as selective enrichment • The term “specific” can of course be used without confusion to denote a physical quantity obtained after division of a measurement by mass, e.g., specific volume. 26September 29, 2015 Andhra university

27. Robustness and Ruggedness • For a method to be useful it must provide reliable results. Unfortunately, methods are subject to a variety of chemical and physical interferences that contribute uncertainty to the analysis. When a method is relatively free from chemical interferences, we can use it on many analytes in a wide variety of sample matrices. Such methods are considered robust. • Random variations in experimental conditions also introduces uncertainty. If a method’s sensitivity, k, is too dependent on experimental conditions, such as temperature, acidity, or reaction time, then a slight change in any of these conditions may give a significantly different result. A rugged method is relatively insensitive to changes in experimental conditions. 27September 29, 2015 Andhra university

28. – The Mean- measure of central tendency – The Range- difference between largest/smallest observations in a set of data – Standard Deviation measures the amount of data dispersion around mean 28 Statistical control September 29, 2015 Andhra university

29. The Mean • To compute the mean we simply sum all the observations and divide by the total no. of observations. 29September 29, 2015 Andhra university

30. The Range • Range, which is the difference between the largest and smallest observations. 30September 29, 2015 Andhra university

31. Standard Deviation • Standard deviation is a measure of dispersion of a curve. • It measures the extent to which these values are scattered around the central mean. 31September 29, 2015 Andhra university

32. • Extend the use of descriptive statistics to monitor the quality of the product and process • Statistical process control help to determine the amount of variation • To make sure the process is in a state of control Statistical process control 32 32September 29, 2015 Andhra university

33. Control chart • Powerful, easy-to-use technique for the control of routine analyses • ISO/IEC 17025 demands use wherever practicable • It is hard to imagine quality management systems in laboratories without control chart • Assign a target value • Certified value of a RM/CRM (if available) • Mean of often repeated measurements of the control sample (in most cases) 33September 29, 2015 Andhra university

34. September 29, 2015 Andhra university 34 Basic Principle of control chart

35. concentration upper action limit upper warning limit target value lower warning limits lower action limits sample-# 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 17 18 Take control samples during the process Measure a quality indicator Mark the measurement in a chart with warning and action limits Warning / action limits If data are normally distributed 95.5% of the data are in µ ± 2σ 99.7% are in µ ± 3σ x-bar± 2s is taken as warning limits x-bar± 3s is taken as action limit 35September 29, 2015 Andhra university

36. Quality systems - control charts % Fat 3.10 3.15 3.20 3.25 3.30 14/01/02 24/01/02 03/02/02 13/02/02 23/02/02 05/03/02 15/03/02 25/03/02 04/04/02 14/04/02 24/04/02 date %fat A control chart is a means of ensuring that the method remains in ‘control’ - continues to perform in accordance with expectations. This usually means that results from analysing standards fall within + 2 standard deviations of the accepted value (within the blue lines on the chart). Any results appearing outside the red lines (+ 3 standard deviations) indicate that the method is not longer in control and requires investigation. 36September 29, 2015 Andhra university

38. Action Limits: • There is a probability of only (100-99.7) 0.3 % that a (correct) measurement is outside the action limits (3 out of 1000 measurements) • Therefore the process should be stopped immediately and searched for errors Warning Limits: • (100-95.5) 4.5% of the (correct) values are outside the warning limits. • This is not very unlikely. • Therefore this is only for warning, no immediate action required 38September 29, 2015 Andhra university

39. What is a Youden Plot? 39September 29, 2015 Andhra university

41. • In the late 1950's, Dr. William Youden (1900-1971) developed what has now become known as the Youden Plots. • This statistical technique involves both normal and abnormal controls and graphically helps to differentiate between systematic and random errors. • The inner square of the plot (yellow) represents one standard deviation (1SD). The next larger square (green) represents 2SD, and the outer square (blue) represents 3SD. • A horizontal median line is drawn parallel to the X-axis and a second median line is drawn parallel to the Y-axis. • The intersection of the two median lines is called the Manhattan Median. One or two 45-degree lines are drawn through the Manhattan Median. • The results of at least two different levels of controls (e.g. Level 1/Level 2 or Normal/Abnormal) are then plotted on the chart as X-axis versus Y-axis. 41September 29, 2015 Andhra university

43. Using a Youden Plot 43September 29, 2015 Andhra university

49. • Controls are run and plotted. • Plots that lie near the 45-degree reference line and within the one and two standard deviation squares show acceptable results. • Points that lie near the 45-degree reference lines but outside the 2SD square indicate a systematic error. • Points that lie far from ether 45-degree reference line indicate a random error. 49September 29, 2015 Andhra university

50. Elements of quality Assessment & Assurance • Legal base • Regulatory elements - Governmental drug control agencies i. Inspection services ii. Drug quality control laboratory • Technical elements - Quality specifications - Basic tests - Requirements for good manufacturing practices September 29, 2015 Andhra university 50

51. ICH guidelines 51September 29, 2015 Andhra university

58. Quality-Design September 29, 2015 Andhra university 58

60. SOP-standard operating procedures, SPC- statistical process control, PAT-Process analytical technology,QRM-Quality Risk Management, PAT-Process analytical technology, CMA-Conditional marketing authorisation, RTRT-Real Time Release Testing, CPP-Critical Process Parameters, CQA-Critical Quality Attributes, QTPP-Quality target product profile September 29, 2015 Andhra university 60

61. • Define quality target product profile that describes the use, safety and efficacy of the product. • Design and develop product and manufacturing processes. • Identify critical quality attributes, process parameters, and sources of variability. • Establish a control strategy for the entire process • Control manufacturing processes to produce consistent quality over time September 29, 2015 Andhra university 61

64. ISO 9000 and ISO 14000 series-meaning of quality 64September 29, 2015 Andhra university

67. ISO 1400 series • The series is divided into two separate areas-the organization evaluation standards and the product evaluation standards. The first deals with • Environmental Management System (EMS) • Environmental Auditing (EA) • Environmental Performance Evaluation (EPE) • whereas later deals with Environmental Aspects in Product Standards (EAPS) • Environmental Labeling (EL) • Life-Cycle Assessment (LCA). 67September 29, 2015 Andhra university

69. Requirement calibration September 29, 2015 Andhra university 69

70. Acceptance Sampling • Acceptance Sampling – Statistical quality control technique, where a random sample is taken from a lot, and upon the results of the sample taken the lot will either be rejected or accepted • Accept Lot – Ready for customers • Reject Lot – Not suitable for customers • Statistical Process Control(SPC) – Sample and determine if in acceptable limits 70September 29, 2015 Andhra university

71. • Purposes – Determine the quality level of an incoming shipment or, at the end production – Ensure that the quality level is within the level that has been predetermined • Can be either 100% inspection, or a few items of a lot. • Complete inspection – Inspecting each item produced to see if each item meets the level desired – Used when defective items would be very detrimental in some way 71September 29, 2015 Andhra university

72. ACCEPTANCE SAMPLING ACCEPT LOT RETURN LOT TO SUPPLIER 100% INSPECTION DECISION REJECT LOT SAMPLE AGAIN DECISION INSPECT SAMPLE Type title here TAKE SAMPLE 72September 29, 2015 Andhra university

73.  Good Laboratory Practice (GLP) is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. Drugs-Companies Laboratories Government and Company Hazard assesment International trade. GLP DATA September 29, 2015 73Andhra university

74. 1.Test Facility Organisation and Personnel 2. Quality Assurance Programme 3. Facilities 4. Apparatus, Material, and Reagents 5. Test Systems 6. Test and Reference Items 7. Performance of the Study 8. Reporting of Study Results 9. Storage and Retention of Records and Materials GOOD LABORATORY PRACTICE - PRINCIPLES September 29, 2015 74Andhra university

75. 1.Test Facility Organisation and Personnel A. Test Facility Management’s Responsibilities B. Study Director’s Responsibilities C. Principal Investigator’s Responsibilities D. Study Personnel’s Responsibilities September 29, 2015 75Andhra university

76. A.Test Facility Management’s Responsibilities.  Responsibilities of management as defined by these principles of good laboratory practice.  Sufficient number of qualified personnel, appropriate facilities, equipment, and materials are available for the timely and proper conduct of the Study  Ensure the maintenance of a record of the qualifications, training, experience.  Job description for each professional and technical individual.  Documented approval of the study plan by the Study Director.September 29, 2015 76Andhra university

77. B.Study Director’s Responsibilities.  approve the study plan.  Any amendments to the study plan by dated Signature.  Availability of SOPS to the personnel.  Raw data generated are fully documented and recorded.  Computerised systems used in the study have been validated.  Sign and date the final report to indicate acceptance of responsibility for the validity of the data.  Ensure that after completion (including termination) of the study, the study plan,the final report, raw data and supporting material are archived. September 29, 2015 77Andhra university

78. C.Principal Investigator’s Responsibilities  The Principal Investigator will ensure that the delegated phases of the study are conducted in accordance with the applicable Principles of Good Laboratory Practice September 29, 2015 78Andhra university

79. Knowledgeable Instructions Recording Health precautions Responsibilities September 29, 2015 79Andhra university

80. 2.Quality Assurance Programme 1.Quality assurance personnel 2.Study plan contains the information-verification 3.conduct inspections Study-based inspections Facility-based inspections Process-based inspections. 4.Records of such inspections should be retained September 29, 2015 80Andhra university

81. 3. Facilities 1.Test system facilities  Sufficient number of rooms or areas assure the isolation of test systems and the isolation of individual projects involving substances or organisms known to be or suspected of being biohazardous.  There should be storage rooms or areas as needed for supplies and equipment.  Areas should be available for the diagnosis, treatment and control of diseases, in order to ensure that there is no unacceptable degree of deterioration of test systems. September 29, 2015 81Andhra university

82. Archive Facilities  Archive facilities should be provided for the secure storage and retrieval of study plans, raw data, final reports, samples of test items and specimens.  Archive design and archive conditions should protect contents from untimely deterioration.  Handling and disposal of wastes should be carried out in such a way as not to jeopardise the integrity of studies. This includes provision for appropriate collection, storage and disposal facilities, and decontamination and transportation procedures waste disposal September 29, 2015 82Andhra university

83. 4. Apparatus, Material, and Reagents  Apparatus, including validated computerised systems, used for the generation, storage and retrieval of data, and for controlling environmental factors relevant to the study.  Apparatus used in a study should be periodically inspected, cleaned, maintained, and calibrated according to Standard Operating Procedures.  Apparatus and materials used in a study should not interfere adversely with the test systems.  Chemicals, reagents, and solutions should be labelled to indicate identity (with concentration if appropriate), expiry date and specific storage instructions. Information concerning source, preparation date and stability should be available. The expiry date may be extended on the basis of documented evaluation or analysis. September 29, 2015 83Andhra university

84. 5&6.Test Items and test systems and characterisation September 29, 2015 84Andhra university

85. Drugs manufactured in the MNCs BioTestingLaboratory Send to the labs for quality assurance and also testing for the toxicity aganist to the mammals. and environment. 2.Characterization:  Test item-product going to be tested – composition, stability, chemical nature solubility, new formula or modified previous product formula, identity, potency, impurity profile,  Test system-to which animal is going to be administere Results submitted to the FDA-US Government and OECD (International standards). Further release into the market and reproduction. September 29, 2015 85Andhra university

86. 7.Performance of the Study 1. Study Plan 2. Content of the Study Plan 3. Dates 4. Test Methods 5. Issues (where applicable) 6. Records. 7. A list of records to be retained. 8. Conduct of the Study. September 29, 2015 86Andhra university

87. 8.Reporting of Study Results 1. Content of the Final Report 2. Identification of the Study, the Test Item and Reference Item 3. Information Concerning the Sponsor and the Test Facility 4. Dates 5. Statement 6. Description of Materials and Test Methods 7. Results 8. Storage September 29, 2015 87Andhra university

88. 9. Storage and Retention of Records and Materials  The study plan, raw data, samples of test and reference items, specimens and the final report of each study.  Records of all inspections performed by the Quality Assurance Programme, as well as master schedules.  Records of qualifications, training, experience and job descriptions of personnel.  Records and reports of the maintenance and calibration of apparatus.  Validation documentation for computerised systems. September 29, 2015 88Andhra university

89. GLP AT A GLANCE September 29, 2015 89Andhra university

90. Product manufacturing Testing laboratories Nonclinicaland environmentalsafetystudies 1.Test Facility Organisation and Personnel 2. Quality Assurance Programme 3. Facilities 4. Apparatus, Material, and Reagents 5. Test Systems 6. Test and Reference Items 7. Performance of the Studynon 8. Reporting of Study Results 9. Storage and Retention of Records and Materials. Data submission to the regulated authorities - Government ,FDA SAFETYNON SAFETY Relesed into the market OECD PRINCIPLES OF GLP INTERNATIONAL TRADE September 29, 2015 90Andhra university

91. GLP IN OUR COUNTRY INDIA September 29, 2015 91Andhra university

92.  National GLP-compliance Monitoring Authority was established by the Department of Science & Technology  approval of the Union Cabinet on April 24, 2002  A provisional member of the OECD for GLP.  India is an Observer to the OECD’s Working Group on GLP  The Authority has trained 33 experts in the country as GLP inspectors. September 29, 2015 92Andhra university

93. GLP-COMPLIANCE CERTIFICATION The test facilities/laboratories have to apply in the prescribed application form GLP-compliance Certification is valid for a period of three years The report, prepared by the inspection team, is put to the Technical Committee for recommendation to Chairman, National GLP- Compliance Monitoring Authority After the application for GLP certification is received, a pre- inspection of the laboratory is carried out by the GLP inspectors, followed by a final inspection. September 29, 2015 93Andhra university

94. September 29, 2015 94Andhra university

95. Dr D R Prasada Raju Head /Scientist G drpraju@nic.in National GLP Compliance Monitoring Authority Department of Science and Technology Technology Bhawan, New Mehrauli Road, New Delhi-110 016 (Telefax 011-26510686) Mrs Ekta Kapoor Scientist D Department of Science and Technology Technology Bhawan, New Mehrauli Road, New Delhi-110 016 (Phone: 011-26590242) E-mail: -ektakapoor.glp@gmail.com HEAD OF NGCMA: September 29, 2015 95Andhra university

96. Our aim : is to be get the status of full membership in the near future so that the Indian industries do not have to get their test facility (products) certified from safety angle by other GLP monitoring authorities and do not lose on the trade front. September 29, 2015 96Andhra university

98. Thanking you by lavakusa Nayak September 29, 2015 Andhra university 98

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