Calibration and Validation, Slides of Pharmaceutical Analysis

Download Calibration and Validation and more Slides Pharmaceutical Analysis in PDF only on Docsity! Calibration and Validation Calibration • Instrument calibration is one of the primary processes used to maintain instrument accuracy. Calibration is the process of configuring an instrument to provide a result for a sample within an acceptable range by eliminating or minimizing factors that cause inaccurate measurements. • Above all, Calibration is the measurement technology to compare between values obtained by a device under test with those of a calibration standard of known accuracy. • Calibration involves measuring and adjusting the instrument response using known standards. Performance verification verifies the operation and performance characteristics of an instrument against a predetermined set of requirements. Calibration is a part of performance verification. 2 Validation parameters i >> Led [>not Detection) [> L_tn of wanton _} OS) Pet > Le aa) Linearity • Linearity of an analytical procedure as the ability (within a given range) to obtain test results of variable data which are directly proportional to the concentration (amount of analyte) in the sample. • The data variables are the peak areas, peak heights, or the ratio of peak areas (heights) of analyte. • At least five concentration levels should be used. Under normal circumstances, linearity is achieved when the coefficient of determination (r2) is ≥0.997. 6 Accuracy • The degree of closeness of the determined value to the known true/standard value under prescribed conditions. This is sometimes termed trueness. • For example, if in lab somebody obtains a weight measurement of 3.2 kg for a given substance, but the actual or known weight is 10 kg, then your measurement is not accurate. In this case, measurement is not close to the known value. 7 Precision Precision is usually investigated at three levels: • Repeatability • Intermediate precision and • Reproducibility • Repeatability (Precision): Repeatability is a measure of the precision under the same operating conditions over a short interval of time. Above all, Repeatability is the variation in measurements taken by a single person or instrument on the same item, under the same conditions, and in a short period of time. Such variability can be caused by, for example, intra-individual variability and intra-observer variability. A measurement may be said to be repeatable when this variation is smaller than a pre- determined acceptance criterion. 10 Precision • Intermediate Precision: Intermediate precision is defined as the variation within the same laboratory. The extent to which intermediate precision needs to be established depends on the circumstances under which the procedure is intended to be used. • Reproducibility: Reproducibility is the ability of an entire analysis of an experiment or study to be duplicated or getting the same/closed result for multiple operations, either by the same researcher or by someone else working independently, whereas reproducing an experiment is called replicating it. 11 Robustness • The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in the analytical procedure parameters. 12 Detection limit (LOD) The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value. Recovery The extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method. 15 Inter-relationship between qualification and validation Calibration Qualification Validation 16  Design Specification/ Qualification | Installation Qualification v Operational Qualification ¥ Process Validation or Performance Qualification Y Change Control Inter-relationship between qualification and validation Validation master plan (VMP) • A Validation Master Plan is a document that summarizes the company's overall philosophy, intentions and approach to be used for establishing performance adequacy. • Validation master plan = Design qualification (DQ) + Installation qualification (IQ) + Operational qualification (OQ) + Process Validation or Performance qualification (PQ). VMP= DQ+IQ+OQ+PQ Format and Content • The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOP's and Validation Protocols. The VMP should be agreed by management. 20 Validation master plan (VMP) A VMP should contain data on the following subjects: • Introduction Company's validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities). • Organizational structure of all validation activities Personnel responsibility for • The VMP • Protocols of individual validation projects, • Report and document preparation and control, • Approval of validation protocols and reports in all stages of validation processes • Tracking system for reference and review, • Training needs in support of validation. 21 Validation master plan (VMP) • Plant / Process / Product description A rationale for the inclusion or exclusion of validations, for the validation approach and the extent of validation should be included. • Specific process considerations Under this heading specific requirements of the plant / process that are critical for yielding a quality product and need extra attention may be briefly outlined here. 22 Validation protocol A document describing the activities to be performed during a validation, including the acceptance criteria for the approval of a process or system for intended use. Contents: 1. The objectives 2. The site 3. The responsible personnel 4. Description of the standard operating procedures SOPs to be followed 5. Equipment to be used 6. Standards and criteria as appropriate 7. The stage of validation or qualification 25 Validation protocol Contents: 8. The processes and/or parameters 9. Sampling, testing and monitoring requirements 10. Stress testing where appropriate 11. Calibration requirements 12. Predetermined acceptance criteria for drawing conclusions 13. Review and interpretation of results 14. Change control, deviations 15. Archiving and retention 26 Qualification and validation reports A document in which the records, results and evaluation of validation are assembled and summarized. It may also contain proposals for the improvement of processes and/or systems and/or equipment. • There should be written reports on the qualification and validation performed. • Reports should reflect the protocols and procedures followed and include at least the title and objective of the study; make reference to the protocol; reference to the appropriate risk assessment; details of materials, equipment, program and cycles used; procedures and test methods with appropriate traceability. • Results should be recorded. 27 Types of validation (1) Prospective process validation (2) Retrospective process validation (3) Concurrent validation (4) Revalidation 30 Prospective Process Validation In prospective process validation, an experimental plan called the validation protocol is executed before the process is put into commercial use or the product going to the market. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. 31 Retrospective Validation The retrospective validation option is chosen for established products whose manufacturing processes are considered stable and when on the basis of economic considerations alone and resource limitations, prospective validation programs cannot be justified. Prior to undertaking retrospective validation, the numerical in-process and/or end-product test data of production batches are analysized, the equipment, facilities and subsystems used in connection with the manufacturing process must be qualified according to cGMP requirements. The basis for retrospective validation is stated as - “Valid in-process specifications shall be consistent with drug product final specifications and shall be derived from previous acceptable process average”. 32 Operation Qualification for an HPLC system Typical OQ tests for HPLC modules • Pump: flow rate accuracy and gradient accuracy • Detector: linearity of response, noise and wavelength accuracy • Injector: precision, linearity, and carryover • Column heater: temperature accuracy 35 Operation Qualification for an HPLC system • Flow Rate Accuracy The flow-rate accuracy of the pump can be evaluated simply by calculating the time required to collect a predetermined volume of mobile phase at different flow rate settings. For example, the flow-rate accuracy at 2 mL/min can be verified by using a calibrated stopwatch to measure the time it takes to collect 25 mL of effluent from the pump into a 25-mL volumetric flask. A calibrated flow meter can be used to determine the flow rate as well. 36 Operation Qualification for an HPLC system • Gradient Accuracy and Precision For gradient analysis, the ability of the pump to deliver the mobile phase at various solvent strengths over time by varying the composition of the mobile phase accurately is crucial to achieving the proper chromatographic separation and reproducibility. The gradient operation precision can be assessed indirectly by monitoring the relative standard deviation in retention time of peaks in the chromatographs from repeated injections. 37 Operation Qualification for an HPLC system • Pressure Test 40 Operation Qualification for an HPLC system • Pressure Test As the pressure increases to about 3000 psi, the flow rate is reduced to 0.1 mL/min. The pressure will gradually rise to the shutdown pressure if the check valves are able to hold the mobile phase in the pump chamber as would normally be expected. If the check valve is not functioning properly, the pressure will fluctuate instead of reaching the shutdown pressure. The pressure in the pump head decreases slowly over time after the automatic shutdown. Typically, the pressure drop is less than 10% over 5 min. A steep decrease in pressure over time implies poor check-valve performance or leaks within the pumping system. 41 Operation Qualification for an HPLC system • HPLC Noise: Baseline noise is the short time variation of the baseline from a straight line caused by electric signal fluctuations, lamp instability, temperature fluctuations and other factors. • HPLC Drift: Due to the continuous signal fluctuation baseline deviates as little as possible from the horizontal line in chromatograph. 42