Q2R1.pptx

ICH Q2R1 guideline of analytical method development and validation

1. Q2R1 BY- ASST. PROF. SANJAYKUMAR UCHIBAGLE, GHRU, SAIKHEDA.

2. VALIDATION OF ANALYTICAL PROCEDURES: TEXT AND METHODOLOGY Q2(R1)

3. INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

4. LIST OF ICH GUIDELINE Q1A (R2) –   Stability Testing of New Drug Substances and Products Q2 (R1)  – Validation of Analytical Procedures : Text and Methodology Q3A (R2) –   Impurities in New Drug Substances Q4  – Pharmacopoeias Q5B –  Quality of Biotechnology Products Q6A  – Specifications : Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances Q7  – Good Manufacturing Guide for Active Pharmaceutical Ingredients Q8(R2)  – Pharmaceutical Development Q9  – Quality Risk Management Q10 –  Pharmaceutical Quality System Q11 –  Development and Manufacture of Drug Substances (Chemical Entities Biotechnological/Biological Entities ) Q12  – Life Cycle Management Q13  -EWG Continuous Manufacturing of Drug Substances and Drug Products Q2(R2)/Q14  –  EWG Analytical Procedure Development and Revision of Q2 (R1) Analytical Validation

5. ICH Q1 UIDELINE Q1A (R2)  – Stability Testing of New Drug Substances and Products. Q1 B  – Stability Testing : Photo Stability Testing of New Drug Substances and Products. Q1C  – Stability Testing for New Dosage Forms. Q1D  – Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products. Q1E  – Evaluation of Stability Data. Q1F  – Stability Data Package for Registration Application in Climatic Zones III and IV.

6. Q2 (R1)  – Validation of Analytical Procedures : Text and Methodology Q3A (R2)  – Impurities in New Drug Substances Q3B (R2)  – Impurities in New Drug Products Q3C (R5)  – Impurities : Guideline for Residual Solvents Q3D  – Impurities : Guideline for Elemental Impurities  

7. Q4A  – Pharmacopoeial Harmonisation Q4B  – Evaluation and Recommendation of Pharmacopoeial Text for use in the ICH Regions Q4B   Annex 1(R1)  – Residue on Ignition /Sulphated Ash General Chapter Q4B Annex 2(R1 ) – Test for Extractable Volume of Parenteral Preparation General Chapter

8. Q5A(R1) –  Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Q5B –  Quality of Biotechnology Products Q5C  – Quality of Biotechnology Products :Quality of Biotechnological Q5D  – Derivation and Characterisation of Cell Substrates used for Production of Biotechnological/Biological Products Q5E  – Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

9. Q6A  – Specifications : Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Q6B  – Specifications : Test Procedure and Acceptance Criteria for Biotechnological/Biological. Q7  – Good Manufacturing Guide for Active Pharmaceutical Ingredients Q8(R2)  – Pharmaceutical Development Q9  – Quality Risk Management

10. Q10  – Pharmaceutical Quality System Q11 – Development and Manufacture of Drug Substances (Chemical Entities Biotechnological/Biological Entities ) Q12  – Life Cycle Management Q13  - EWG Continuous Manufacturing of Drug Substances and Drug Products Q2(R2 )/Q14  – EWG Analytical Procedure Development and Revision of Q2 (R1) Analytical Validation

11. STEPES INVOLVED IN THE ICH Q2R1 GUIDELINE SPECIFICITY ACCURACY PRECISION DETECTION LIMIT QUANTITATION LIMIT LINEARITY RANGE ROBUSTNESS SYSTEM SUITABILITY TESTING

12. 1. SPECIFICITY Specificity is the ability of a method to detect and differentiate the analyte from other substances, including its related substances. e.g ., substances that are structurally similar to the analyte, metabolites, isomers, impurities, degradation products formed during sample preparation. Identification - tests should be able to discriminate between compounds of closely related structures which are likely to be present. Assay and Impurity Test(s )-For critical separations, specificity can be demonstrated by the resolution of the two components which elute closest to each other. Impurities are available -This can be done by spiking pure substances with appropriate levels of impurities and/or excipients and demonstrating that the assay result is unaffected by the presence of these materials. Impurities are not available - by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure e.g.: Pharmacopoeial method or other validated analytical procedure.

13. 2. ACCURACY (Trueness) The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found . DRUG SUBSTANCES & DRUG PRODUCTS. A pplication of an analytical procedure to an analyte of known purity (e.g. reference material ). Comparison of the results of the proposed analytical procedure with those of a second well-characterized procedure, the accuracy of which is stated and/or defined (independent procedure). Impurities (Quantitation ) In cases where it is impossible to obtain samples of certain impurities and/or degradation products, it is considered acceptable to compare results obtained by an independent procedure.

14. 3. PRECISION 3.1 . Repeatability / Intra-assay Precision. 3.2. Intermediate precision 3.3. Reproducibility 3.1 . Repeatability / Intra-assay Precision . Repeatability expresses the precision under the same operating conditions over a short interval of time . 3.2. Intermediate precision Intermediate precision expresses within -laboratories variations: different days, different analysts, different equipment, etc. 3.3. Reproducibility Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

15. 3.1 . Repeatability / Intra-assay Precision. Repeatability should be assessed using: a) a minimum of 9 determinations covering the specified range for the procedure (e.g., 3 concentrations/3 replicates each ); or b) a minimum of 6 determinations at 100% of the test concentration. 3.2 . Intermediate precision Typical variations to be studied include within lab. Different days , Different analysts , Different equipment , etc. It is not considered necessary to study these effects individually.

16. 3.3 . Reproducibility Reproducibility is assessed by means of an inter-laboratory trial. Reproducibility should be considered in case of the standardization of an analytical procedure.

17. 4. DETECTION LIMIT The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value . 4.1. Based on Visual Evaluation The detection limit is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected . 4.2. Based on Signal-to-Noise This approach can only be applied to analytical procedures which exhibit baseline noise . signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and establishing the minimum concentration at which the analyte can be reliably detected. A signal-to-noise ratio generally considered 3 or 2:1

18. 4.3 Based on the Standard Deviation of the Response and the Slope The detection limit (DL) may be expressed as : DL = 3.3 σ / S where σ = the standard deviation of the response ( variety of ways) S = the slope of the calibration curve of analyte. 4.3.1. Based on the Standard Deviation of the Blank Measurement of the magnitude of analytical background response is performed by analysing an appropriate number of blank samples and calculating the standard deviation of these responses . 4.3.2. Based on the Calibration Curve The residual standard deviation of a regression line or the standard deviation of y-intercepts of regression lines may be used as the standard deviation.

19. 5.QUANTITATION LIMIT The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy . 5.1. Based on Visual Evaluation The analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be quantified with acceptable accuracy and precision . 5.2. Based on Signal-to-Noise Approach A pplied to analytical procedures that exhibit baseline noise . Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and by establishing the minimum concentration at which the analyte can be reliably quantified. A typical signal-to-noise ratio is 10:1.

20. 5.3. Based on the Standard Deviation of the Response and the Slope The quantitation limit (QL) may be expressed as: QL = 10 σ / S where σ = the standard deviation of the response S = the slope of the calibration curve σ = the standard deviation of the response can be calculated by using 5.3.1. Based on Standard Deviation of the Blank 5.3.2. Based on the Calibration Curve

21. 6. ROBUSTNESS The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage . Examples of typical variations are: - stability of analytical solutions; extraction time. In the case of liquid chromatography, examples of typical variations are: - influence of variations of pH in a mobile phase; - influence of variations in mobile phase composition; - different columns (different lots and/or suppliers); - temperature; - flow rate .

22. 7. RANGE Analytical procedure is the interval between the upper and lower concentration of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity . A ssay of a drug substance or finished (drug) product: 80 to 120 % for content uniformity, covering a minimum of 70 to 130 for dissolution testing: +/-20 % over the specified range ; for the determination of an impurity: from the reporting level of an impurity1 to 120% of the specification ; if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities1 to 120% of the assay specification .

23. 8. LINEARITY The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample . Linearity should be evaluated by visual inspection of a plot of signals as a function of analyte concentration or content . If there is a linear relationship, test results should be evaluated by appropriate statistical methods, for example, by calculation of a regression line by the method of least squares . The correlation coefficient, y-intercept, slope of the regression line and residual sum of squares should be submitted. A plot of the data should be included. In addition, an analysis of the deviation of the actual data points from the regression line may also be helpful for evaluating linearity.

24. 9. SYSTEM SUITABILITY TESTING System suitability testing is an integral part of many analytical procedures . the equipment, electronics, analytical operations and samples to be analysed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated.

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