Verification of Compendial Methods

Transcription

1 Verification of Compendial Methods ภญ.ดร ดร.ส ภาณ ดวงธ รปร ชา ส าน กยาและว ตถ เสพต ด กรมว ทยาศาสตร การแพทย 7 ม ถ นายน

2 Scopes : Overview Asean Analytical Validation Guidelines Verification of Compendial Methods EDQM AOAC USP ACTD BDN? 2

3 From ASEAN Analytical Validation Guidelines Type of Analytical Procedure Identification Testing for Impurities Assay Performance Characteristic Quantitative Limit test dissolution content/potency Accuracy Precision Repeatability Interm.Precision LOD LOQ Linearity Range 3

4 : The ability to measure accurately and specificity the analyte in the presence of components that may be expected to be present in the matrix The degree of interference : Active ingredients Excipients Impurities Degradation Products etc 4

5 : Identification Tests Demonstrate ability to select between compounds of closely related structure confirm positive and negative results Assay Demonstrate that the results are unaffected by spiked impurities or excipients Impurities Spike the drug product/substance with impurities and demonstrate appropriate accuracy and precision 5

6 : Impurities are available Demonstrate that the assay is unaffected by the present of spiked material (impurities and/or excipients) Impurities are not available Compare test results to a second wellcharacterized procedure For assay : compare the two result For Impurity Tests : compare purity profiles Peak Purity Test (e.g. PDA, MS) 6

7 Linearity: The ability of the method to elicit test results that are directly proportational to concentration within a given range Range: Interval between upper and lower levels of analyte demonstrated by the method Precision and accuracy expressed in the same units as the test results 7

8 Evaluation of Linearity Established across the range of the method Dilutions Separate weighings Evaluate by appropriate statistical methods (e.g.regression) include correlation coefficient, yintercept, slope, plot Minimum 5 concentrations 8

9 Determination of appropriate range Minimum specified range : assay : 80120% Impurity test : from QL to 120% spec Content unformity : 70130% test conc Dissolution testing : / 20% over specified range 9

10 Precision: The measure of the degree of agreement among test results when the method is applied repeatedly to multiple samplings of a homogeneous sample Expressed as %RSD for a statiscally significant number of samples 10

11 Precision: should be performed at 3 levels Repeatability Intermediate Precision Reproducibility 11

12 Precision: Repeatability Same operating conditions, short time interval Min of 9 determinations covering specified range of procedure (3 levels, 3 reps each) Min of 6 determinations at 100% test conc Intermediate Precision Withinlab variations Different days, analysts, equipment Reproducibility Precision between labs Collaborative studies 12

13 Accuracy: The closeness of test results to the true value obtained by the method established across the range 13

14 Accuracy: Drug Substance Analysis of reference material Compare results to a second, wellcharacterized method Drug Product Analysis of synthetic mixtures spiked with known quantities of components Compare results to a second, wellcharacterized method Determined concurrently with precision, linearlity and specificity 14

15 Accuracy: Impurities (Quantitation( Quantitation) Analysis of sample (Drug substances/drug product) spiked with known amounts of impurities Recommended Data Min of 9 determinations over a min of 3 conc levels covering the specified range (e.g. 3 conc/3 replicates each) Report as % recovery of known, added amount, or difference between the mean and true value, with confidence intervals 15

16 Detection Limit (LOD): Lowest concentration of analyte in a sample that can be detected (not necessarily quantitated) Limit test : above or below a certain level Expressed as concentration (%, ppb) Almost necessary not determine actual detection limit 16

17 Detection Limit (LOD): Visual (Noninstrumental methods) Signal to noise ratio (3:1 or 2:1 generally accepted) Detection limit may be based on the standard deviation of the response and slope: DL = (3.3)STD/S STD = standard deviation of the response S = slope of the calibration curve 17

18 Quantitation Limit (LOQ): Lowest concentration of analyte in a sample that can be determined with acceptable precision and accuracy under stated operational conditions Expressed as concentration of analyte accuracy precision 18

19 Quantitation Limit (LOQ): Visual (Noninstrumental methods) Signal to noise ratio (10:1 is typical) Quantitation limit may be based on the standard deviation of the response and slope: QL = (10)STD/S STD = standard deviation of the response S = slope of the calibration curve Both DL and QL are validated by analyzing a suitable number of samples. Method should be documented. 19

20 Verification of Compendial Methods EDQM AOAC USP ACTD 20

21 From EDQM : 1. Transfer of a Method A verification of suitability under conditions of use (=method transfer check) has to be done 1.1 Pharmacopoeial (compendial) method Active substance Identification: no formal validation required Testing for Impurities: no formal validation required Assay: no formal validation required 21

22 From EDQM : 1.1 Pharmacopoeial (compendial) method Medicinal product Identification: no formal validation required Testing for Impurities: specificity: no interference from excipients reporting threshold (at least the quant. limit) Assay: specificity accuracy: mainly recovery, min 1 det. precision (repeatability): around the target test conc. (min 2 independent det.) linearity at three measuring points in the range around the target value. 22

23 From AOAC : How to meet ISO requirements for Method Verification Activities needed for method verification are a subset of those for validation. 23

24 From AOAC : Performance Characteristics Included in a Validation Performance Characteristic Identification 1 Analyte at low conc quantitative 2 Analyte at low conc Limit test 3 Analyte at high conc quantitative 4 Analyte at high conc Limit test 5 Quanlitative 6 Accuracy No No No Precision No No No LOD No /No No No LOQ No No /No No No Ruggedness No No No No Linearity/ Range No No No No 24

25 From AOAC : How to meet ISO requirements for Method Verification Category1 : Confirmation of identity A method that ensures a material is what it purports to be or confirms the detection of the target analyte 25

26 Category1 : Identification Performance Characteristic Verification No If the lab s samples are identical to those in the standard method and if and differences in instrumentation do not impact specificity if the lab s sample differ from those in the standard method if differences between instruments could affect specificity Verification Activities NA Same as those required for validation The activity need only deal with the unique aspect s of the lab s samples or instrumentation 26

27 From AOAC : How to meet ISO requirements for Method Verification Category2 : Analyte at Low Concentration, Quantitative 27

28 Category2:Analyte at Low Concentration, Quantitative Performance Characteristic 1. Accuracy Verification Verification Activities If the concentration range for which the method is validated is narrow (<1 order of magnitude), analyze one reference material/standard/spike at one concentration level. Otherwise, demonstrate accuracy at each concentration level (low, middle, high) by anlyzing one reference material/standard/spike at each level. 28

29 Category2:Analyte at Low Concentration, Quantitative Performance Characteristic 2. Precision Verification Verification Activities Perform the repeatability test once. If the method covers a concentration range>1 order of magnitude, then the repeatability test must include low, middle and high concentrations. 29

30 Category2:Analyte at Low Concentration, Quantitative Performance Characteristic 3. Verification No/ Verification Activities 4. LOD Run a sample close to LOD 5. LOQ Run a sample close to LOQ 30

31 From AOAC : How to meet ISO requirements for Method Verification Category3 : Analyte is present above or below a specified, low concentration (Limit Test) 31

32 Category3 : Limit Test Performance Characteristic 1. Verification No/ Verification Activities 2. LOD Run a sample close to LOD 3. LOQ Run a sample close to LOQ 32

33 From AOAC : How to meet ISO requirements for Method Verification Category4 : Quantifying an analyte at high concentration 33

34 Category4 : Assay Performance Characteristic 1. Accuracy Verification Verification Activities If the concentration range for which the method is validated is narrow (<1 order of magnitude), analyze one reference material/standard/ spike at one concentration level. Otherwise, demonstrate accuracy at each concentration level (low, middle, high) by anlyzing one reference material/standard/spike at each level. 34

35 Category4 : Assay Performance Characteristic 2. Precision 3. Verification No/ Verification Activities Perform the repeatability test once. If the method covers a concentration range>1 order of magnitude, then the repeatability test must include low, middle and high concentrations. 35

36 From USP : Verification of Compendial Procedures <1226> 36

37 USP: Validation of Compendial Procedures <1225> Category II Performance Characteristic Category I (Assay) (Impurities) Quantitative Limit test Category III (dissolution) Category IV (Identification) Accuracy Precision LOD LOQ Linearity Range 37

38 Verification of Compendial Procedures<1226> Verification of Compendial Procedures. The purpose of this new general information chapter is to provide guidelines for verifying the suitability of a compendial procedure under actual conditions of use,, as stated in 21 CFR (a)(2). Because it is not necessary for users of compendial procedures to perform a complete validation, but rather, to confirm that the procedure works for their drug substance, excipient, or dosage form,, verification can be accomplished by assessing a subset of validation characteristics. This new chapter is considered an extension of the general information chapter Validation of Compendial Methods <1225>, and both chapters use similar terminology. Interested parties are encouraged to submit comments by July 15,

39 Verification of Compendial Procedures<1226> verifying the suitability of a compendial procedure under actual conditions of use But No Guidelines 39

40 Data Elements for Verification of Drug Substances and and Excipients* Technique Category (assay) Category II (impurities) Category III (dissolution) Category IV (identification) Quantitative Limit test HPLC/GC Precision Precision LOQ LOD Spectro photometric/ colorimetric Precision Precision LOQ LOD Titrimetric Precision Precision TLC LOQ LOD Gel Electro Phoresis LOQ LOD * Not official 40

41 Data Elements for Verification of Dosage Forms Technique Category I (assay) Category II (impurities) Category III (dissolution) Category IV (identification) Quantitative Limit test HPLC/GC Precision Linearity Range Precision LOQ LOD Precision Spectro photometric/ colorimetric Precision Linearity Range Precision LOQ LOD Precision Titrimetric Precision Linearity Range TLC Gel Electro phoresis * Not official Precision LOQ LOQ LOD LOD 41

42 Category I: Analytical procedures for quantitation of major components of drug substances or active ingredients (including preservatives) in finished dosage forms. Category II: Analytical procedures for determination of impurities in drug substances or degradation compounds in finished pharmaceutical products. These procedures include quantitative assays and limit tests. Category III: Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release). Category IV: Identification procedures. 42

43 From ACTD P5 : Control of Finished Product 5.3 Validation of Analytical Procedure Verification of compendial method applicability Accuracy Precision 43

44 Comparison : Assay USP Precision Linearity Range EDQM Precision Linearity Accuracy AOAC Precision Accuracy 44

45 Recommendation (BDN): For Assay: Precision at 100 % (6 det.) Accuracy at 100% (3 det.) Linearity (5 points) 45

46 Comparison : Impurity (Quantitative) USP Precision LOQ EDQM LOQ AOAC Precision LOQ, LOD Accuracy 46

47 Recommendation (BDN): For Impurity (Quantitative) : LOQ Precision (6 det.) Accuracy (3 det.) 47

48 Comparison : Impurity (Limit tests) USP LOD EDQM LOQ (LOD?) AOAC LOQ, LOD 48

49 Recommendation (BDN): For Impurity (Limit tests) : LOD 49

50 Comparison : Identification USP EDQM No formal validation required AOAC 50

51 Verification documentation : The verification exercise must be planned, approved, and documented and a final report kept on file to demonstrate the lab can perform the method adequately. Verification documentation should be created that: Described the procedure to be verified Details the analytical performance characteristics to be evaluated Established acceptance criteria used to determine that the procedure perform suitably Justifies deviations from reference method 51

52 Thank You for Your Attention 52