浙江大学远程教育学院：《药物分析》课程教学资源（参考资料）课外阅读二 分析方法论证

课外阅读二分析方法论证 ANALYTICAL PERFORMANCE CHARACTERISTICS Accuracy Definition-The accuracy of an analytical method is the closeness of test results obtained by that method to the true value The accuracy of an analytical method should be established across its range Determination-In the case of the assay of a drug substance, accuracy may be determined by application of the analytical method to an analyte of known purity(e.g, a Reference Standard) or by comparison of the results of the method with those of a econd, well-characterized method, the accuracy of which has been stated or defined In the case of the assay of a drug in a formulated product, accuracy may be determined by application of the analytical method to synthetic mixtures of the drug product components to which known amounts of analyte have been added within the range of the method. If it is not possible to obtain samples of all drug product components, it may be acceptable either to add known quantities of the analyte to the drug product (i.e,"to spike")or to compare results with those of a second well-characterized method, the accuracy of which has been stated or defined In the case of quantitative analysis of impurities, accuracy should be assessed on samples(of drug substance or drug product) spiked with known amounts of impurities. Where it is not possible to obtain samples of certain impurities or degradation products, results should be compared with those obtained by an independent method In the absence of other information, it may be necessary to calculate the amount of an impurity based on comparison of its response to that of the drug substance; the ratio of the responses of equal amounts of the impurity and the drug substance(response factor) should be used if known Accuracy is calculated as the percentage of recovery by the assay of the known added amount of analyte in the sample, or as the difference between the mean and the accepted true value, together with confidence intervals The ICH documents recommend that accuracy should be assessed using a minimum of nine determinations over a minimum of three concentration levels, covering the specified range (i.e, three concentrations and three replicates of each concentration) Precision Definition-The precision of an analytical method is the degree of agreement among individual test results when the method is applied repeatedly to multiple samplings of a homogeneous sample. The precision of an analytical method is usually expressed as the standard deviation or relative standard deviation(coefficient of variation) of a series of measurements Precision may be a measure of either the degree of reproducibility or of repeatability of the analytical method under normal operating conditions. In this context, reproducibility refers to the use of the analytical procedure in different laboratories, as in a collaborative study. Intermediate precision expresses within-laboratory variation, as on different days, or with different analysts

课外阅读二 分析方法论证 ANALYTICAL PERFORMANCE CHARACTERISTICS Accuracy Definition­The accuracy of an analytical method is the closeness of test results obtained by that method to the true value.  The accuracy of an analytical method should be established across its range. Determination­In the case of the assay of a drug substance, accuracy may be determined by application of the analytical  method to an analyte of known purity (e.g., a Reference Standard) or by comparison of the results of the method with those of a second, well­characterized method, the accuracy of which has been stated or defined.  In the case of the assay of a drug in a formulated product, accuracy may be determined by application of the analytical  method to synthetic mixtures of the drug product components to which known amounts of analyte have been added within the range of the method. If it is not possible to obtain samples of all drug product components, it may be acceptable either to add  known quantities of the analyte  to the drug product (i.e.,  “to spike”) or to  compare results with those of a second,  well­characterized method, the accuracy of which has been stated or defined.  In the case of quantitative analysis  of impurities,  accuracy should be assessed on samples (of drug substance or drug  product)  spiked with known amounts of impurities.  Where it is not  possible to obtain samples  of certain  impurities  or degradation products,  results should be compared with those obtained by an independent  method.  In the absence of other information, it may be necessary to calculate the amount of an impurity based on comparison of its response to that of the drug  substance; the ratio of the responses of equal amounts of the impurity and the drug substance (response factor) should be used if known. Accuracy is calculated as the percentage of recovery by the assay of the known added amount of analyte in the sample, or as the difference between the mean and the accepted true value, together with confidence intervals.  The ICH  documents recommend  that  accuracy should  be assessed using a minimum of nine determinations over a minimum of three concentration levels,  covering the specified range (i.e.,  three concentrations  and three replicates  of each  concentration). Precision Definition­The precision of an analytical method is the degree of agreement among individual test results when the method  is applied repeatedly to multiple samplings  of a homogeneous  sample.  The precision of an analytical  method is usually  expressed as  the standard deviation or relative standard deviation (coefficient  of variation) of a series  of measurements.  Precision may be a measure of either the degree of reproducibility or of repeatability of the analytical method under normal  operating conditions. In this context, reproducibility refers to the use of the analytical procedure in different laboratories, as in a collaborative study. Intermediate precision expresses within­laboratory variation, as on different days, or with different analysts

or equipment within the same laboratory. Repeatability refers to the use of the analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment. For most purposes, repeatability is the criterion of concern in USP analytical procedures, repeatability is the criterion of concern in USP analytical procedures, although producibility between laboratories or intermediate precision may well be considered during the standardization of a procedure before it is submitted to the Pharmacopeia. Determination- The precision of an analytical method is determined by assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically valid estimates of standard deviation or relative standard deviation (coefficient of variation). Assays in this context are independent analyses of samples that have been carried through the complete analytical procedure from sample preparation to final test result The ICH documents recommend that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e, three concentrations and three replicates of each concentration or using a minimum of six deter minations at 100% of the test concentration) Specificit Definition-The ICh documents define specificity as the ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities, degradation products, and matrix components. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedures. INOTE-Other reputable international authorities(IUPAC, AOAC) have preferred the term"selectivity", reserving"specificity"for those procedures that are completely selective. For the test or assay methods below, the above definition has the following implications IDENTIFICATION TESTS: ensure the identity of the analyte PURITY TESTS: ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte(e.g, related substances test, heavy metals limit, organic volatile impurity limit) ASSAYS: provide an exact result, which allows an accurate statement on the content or potency of the analyte in a sample Determination-In the case of qualitative analyses(identification tests), the ability to select between compounds of closely related structure that are likely to be present should be demonstrated. This should be confirmed by obtaining positive results (perhaps by comparison to a known reference material) from samples containing the analyte, coupled with negative results from samples that do not contain the analyte and by confirming that a positive response is not obtained from materials structurally similar to or closely related to the analyte In the case of analytical procedure for impurities, specificity may be established by spiking the drug substance or product with appropriate levels of impurities and demonstrating that these impurities are determined with appropriated accuracy and In the case of the assay, demonstration of specificity requires that it can be shown that the procedure is unaffected by the presence of impurities or excipients. In practice, this can be done by spiking the drug substance or product with appropriate

or equipment within the same laboratory. Repeatability refers to the use of the analytical procedure within a laboratory over a short  period of time using the same analyst with the same equipment.  For most purposes,  repeatability is the criterion of concern in USP analytical  procedures,  repeatability is the criterion of concern in USP analytical  procedures,  although  reproducibility between laboratories or intermediate precision may well be considered during the standardization of a procedure before it is submitted to the Pharmacopeia. Determination­The precision of an analytical  method is determined by assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically  valid estimates  of standard deviation or relative standard deviation  (coefficient  of variation).  Assays  in  this context  are independent  analyses  of samples  that  have been carried through the complete analytical procedure from sample preparation to final test result.  The ICH documents recommend that repeatability should be assessed using a minimum of nine determinations covering  the specified range for the procedure (i.e., three concentrations and three replicates of each concentration or using a minimum  of six deter minations at 100% of the test concentration). Specificity Definition­The ICH  documents define specificity as  the ability to  assess  unequivocally the analyte in  the presence of components that may be expected to be present, such as impurities,  degradation products,  and matrix  components.  Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedures. [NOTE­Other reputable international  authorities  (IUPAC,  AOAC) have preferred the term “selectivity”,  reserving “specificity” for those procedures  that  are completely  selective.] For the test or assay methods  below,  the above definition  has  the following  implications: IDENTIFICATION TESTS: ensure the identity of the analyte.  PURITY TESTS:  ensure that  all the analytical  procedures  performed allow an accurate statement  of the content  of impurities of an analyte (e.g., related substances test, heavy metals limit, organic volatile impurity limit).  ASSAYS: provide an exact result, which allows an accurate statement on the content or potency of the analyte in a sample. Determination­In the case of qualitative analyses (identification tests), the ability to select between compounds of closely  related structure that are likely to be present should be demonstrated. This should be confirmed by obtaining positive results  (perhaps by comparison to a known reference material) from samples containing the analyte, coupled with negative results from  samples that do not contain the analyte and by confirming that a positive response is not obtained from materials structurally  similar to or closely related to the analyte.  In the case of analytical procedure for impurities, specificity may be established by spiking the drug substance or product  with appropriate levels of impurities  and demonstrating that these impurities are determined with appropriated accuracy and  precision.  In the case of the assay, demonstration of specificity requires that it can be shown that the procedure is unaffected by the presence of impurities or excipients. In practice, this can be done by spiking the drug substance or product with appropriate

levels of impurities or excipients and demonstrating that the assay result is unaffected by the presence of these extraneous materials If impurity or degradation product standards are unavailable, specificity may be demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure(e.g, a pharmacopeial or other validated procedure). These comparisons should include samples stored under relevant stress conditions(. g, light, heat humidity, acid/base hydrolysis, oxidation). In the case of the assay, the results should be compared; in the case of chromatographic impurity tests, the impurity profiles should be compared The ICh documents state that when chromatographic procedures are used, representative chromatograms should be presented to demonstrate the degree of selectivity, and peaks should be appropriatedly labeled Peak purity tests(e.g, using diode array or mass spectrometry) may be useful to show that the analyte chromatographic peak is not attributable to more than Detection Limit Definition-The detection limit is a characteristic of limit tests. It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. Thus, limit tests merely substantiate that the amount of analyte is above or below a certain level. The detection limit is usually expressed as the concentration of analyte(e. g percentage. parts per billion) in the sample Determination-For noninstrumental methods, the detection limit is generally 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 For instrumental procedures, the same method may be used as for noninstrumental. In the case of methods submitted for consideration as official compendial methods, it is almost never necessary to determine the actual detection limit. Rather, the detection limit is shown to be sufficiently low by the analysis of samples with known concentration of analyte above and below the require detection vevel. For example, if it is required to detect an impurity at the level of 0. 1%, it should be demonstrated that the procedure will reliably detect the impurity at that level In the case of instrumental analytical procedures that exhibit back ground noise, the ICh documents describe a common approach, which is to compare measure signals from samples with known low concentrations at which the analyte can reliably be detected is established, Typically acceptable signal-to-noise ratios are 2: 1 or 3: 1. Other approaches depend on the determination of the slope of the calibation curve and the standard deviation of responses. Whatever method is used,the detection limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at the detection limit Quantitation limit- Definition-The quantitation limit is a characteristic of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions

levels of impurities or excipients and demonstrating that the assay result is unaffected by the presence of these extraneous  materials.  If impurity or degradation product standards are unavailable, specificity may be demonstrated by comparing the test results  of samples  containing impurities or degradation products to a second well­characterized procedure (e.g.,  a pharmacopeial or other validated procedure). These comparisons should include samples stored under relevant stress conditions (e.g., light, heat,  humidity,  acid/base hydrolysis,  oxidation).  In the case of the assay,  the results should be compared;  in the case of chromatographic impurity tests, the impurity profiles should be compared.  The ICH  documents state that  when chromatographic procedures  are used,  representative chromatograms  should be presented to demonstrate the degree of selectivity,  and peaks should be appropriatedly labeled. Peak purity tests (e.g., using  diode array or mass spectrometry) may be useful to show that the analyte chromatographic peak is not attributable to more than  one component. Detection Limit Definition­The detection limit is a characteristic of limit tests. It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. Thus, limit tests merely substantiate that the amount of analyte is above or below a certain level. The detection limit is usually expressed as the concentration of analyte (e.g.,  percentage. parts per billion) in the sample. Determination­For noninstrumental methods, the detection limit is generally 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.  For instrumental procedures, the same method may be used as for noninstrumental. In the case of methods submitted for consideration as official compendial methods, it is almost never necessary to determine the actual detection limit. Rather, the detection limit is shown to be sufficiently low by the analysis of samples with known concentration of analyte above and below  the require detection vevel. For example, if it is required to detect an impurity at the level of 0.1%, it should be demonstrated  that the procedure will reliably detect the impurity at that level.  In the case of instrumental analytical procedures that exhibit back ground noise, the ICH documents describe a common  approach, which is to compare measure signals from samples with known low concentrations at which the analyte can reliably  be detected is established,  Typically acceptable signal­to­noise ratios  are 2:1  or 3:1.  Other approaches  depend on the determination of the slope of the calibation curve and the standard deviation of responses.  Whatever method is used,  the detection limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared  at, the detection limit. Quantitation Limit￾Definition­The quantitation limit is a characteristic of quantitative assays for low levels of compounds in sample matrices,  such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. It is the lowest amount  of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions

The quantitation limit is expressed as the concentration of analyte(e. g, percentage, parts per billion) in the sample Determination-For noninstrumental methods, the quantitation limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision For instrumental procedures, the same method may be used as for noninstrumental. In the case of methods submitted for consideration as official compendial methods, it is almost never necessary to determine the actual quantitation limit. Rather, the quantitation limit is shown to be sufficiently low by the analysis of samples with known concentrations of analyte above and below the quantitation level. For example, if it is required to assay an analyte at the level of 0. lmg per tablet, it should be demonstrated that the method will reliably quantitate the analyte at that level In the case of instrumental analytical methods that exihibit back-ground noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be quantified is established. a typically acceptable signal-to-noise ratio is 10: 1. Other approaches depend on the determination of the slope of the calibration curve and the standard deviation of responses. Whatever method is used, the quantitation limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at, the quantitation limit Linearity and Range Definition of linearity-The linearity of an analytical method is its ability to elicit test results tha at are well-defined mathematical transformation, proportional to the concentration of analyte in samples within a given range Definition of Range-The range of an analytical method is the interval between the upper and lower levels of analyte (including thses levels)that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity using the method as written. The range is normally expressed in the same units as test results(e.g, percent, parts per million) btained by the analytical method. Determination of Linearity and Range-Linearity should be established across the range of the analytical procedure. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. If there appears to be a linear relationship, test results should be established by appropriate statistical methods(e.g, by calculatio of a regression line by the method of least squares). In some cases, to obtain linearity between the response of an analyte and its concentration, the test, data may have to be subjected to a mathematical transformation. Data from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity. The correlation coefficient, y-intercept. slope of the regression line, and residual sum of squares should be submitted The range of the method is validate by verifying that the analytical method provides acceptable precision, accuracy, and linearity when applied to samples containing analyte at the extremes of the range as well as within the range ICH recommends that, for the establishment of linearity, a minimum of five concentrations normally be used It is also recommended that the following minimum specified ranges should be considered

The quantitation limit is expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample. Determination­For noninstrumental methods, the quantitation limit is generally determined by the analysis of samples with  known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision.  For instrumental procedures, the same method may be used as for noninstrumental. In the case of methods submitted for consideration as official compendial methods, it is almost never necessary to determine the actual quantitation limit. Rather, the  quantitation limit is shown to be sufficiently low by the analysis of samples with known concentrations of analyte above and  below the quantitation level. For example, if it is required to assay an analyte at the level  of 0.1mg  per tablet, it should be demonstrated that the method will reliably quantitate the analyte at that level.  In the case of instrumental  analytical methods that exihibit back­ground noise, the ICH documents describe  a common  approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank  samples.  The minimum concentration at  which the analyte can reliably be quantified is established.  A typically acceptable signal­to­noise ratio is 10:1.  Other approaches  depend on the determination of the slope of the calibration curve and the standard deviation of responses.  Whatever method is used,  the quantitation limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at, the quantitation limit. Linearity and Range Definition  of  linearity­The linearity of an analytical  method is its  ability to elicit test results  that  are directly,  or by a well­defined mathematical transformation, proportional to the concentration of analyte in samples within a given range. Definition  of  Range­The range of an analytical  method is the interval  between the upper and lower levels  of analyte (including thses levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity  using the method as written. The range is normally expressed in the same units as test results (e.g., percent, parts per million) obtained by the analytical method.  Determination of Linearity and Range­Linearity should be established across  the range of the analytical  procedure.  It  should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. If there appears to be a linear relationship, test results should be established by appropriate statistical methods (e.g., by calculation  of a regression line by the method of least squares). In some cases, to obtain linearity between the response of an analyte and its  concentration, the test, data may have to be subjected to a mathematical transformation. Data from the regression line itself may  be helpful to provide mathematical  estimates of the degree of linearity. The correlation coefficient, y­intercept. slope of the regression line, and residual sum of squares should be submitted.  The range of the method is validate by verifying that the analytical method provides acceptable precision, accuracy, and  linearity when applied to samples containing annalyte at the extremes of the range as well as within the range.  ICH recommends that, for the establishment of linearity,  a minimum of five concentrations normally be used. It is also  recommended that the following minimum specified ranges should be considered:

ASSAY OF A DRUG SUBSTANCE (or a finished product): from 80% to 120% of the test concentration. DETERMINATION OF AN IMPURITY: from 50% to 120% of the specification. FOR CONTENT UNIFORMITY: a minimum of 70% to 130% of the test concentration, unless a wider or more appropriate range, based on the nature of the dosage form(e.g, metered-dose)inhalers) is justified FOR DISSOLUTION TESTING +20% over the specified range(e.g, if the specifications for a controlled-release product cover a region from 20%, after I hour, and up to 90%, after 24 hours, the validated range would be 0% to 110% of the label Ruggedness Definition-The ruggedness of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of conditions, such as different laboratories, different analysts, different instruments different lots of reagents, different elapsed assay times, different assay temperatures, different days, etc. Ruggedness is normally expressed as the lack of influence on test results of operational and environmental variables of the analytical method Ruggedness is a measure of reproducibility of test results under the variation in conditions normally expected from laboratory to laboratory and from analyst to analyst Determination- The ruggedness of an analytical method is determined by analysis of aliquots from homogeneous lots in different laboratories, by different analysts, using operational and environmental conditions that may differ but are still within the specified parameters of the assay. The degree of reproducibility of test results is then determined as a function of the assay variables. This reproducibility may be compared to the precision of the assay under normal conditions to obtain a measure of the ruggedness of the analytical method. Robustness Definition-The robustness of an analytical method 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 System Suitability-lf measurements are susceptible to variation in analytical conditions, these should be suitably controlled, or a precautionary statement should be included in the method. One consequence of the evaluation of robusness and ruggedness should be that a series of system suitability parameters is established to ensure that the validity of the analytical method is maintained whenever used. Typical variations are the stability of analytical solutions, different equipment, and different analysts In the case of liquid chromatography, typical variations are the ph of the mobile phase, the mobile phase compositions. different lots or suppliers of columns, the temperature, and the flow rate. In the case of gas chromatography, typical variations are different lots or suppliers of columns, the temperature, and the flow rate System suitability tests are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a articular method depend on the type of method being evaluated. They are especially important in the case of chromatographic methods, and submissions to the USP should make note of the requirements under the System Suitability section in the general

ASSAY OF A DRUG SUBSTANCE (or a finished product): from 80% to 120% of the test concentration.  DETERMINATION OF AN IMPURITY: from 50% to 120% of the specification.  FOR  CONTENT UNIFORMITY:  a minimum of 70% to 130% of the test concentration,  unless  a wider or more appropriate range,  based on the nature of the dosage form (e.g., metered­dose) inhalers) is justified.  FOR DISSOLUTION TESTING±20% over the specified range (e.g., if the specifications for a controlled­release product  cover a region from 20%, after 1 hour, and up to 90%, after 24 hours, the validated range would be 0% to 110% of the label  claim). Ruggedness Definition­The ruggedness of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same samples  under a variety of conditions, such as  different  laboratories,  different  analysts,  different  instruments,  different  lots of reagents,  different  elapsed assay times,  different  assay temperatures,  different  days,  etc.  Ruggedness  is normally expressed as the lack of influence on test results of operational and environmental variables of the analytical method.  Ruggedness is a measure of reproducibility of test results under the variation in conditions normally expected from laboratory  to laboratory and from analyst to analyst. Determination­The ruggedness  of an analytical method is determined by analysis of aliquots from homogeneous lots in  different laboratories, by different analysts, using operational and environmental conditions that may differ but are still within  the specified parameters of the assay. The degree of reproducibility of test results is then determined as a function of the assay  variables. This reproducibility may be compared to the precision of the assay under normal conditions to obtain a measure of the ruggedness of the analytical method. Robustness Definition­The robustness of an analytical method 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.  System Suitability­If measurements are susceptible to variation in analytical conditions, these should be suitably controlled,  or a precautionary statement should be included in the method. One consequence of the evaluation of robusness and ruggedness  should be that  a series  of system suitability parameters  is established to ensure that the validity of the analytical method is maintained whenever used.  Typical  variations  are the stability of analytical  solutions,  different  equipment,  and different  analysts. In the case of liquid chromatography, typical variations are the pH of the mobile phase, the mobile phase compositions,  different lots or suppliers of columns, the temperature, and the flow rate. In the case of gas chromatography, typical variations  are different lots or suppliers of columns, the temperature, and the flow rate.  System suitability tests are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular method depend on the type of method being evaluated. They are especially important in the case of chromatographic methods, and submissions to the USP should make note of the requirements under the System Suitability section in the general

test chapter Chromatography(621) DATA ELEMENTS REQUIRED FOR ASSAY VALIDATION Compendial assay procedures vary from highly exacting analytical determinations to subjective evaluation of attributes Considering this variety of assays. It is only logical that different test methods require different validatio mes. this chapter covers only the most common categories of assays for which validation data should be required These categories are as follows. Category 1-Analytical methods for quantiation of major components of bulk drug substances or active ingredients (incluing preservatives) in finished pharmaceutical products Category I-Analytical methods for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These methods include quantitative assays and limit tests Category II-Analytical methods for determination of performance characteristics(e.g, dissolution, drug release) Category I-ldentification tests For each assay category, different analytical information is needed. Listed in Table 2 are data elements that are normally for each of the categ Already established general assays and tests(. g, titrimetric method of water determination, bacterial endotoxins test) should be revalidated to verify their accuracy(and absence of possible interference)when used for a new product or raw material The validity of an analytical method can be verified only by laboratory studies. Therefore, documentation of the successful completion of such studies is a basic requirement for determining whether a method is suitable for its intended applications ppropriate documentation should accompany any proposal for new or revised compendial analytical procedures Table 2. Data Elements Required for Assay Validation Analytical Performance Assay Category II Assay Assay Characteristics Category I Quantitative Limit Tests Category Il Category IV Accuracy Y Yes ecision es Detection Limit No Quantitation Limit No Yes Linearity Y Yes N May be required, depending on the nature of the specific test

test chapter Chromatography (621). DATA ELEMENTS REQUIRED FOR ASSAY VALIDATION Compendial  assay procedures  vary from highly exacting analytical  determinations  to subjective evaluation of attributes.  Considering  this variety of assays.  It  is only logical  that  different  test methods  require different  validation schemes.  This chapter covers only the most common categories of assays for which validation data should be required These categories are as  follows: Category  I­Analytical  methods  for quantiation of major components of bulk drug substances  or active ingredients  (incluing preservatives) in finished pharmaceutical products. Category  Ⅱ­Analytical methods for determination of impurities in bulk drug substances  or degradation compounds in  finished pharmaceutical products. These methods include quantitative assays and limit tests. Category  Ⅲ­Analytical methods for determination of performance characteristics (e.g., dissolution, drug release). Category  Ⅳ­Identification tests.  For each assay category, different analytical information is needed. Listed in Table 2 are data elements that are normally  required for each of the categories of assays.  Already established general  assays  and tests (e.g.,  titrimetric method of water determination,  bacterial  endotoxins test)  should be revalidated  to verify their  accuracy (and absence of possible interference) when used for a new product  or raw  material.  The validity of an analytical method can be verified only by laboratory studies. Therefore, documentation of the successful  completion of such studies is a basic requirement for determining whether a method is suitable for its intended applications.  Appropriate documentation should accompany any proposal for new or revised compendial analytical procedures.  Table 2. Data Elements Required for Assay Validation  Analytical Performance Assay  Category  Ⅱ Characteristics  Assay  Category I Quantitative Limit Tests Assay  Category  Ⅲ Assay  Category IV  Accuracy  Yes  Yes  *  *  No  Precision  Yes  Yes  No  Yes  No  Specificity  Yes  Yes  Yes  *  Yes  Detection Limit No  No  Yes  *  No  Quantitation Limit No  Yes  No  *  No  Linearity  Yes  Yes  No  *  No  Range Yes  Yes  *  *  No  * May be required, depending on the nature of the specific test