美国药典35版USP 1225 VALIDATION OF COMPENDIAL PROCEDURES

It is recommended that expired, aged, or spiked samples ELEMENTS RECOMMENDED FOR THE

be carefully chosen and evaluated to identify potential TRANSFER OF ANAYTICAL PROCEDURES

problems related to differences in sample preparation equip-

ment and to evaluate the impact of potential aberrant re-Several elements, many of which may be interrelated, are sults on marketed products. The documentation section of

recommended for a successful TAP. When appropriate and the transfer protocol may include report forms to ensure

as a part of pretransfer activities, the transferring unit should consistent recording of results and to improve consistency provide training to the receiving unit, or the receiving unit between laboratories. This section should contain the addi-should run the procedures and identify any issues that may tional information that will be included with the results, need to be resolved before the transfer protocol is signed.such as example chromatograms and spectra, along with Training should be documented.additional information in case of a deviation. The protocol The transferring unit, often the development unit, is re-should also explain how any deviation from the acceptance sponsible for providing the analytical procedure, the refer-criteria will be managed. Any changes to the transfer proto-ence standards, the validation reports, and any necessary col following failure of an acceptance criterion must be ap-documents, as well as for providing the necessary training proved before collection of additional data.

and assistance to the receiving unit as needed during the

transfer. The receiving unit may be a quality control unit,

another intracompany facility, or another company such as THE ANALYTICAL PROCEDURE

a contract research organization. The receiving unit provides

qualified staff or properly trains the staff before the transfer,The procedure should be written with sufficient detail and ensures that the facilities and instrumentation are properly explicit instructions, so that a trained analyst can perform it calibrated and qualified as needed, and verifies that the lab-without difficulty. A pretransfer meeting between the trans-oratory systems are in compliance with applicable regula-ferring and receiving units is helpful to clarify any issues and tions and in-house general laboratory procedures. Both the answer any questions regarding the transfer process. If com-transferring and receiving units should compare and discuss plete or partial validation data exist, they should be availa-data as well as any deviations from the protocol. This dis-ble to the receiving unit, along with any technical details cussion addresses any necessary corrections or updates to required to perform the test in question. In some cases it the final report and the analytical procedure as necessary to may be useful for the individuals who were involved with reproduce the procedure.the initial development or validation to be on site during

A single lot of the article may be used for the transfer,the transfer. The number of replicates and injection se-because the aim of the transfer is not related to the manu-quences in the case of liquid or gas chromatography should facturing process but rather to the evaluation of the analyti-be clearly expressed, and, in the case of dissolution testing, cal procedure’s performance at the receiving site.the number of individual dosage units should be stipulated.

PREAPPROVED PROTOCOL TRANSFER REPORT

A well-designed protocol should be discussed, agreed When the TAP is successfully completed, the receiving upon, and documented before the implementation of TAP.unit should prepare a transfer report that describes the re-The document expresses a consensus between the parties,sults obtained in relation to the acceptance criteria, along indicating an intended execution strategy, and should in-with conclusions that confirm that the receiving unit is now clude each party’s requirements and responsibilities. It is qualified to run the procedure. Any deviations should be recommended that the protocol contain the following top-thoroughly documented and justified. If the acceptance cri-ics as appropriate: objective, scope, responsibilities of the teria are met, the TAP is successful and the receiving unit is transferring and receiving units, materials and instruments qualified to run the procedure. Otherwise, the procedure that will be used, analytical procedure, experimental design,cannot be considered transferred until effective remedial and acceptance criteria for all tests and/or methods included steps are adopted in order to meet the acceptance criteria. in the transfer. Based on the validation data and procedural An investigation may provide guidance about the nature knowledge, the transfer protocol should identify the specific and extent of the remedial steps, which may vary from fur-analytical performance characteristics (see ?1225?and ther training and clarification to more complex approaches,?1226?) that will be evaluated and the analysis that will be depending on the particular procedure.

v USP35

used to evaluate acceptable outcomes of the transfer

exercise.

The transfer acceptance criteria, which are based on

method performance and historical data from stability and

release results, if available, should include the comparability

criteria for results from all study sites. These criteria may be

derived using statistical principles based on the difference?1225? VALIDATION OF between mean values and established ranges and should be

accompanied by an estimation of the variability (e.g., per-COMPENDIAL PROCEDURES cent relative standard deviation [%RSD] for each site), par-

ticularly for the intermediate precision %RSD of the receiv-

ing unit and/or a statistical method for the comparison of

the means for assay and content uniformity tests. In in-Test procedures for assessment of the quality levels of stances of impurity testing, where precision may be poorer pharmaceutical articles are subject to various requirements. such as in the case of trace impurities, a simple descriptive According to Section 501 of the Federal Food, Drug, and approach can be used. Dissolution can be evaluated by a Cosmetic Act, assays and specifications in monographs of comparison of the dissolution profiles using the similarity the United States Pharmacopeia and the National Formulary factor f2 or by comparison of data at the specified time constitute legal standards. The Current Good Manufacturing points. The laboratories should provide appropriate rationale Practice regulations 211.194(a)] require that test methods, for any analytical performance characteristic not included.which are used for assessing compliance of pharmaceutical The materials, reference standards, samples, instruments,articles with established specifications, must meet proper and instrumental parameters that will be used should be standards of accuracy and reliability. Also, according to described.these regulations 211.194(a)(2)], users of analytical methods

described in USP–NF are not required to validate the accu-

racy and reliability of these methods, but merely verify their sure. Thus, a test result can be a result calculated from sev-suitability under actual conditions of use. Recognizing the eral observed values. In the simple case, the test result is the legal status of USP and NF standards, it is essential, there-observed value itself.” A test result also can be, but need fore, that proposals for adoption of new or revised com-not be, the final, reportable value that would be compared pendial analytical procedures be supported by sufficient lab-to the acceptance criteria of a specification. Validation of oratory data to document their validity.physical property methods may involve the assessment of The text of this information chapter harmonizes, to the chemometric models. However, the typical analytical charac-extent possible, with the Tripartite International Conference teristics used in method validation can be applied to the

on Harmonization (ICH) documents Validation of Analytical methods derived from the use of the chemometric models. Procedures and the Methodology extension text, which are The effects of processing conditions and potential for seg-concerned with analytical procedures included as part of re-regation of materials should be considered when obtaining gistration applications submitted within the EC, Japan, and a representative sample to be used for validation of

the USA.procedures.

Table 1. Typical Analytical Characteristics SUBMISSIONS TO THE COMPENDIA

Used in Method Validation

Submissions to the compendia for new or revised analyti-Accuracy

cal procedures should contain sufficient information to en-Precision

able members of the USP Council of Experts and its Expert

Specificity

Committees to evaluate the relative merit of proposed pro-

Detection Limit

cedures. In most cases, evaluations involve assessment of

Quantitation Limit

the clarity and completeness of the description of the ana-

lytical procedures, determination of the need for the proce-Linearity

dures, and documentation that they have been appropri-Range

ately validated. Information may vary depending upon the Robustness

type of method involved. However, in most cases a submis-

sion will consist of the following sections.In the case of compendial procedures, revalidation may

be necessary in the following cases: a submission to the USP Rationale—This section should identify the need for the

of a revised analytical procedure; or the use of an estab-procedure and describe the capability of the specific proce-

lished general procedure with a new product or raw mate-dure proposed and why it is preferred over other types of

rial (see below in Data Elements Required for Validation). determinations. For revised procedures, a comparison

The ICH documents give guidance on the necessity for should be provided of limitations of the current compendial

revalidation in the following circumstances: changes in the procedure and advantages offered by the proposed

synthesis of the drug substance; changes in the composition procedure.

of the drug product; and changes in the analytical Proposed Analytical Procedure—This section should

procedure.

contain a complete description of the analytical procedure

Chapter ?1225? is intended to provide information that is sufficiently detailed to enable persons “skilled in the art” to

appropriate to validate a wide range of compendial analyti-replicate it. The write-up should include all important opera-

cal procedures. The validation of compendial procedures tional parameters and specific instructions such as prepara-

may use some or all of the suggested typical analytical char-tion of reagents, performance of system suitability tests,

acteristics used in method validation as outlined in Table 1 description of blanks used, precautions, and explicit formu-

and categorized by type of analytical method in Table 2.

las for calculation of test results.

For some compendial procedures the fundamental principles Data Elements—This section should provide thorough of validation may extend beyond characteristics suggested

and complete documentation of the validation of the analyt-in Chapter ?1225?. For these procedures the user is referred ical procedure. It should include summaries of experimental to the individual compendial chapter for those specific ana-data and calculations substantiating each of the applicable lytical validation characteristics and any specific validation analytical performance characteristics. These characteristics requirements.

are described in the following section.

Analytical Performance Characteristics VALIDATION

Validation of an analytical procedure is the process by

which it is established, by laboratory studies, that the per-ACCURACY

formance characteristics of the procedure meet the require-

ments for the intended analytical applications. Typical ana-Definition—The accuracy of an analytical procedure is lytical performance characteristics that should be considered the closeness of test results obtained by that procedure to in the validation of the types of procedures described in this the true value. The accuracy of an analytical procedure document are listed in Table 1. Because opinions may differ should be established across its range. [A note on terminol-with respect to terminology and use, each of the perfor-ogy: The definition of accuracy in ?1225? and ICH Q2 corre-mance characteristics is defined in the next section of this sponds to unbiasedness only. In the International Vocabulary chapter, along with a delineation of a typical method or of Metrology (VIM) and documents of the International Or-methods by which it may be measured. The definitions refer ganization for Standardization (ISO), “accuracy” has a differ-to “test results.” The description of the analytical procedure ent meaning. In ISO, accuracy combines the concepts of should define what the test results for the procedure are. As unbiasedness (termed “trueness”) and precision.]

noted in ISO 5725-1 and 3534-1, a test result is “the value

Determination—In the case of the assay of a drug sub-of a characteristic obtained by carrying out a specified test

stance, accuracy may be determined by application of the method. The test method should specify that one or a num-

analytical procedure to an analyte of known purity (e.g., a ber of individual measurements be made, and their average,

Reference Standard) or by comparison of the results of the or another appropriate function (such as the median or the

procedure with those of a second, well-characterized proce-standard deviation), be reported as the test result. It may

dure, the accuracy of which has been stated or defined. also require standard corrections to be applied, such as cor-

In the case of the assay of a drug in a formulated prod-rection of gas volumes to standard temperature and pres-

uct, accuracy may be determined by application of the ana-

lytical procedure to synthetic mixtures of the drug product through the complete analytical procedure from sample components to which known amounts of analyte have been preparation to final test result.

added within the range of the procedure. If it is not possible The ICH documents recommend that repeatability should to obtain samples of all drug product components, it may be assessed using a minimum of nine determinations cover-be acceptable either to add known quantities of the analyte ing the specified range for the procedure (i.e., three con-

to the drug product (i.e., “to spike”) or to compare results centrations and three replicates of each concentration) or with those of a second, well-characterized procedure, the using a minimum of six determinations at 100% of the test accuracy of which has been stated or defined.concentration.

In the case of quantitative analysis of impurities, accuracy

should be assessed on samples (of drug substance or drug

SPECIFICITY

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 Definition—The ICH documents define specificity as the those obtained by an independent procedure. In the ab-ability to assess unequivocally the analyte in the presence of sence of other information, it may be necessary to calculate components that may be expected to be present, such as the amount of an impurity based on comparison of its re-impurities, degradation products, and matrix components. sponse to that of the drug substance; the ratio of the re-Lack of specificity of an individual analytical procedure may sponses of equal amounts of the impurity and the drug sub-be compensated by other supporting analytical procedures. stance (relative response factor) should be used if known.[N OTE—Other reputable international authorities (IUPAC, Accuracy is calculated as the percentage of recovery by AOAC-I) have preferred the term “selectivity,” reserving

the assay of the known added amount of analyte in the“specificity” for those procedures that are completely selec-sample, or as the difference between the mean and the ac-tive.] For the tests discussed below, the above definition has cepted true value, together with confidence intervals.the following implications:

The ICH documents recommend that accuracy should be Identification Tests:ensure the identity of the analyte. assessed using a minimum of nine determinations over a Purity Tests:ensure that all the analytical procedures minimum of three concentration levels, covering the speci-performed allow an accurate statement of the content of fied range (i.e., three concentrations and three replicates of impurities of an analyte (e.g., related substances test, heavy each concentration).metals limit, organic volatile impurities).

Assessment of accuracy can be accomplished in a variety

Assays:provide an exact result, which allows an accu-of ways, including evaluating the recovery of the analyte

rate statement on the content or potency of the analyte in a (percent recovery) across the range of the assay, or evaluat-

sample.

ing the linearity of the relationship between estimated and

Determination—In the case of qualitative analyses (iden-actual concentrations. The statistically preferred criterion is

tification tests), the ability to select between compounds of that the confidence interval for the slope be contained in an

closely related structure that are likely to be present should interval around 1.0, or alternatively, that the slope be close

be demonstrated. This should be confirmed by obtaining

to 1.0. In either case, the interval or the definition of close-

positive results (perhaps by comparison to a known refer-ness should be specified in the validation protocol. The ac-

ence material) from samples containing the analyte, coupled ceptance criterion will depend on the assay and its variabil-

with negative results from samples that do not contain the ity and on the product. Setting an acceptance criterion

analyte and by confirming that a positive response is not based on the lack of statistical significance of the test of the

obtained from materials structurally similar to or closely re-null hypothesis that the slope is 1.0 is not an acceptable

lated to the analyte.

approach.

In the case of analytical procedures for impurities, specific-Accuracy of physical property methods may be assessed

ity may be established by spiking the drug substance or through the analysis of standard reference materials, or al-

product with appropriate levels of impurities and demon-ternatively, the suitability of the above approaches may be

strating that these impurities are determined with appropri-considered on a case-by-case basis.

ate accuracy and precision.

In the case of the assay, demonstration of specificity re-PRECISION quires 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 Definition—The precision of an analytical procedure is

appropriate levels of impurities or excipients and demon-the degree of agreement among individual test results when

strating that the assay result is unaffected by the presence the procedure is applied repeatedly to multiple samplings of

of these extraneous materials.

a homogeneous sample. The precision of an analytical pro-

If impurity or degradation product standards are unavaila-cedure is usually expressed as the standard deviation or rela-

ble, specificity may be demonstrated by comparing the test tive standard deviation (coefficient of variation) of a series of

results of samples containing impurities or degradation measurements. Precision may be a measure of either the

products to a second well-characterized procedure (e.g., a degree of reproducibility or of repeatability of the analytical

Pharmacopeial or other validated procedure). These compar-procedure under normal operating conditions. In this con-

isons should include samples stored under relevant stress text, reproducibility refers to the use of the analytical proce-

conditions (e.g., light, heat, humidity, acid/base hydrolysis, dure in different laboratories, as in a collaborative study. In-

and oxidation). In the case of the assay, the results should termediate precision (also known as ruggedness) expresses

be compared; in the case of chromatographic impurity tests, within-laboratory variation, as on different days, or with dif-

the impurity profiles should be compared.

ferent analysts or equipment within the same laboratory.

The ICH documents state that when chromatographic Repeatability refers to the use of the analytical procedure

procedures are used, representative chromatograms should within a laboratory over a short period of time using the

be presented to demonstrate the degree of selectivity, and same analyst with the same equipment.

peaks should be appropriately labeled. Peak purity tests Determination—The precision of an analytical procedure

(e.g., using diode array or mass spectrometry) may be use-is determined by assaying a sufficient number of aliquots of

ful to show that the analyte chromatographic peak is not

a homogeneous sample to be able to calculate statistically

attributable to more than one component.

valid estimates of standard deviation or relative standard

For validation of specificity for qualitative and quantitative deviation (coefficient of variation). Assays in this context are

determinations by spectroscopic methods, chapters related independent analyses of samples that have been carried

to topics such as near-infrared spectrophotometry, raman

spectroscopy, and X-ray powder diffraction should be samples with known low concentrations of analyte with consulted.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 ap-DETECTION LIMIT proaches depend on the determination of the slope of the

calibration curve and the standard deviation of responses.

Definition—The detection limit is a characteristic of limit Whatever approach is used, the quantitation limit should be tests. It is the lowest amount of analyte in a sample that can subsequently validated by the analysis of a suitable number be detected, but not necessarily quantitated, under the of samples known to be near, or prepared at, the quantita-stated experimental conditions. Thus, limit tests merely sub-tion limit.

stantiate that the amount of analyte is above or below a

certain level. The detection limit is usually expressed as the

LINEARITY AND RANGE

concentration of analyte (e.g., percentage, parts per billion)

in the sample.

Definition of Linearity—The linearity of an analytical Determination—For noninstrumental procedures, the

procedure is its ability to elicit test results that are directly, detection limit is generally determined by the analysis of

or by a well-defined mathematical transformation, propor-samples with known concentrations of analyte and by estab-

tional to the concentration of analyte in samples within a lishing the minimum level at which the analyte can be relia-

given range. Thus, in this section, “linearity” refers to the bly detected.

linearity of the relationship of concentration and assay meas-For instrumental procedures, the same approach may be

urement. In some cases, to attain linearity, the concentra-used as for noninstrumental procedures. In the case of pro-

tion and/or the measurement may be transformed. (Note cedures submitted for consideration as official compendial

that the weighting factors used in the regression analysis procedures, it is almost never necessary to determine the

may change when a transformation is applied.) Possible actual detection limit. Rather, the detection limit is shown

transformations may include log, square root, or reciprocal, to be sufficiently low by the analysis of samples with known

although other transformations are acceptable. If linearity is concentrations of analyte above and below the required de-

not attainable, a nonlinear model may be used. The goal is tection level. For example, if it is required to detect an im-

to have a model, whether linear or nonlinear, that describes purity at the level of 0.1%, it should be demonstrated that

closely the concentration-response relationship.

the procedure will reliably detect the impurity at that level.

In the case of instrumental analytical procedures that ex-Definition of Range—The range of an analytical proce-hibit background noise, the ICH documents describe a com-dure is the interval between the upper and lower levels of mon approach, which is to compare measured signals from analyte (including these levels) that have been demon-samples with known low concentrations of analyte with strated to be determined with a suitable level of precision, those of blank samples. The minimum concentration at accuracy, and linearity using the procedure as written. The which the analyte can reliably be detected is established.range is normally expressed in the same units as test results Typically acceptable signal-to-noise ratios are 2:1 or 3:1.(e.g., percent, parts per million) obtained by the analytical Other approaches depend on the determination of the slope procedure.

of the calibration curve and the standard deviation of re-Determination of Linearity and Range—Linearity sponses. Whatever method is used, the detection limit should be established across the range of the analytical pro-should be subsequently validated by the analysis of a suita-cedure. It should be established initially by visual examina-ble number of samples known to be near, or prepared at,tion of a plot of signals as a function of analyte concentra-the detection limit.tion 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 QUANTITATION LIMIT method of least squares). Data from the regression line itself

may be helpful to provide mathematical estimates of the Definition—The quantitation limit is a characteristic of degree of linearity. The correlation coefficient, y-intercept, quantitative assays for low levels of compounds in sample slope of the regression line, and residual sum of squares matrices, such as impurities in bulk drug substances and should be submitted.

degradation products in finished pharmaceuticals. It is the The range of the procedure is validated by verifying that lowest amount of analyte in a sample that can be deter-the analytical procedure provides acceptable precision, accu-mined with acceptable precision and accuracy under the racy, and linearity when applied to samples containing stated experimental conditions. The quantitation limit is ex-analyte at the extremes of the range as well as within the pressed as the concentration of analyte (e.g., percentage,range.

parts per billion) in the sample.ICH recommends that, for the establishment of linearity, a Determination—For noninstrumental procedures, the minimum of five concentrations normally be used. It is also quantitation limit is generally determined by the analysis of recommended that the following minimum specified ranges samples with known concentrations of analyte and by estab-should be considered:

lishing the minimum level at which the analyte can be de-Assay of a Drug Substance (or a finished product):from termined with acceptable accuracy and precision.80% to 120% of the test concentration.

For instrumental procedures, the same approach may be Determination of an Impurity:from 50% to 120% of the used as for noninstrumental procedures. In the case of pro-acceptance criterion.

cedures submitted for consideration as official compendial

For Content Uniformity: a minimum of 70% to 130% of procedures, it is almost never necessary to determine the

the test concentration, unless a wider or more appropriate actual quantitation limit. Rather, the quantitation limit is

range based on the nature of the dosage form (e.g., me-shown to be sufficiently low by the analysis of samples with

tered-dose inhalers) is justified.

known concentrations of analyte above and below the

For Dissolution Testing:±20% over the specified range quantitation level. For example, if it is required that an

(e.g., if the acceptance criteria for a controlled-release prod-analyte be assayed at the level of 0.1 mg per tablet, it

uct cover a region from 30%, after 1 hour, and up to 90%, should be demonstrated that the procedure will reliably

after 24 hours, the validated range would be 10% to 110% quantitate the analyte at that level.

of the label claim).

In the case of instrumental analytical procedures that ex-

The traditional definition of linearity, i.e., the establish-hibit background noise, the ICH documents describe a com-

ment of a linear or mathematical relationship between sam-mon approach, which is to compare measured signals from

Table 2. Data Elements Required for Validation

Category II

Analytical

Performance

Limit

Quantitative Tests

Characteristics Category I Category III 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.

ple concentration and response, is not applicable to particle gories of tests for which validation data should be required. size analysis. For particle size analysis, a concentration These categories are as follows:

range is defined (instrument- and particle size-dependent)Category I—Analytical procedures for quantitation of such that the measured particle size distribution is not af-major components of bulk drug substances or active ingre-fected by changes in concentration within the defined con-dients (including preservatives) in finished pharmaceutical centration range. Concentrations below the defined con-products.

centration range may introduce an error due to poor signal-Category II—Analytical procedures for determination of to-noise ratio, and concentrations exceeding the defined impurities in bulk drug substances or degradation com-concentration range may introduce an error due to multiple pounds in finished pharmaceutical products. These proce-scattering.dures include quantitative assays and limit tests.

Category III—Analytical procedures for determination of

performance characteristics (e.g., dissolution, drug release, ROBUSTNESS

etc.).

Category IV—Identification tests.

Definition—The robustness of an analytical procedure is

For each category, different analytical information is

a measure of its capacity to remain unaffected by small but

needed. Listed in Table 2 are data elements that are nor-deliberate variations in procedural parameters listed in the

mally required for each of these categories.

procedure documentation and provides an indication of its

Already established general procedures (e.g., titrimetric suitability during normal usage. Robustness may be deter-

determination of water, bacterial endotoxins) should be veri-mined during development of the analytical procedure.

fied to establish their suitability for use, such as their accu-

racy (and absence of possible interference) when used for a SYSTEM SUITABILITY new product or raw material.

When validating physical property methods, consider the If measurements are susceptible to variations in analytical same performance characteristics required for any analytical conditions, these should be suitably controlled, or a precau-procedure. Evaluate use of the performance characteristics tionary statement should be included in the procedure. One on a case-by-case basis, with the goal of determining that consequence of the evaluation of robustness and rugged-the procedure is suitable for its intended use. The specific ness should be that a series of system suitability parameters acceptance criteria for each validation parameter should be is established to ensure that the validity of the analytical consistent with the intended use of the method. procedure is maintained whenever used. Typical variations Physical methods may also be classified into the four vali-are the stability of analytical solutions, different equipment,dation categories. For example, validation of a quantitative and different analysts. In the case of liquid chromatography,spectroscopic method may involve evaluation of Category I typical variations are the pH of the mobile phase, the mo-or Category II Analytical Performance Characteristics, depend-bile phase composition, different lots or suppliers of col-ing on the method requirements. Qualitative physical prop-umns, the temperature, and the flow rate. In the case of gas erty measurements, such as particle size, surface area, bulk chromatography, typical variations are different lots or sup-and tapped density, which could impact performance char-pliers of columns, the temperature, and the flow rate.acteristics, often best fit in Category III. Category IV Analytical System suitability tests are based on the concept that the Performance Characteristics usually applies to validation of equipment, electronics, analytical operations, and samples qualitative identification spectroscopic methods. However, to be analyzed constitute an integral system that can be the various techniques may be used for different purposes, evaluated as such. System suitability test parameters to be and the specific use of the method and characteristics of the established for a particular procedure depend on the type of material being analyzed should be considered when defini-procedure being evaluated. They are especially important in tively applying a category to a particular type of method. the case of chromatographic procedures. Submissions to the The validity of an analytical procedure can be verified only USP should make note of the requirements under the Sys-by laboratory studies. Therefore, documentation of the suc-tem Suitability section in the general test chapter Chromatog-cessful completion of such studies is a basic requirement for raphy ?621?.determining whether a procedure is suitable for its intended

application(s). Current compendial procedures are also sub-

ject to regulations that require demonstration of suitability Data Elements Required for Validation under actual conditions of use (see Verification of Compendial

Procedures ?1226? for principles relative to the verification of Compendial test requirements vary from highly exacting compendial procedures). Appropriate documentation should analytical determinations to subjective evaluation of attrib-accompany any proposal for new or revised compendial an-utes. Considering this broad variety, it is only logical that alytical procedures.

different test procedures require different validation

schemes. This chapter covers only the most common cate-

terial to which the procedure is applied. Although complete ?1226? VERIFICATION OF revalidation of a compendial method is not required to ver-ify the suitability of v a procedure v USP35 under actual condi-COMPENDIAL PROCEDURES

tions of use, some of the analytical performance characteris-tics listed in chapter ?1225?, Table 2, may be used for the verification process. Only those characteristics that are con-sidered to be appropriate for the verification of the particu-The intent of this general information chapter is to pro-lar v procedure v USP35 need to be evaluated. v The process of vide general information on the verification of compendial assessing the suitability of a compendial analytical test pro-procedures that are being performed for the first time to cedure under the conditions of actual use may or may not yield acceptable results utilizing the personnel, equipment,require actual laboratory performance of each analytical per-and reagents available. This chapter is not intended for ret-formance characteristic.v USP35 The degree and extent of the roactive application to already successfully established labo-verification process may depend on the level of training and ratory procedures. The chapter Validation of Compendial Pro-experience of the user, on the type of procedure and its cedures ?1225? provides general information on

associated equipment or instrumentation, on the specific characteristics that should be considered for various test cat-procedural steps, and on which article(s) are being tested.egories and on the documentation that should accompany v Verification should assess whether the compendial proce-analytical procedures submitted for inclusion in USP–NF. Ver-dure is suitable for the drug substance and/or the drug ification consists of assessing selected analytical performance product matrix, taking into account the drug substance’s characteristics, such as those that are described in chapter synthetic route, the method of manufacture for the drug ?1225?, to generate appropriate, relevant data rather than product, or both, if applicable. Verification should include repeating the validation process.

an assessment of elements such as the effect of the matrix Users of compendial analytical procedures are not re-on the recovery of impurities and drug substances from the quired to validate these procedures when first used in their drug product matrix, as well as the suitability of chromato-laboratories, but documented evidence of suitability should graphic conditions and column, the appropriateness of de-be established under actual conditions of use. In the United tector signal response, etc.v USP35

States, this requirement is established in 21 CFR

As an example, an assessment of specificity is a key pa-211.194(a)(2) of the current Good Manufacturing Practice rameter in verifying that a compendial procedure is suitable regulations, which states that the “suitability of all testing for use in assaying drug substances and drug products. For methods used shall be verified under actual conditions of instance, acceptable specificity for a chromatographic

use.”

method may be verified by conformance with system suita-Verification of microbiological procedures is not covered bility resolution requirements (if specified in the in this chapter because it is covered in USP general test v procedure).v USP35 However, drug substances from different chapters Antimicrobial Effectiveness Testing ?51?, Microbiologi-suppliers may have different impurity profiles that are not cal Examination of Nonsterile Products: Microbial Enumeration addressed by the compendial test procedure. Similarly, the Tests ?61?, Microbiological Examination of Nonsterile Products:excipients in a drug product can vary widely among manu-Tests for Specified Microorganisms ?62?, Sterility Tests ?71?, and facturers and may have the potential to directly interfere in general information chapter Validation of Microbial Recov-with the procedure or cause the formation of impurities that ery from Pharmacopeial Articles ?1227?.

are not addressed by the compendial procedure. In addi-tion, drug products containing different excipients, antioxi-Change to read:

dants, buffers, or container extractives v may affect the re-covery of the drug substance from the matrix.v USP35 In these cases, a more thorough assessment of v the matrix

effects v USP35 may be required to demonstrate suitability of VERIFICATION PROCESS

the v procedure v USP35 for the particular drug substance or product. Other analytical performance characteristics such as v

The verification process for compendial test procedures is an assessment of the limit of detection or quantitation and the assessment of whether the procedure can be used for its precision for impurities procedures may be useful to demon-intended purpose, under the actual conditions of use for a strate the suitability of the compendial v procedure v USP35specified drug substance and/or drug product matrix.v USP35

under actual conditions of use.

Users should have the appropriate experience, knowledge,Verification is not required for basic compendial test pro-and training to understand and be able to perform the cedures that are routinely performed unless there is an indi-compendial procedures as written. Verification should be cation that the compendial procedure is not appropriate for conducted by the user such that the results will provide

the article under test. Examples of basic compendial proce-confidence that the compendial procedure will perform suit-dures include, but are not limited to, loss on drying, residue ably as intended.

on ignition, various wet chemical procedures such as acid If the verification of the compendial procedure is not suc-value, and simple instrumental v determinations v USP35 such as cessful, and assistance from USP staff has not resolved the pH measurements. However, for the application of already problem, it may be concluded that the procedure may not established routine procedures to compendial articles tested be suitable for use with the article being tested in that labo-for the first time, it is recommended that consideration be ratory. It may then be necessary to develop and validate an given to any new or different sample handling or solution alternate procedure as allowed in the General Notices . The preparation requirements.

alternate procedure may be submitted to USP, along with the appropriate data, to support a proposal for inclusion or replacement of the current compendial procedure.

Change to read:

VERIFICATION REQUIREMENTS

Verification requirements should be based on an assess-ment of the complexity of both the procedure and the ma-