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ICH Q2 R1 Guideline. Validation of Analytical procedures (Text and Methodology) Prepared By : Naila Kanwal

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ICH Q2 R1 Guideline.Validation of Analytical procedures (Text and Methodology)

Prepared By : Naila Kanwal

ICH Q2 R1 – INTRODUCTIONValidation of analytical procedures:

Description:The tripartite harmonized ICH Guideline on Text (previously coded Q2A) was finalized in October 1994. The Guideline on Methodology has been incorporated into the Guideline on Text in November 2005 and then renamed Q2(R1), without any changes in the contents of the two Guidelines.

ICH Q2 R1 – INTRODUCTIONValidation of analytical procedures:

PART A : TEXT – Q2APART B : METHADOLOGY

ICH Q2 A R1 TEXT AND METHADOLOGY

ICH Q2 R1 – OBJECTIVEValidation of analytical procedures:

The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. A tabular summation of the characteristics applicable to identification, control of impurities and assay procedures is included. Other analytical procedures may be considered in future additions to this document.

ICH – Q2 R1 : Table of contents

• PART I: • TEXT ON VALIDATION OF ANALYTICAL PROCEDURES1. Introduction2. Types of Analytical Procedures to be Validated

ICH – Q2 R1 : Table of contents

PART II: VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY INTRODUCTION1. SPECIFICITY1.1. Identification1.2. Assay and Impurity Test(s)2. LINEARITY 3. RANGE4. ACCURACY4.1. Assay 4.2. Impurities (Quantitation)4.3. Recommended Data5. PRECISION5.1. Repeatability5.2. Intermediate Precision5.3. Reproducibility

ICH – Q2 R1 : Table of contents

PART II: VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY 5.4. Recommended Data DETECTIONLIMIT6.1. Based on Visual Evaluation6.2. Based on Signal-to-Noise 6.3 Based on the Standard Deviation of the Response and the Slope 6.47. QUANTITATION LIMIT 7.1. Based on Visual Evaluation7.2. Based on Signal-to-Noise Approach7.3. Based on the Standard Deviation of the Response and the Slope 7.4 Recommended Data 8. ROBUSTNESS9. SYSTEM SUITABILITY TESTING

ICH Q2 R1 – Validation of Analytical Procedure.

PART 1 : TEXTANALYTICAL PROCEDURE The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.

ICH Q2 R1 – Validation of Analytical Procedure.

ANALYTICAL PROCEDURESAn analytical procedure is developed to test a defined characteristic

of the drug substance or drug product against established acceptance criteria for that characteristic.

CONTENT OF ANALYTICAL PROCEDURES

A. Principle/ScopeB. Apparatus/EquipmentC. Operating Parameters.

D. Reagents/StandardsE. Sample Preparation

F. Standards Control Solution PreparationG. Procedure

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

ICH Q2 R1 – Validation of Analytical Procedure.

CONTENT OF ANALYTICAL PROCEDURES

H. System SuitabilityI. CalculationsJ. Data Reporting

K. REFERENCE STANDARDS AND MATERIALS

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

ICH Q2 R1 – Validation of Analytical Procedure.

A. Noncompendial Analytical Procedures

Analytical method validation is the process of demonstrating that an analytical procedure is suitable for its intended purpose. The methodology and objective of the analytical procedures should be clearly defined and

understood before initiating validation studies. This understanding is obtained from scientifically-based method development and optimization studies.

Validation data must be generated under a protocol approved by the sponsor following current good manufacturing practices with the description of

methodology of each validation characteristic and predetermined and justified acceptance criteria, using qualified instrumentation.

Protocols.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

ICH Q2 R1 – Validation of Analytical Procedure.

A. Compendial Analytical ProceduresThe suitability of an analytical procedure (e.g., BP.

USP/NF, the Official Methods of Analysis of International, or other recognized standard references)

should be verified under actual conditions of use. Information to demonstrate that USP/NF analytical

procedures are suitable for the drug product or drug substance should be included in the submission and

generated under a verification protocol. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

ICH Q2 R1 – Validation of Analytical Procedure.

Validation Validation is a process of establishing documentary evidence

demonstrating that a procedure, process, or activity carried out in production or testing maintains the desired level of compliance

at all stages.

METHOD VALIDATIONMethod validation is the process used to confirm that

the analytical procedure employed for a specific test is suitable for its intended use. Results from method validation can be

used to judge the quality, reliability and consistency of analytical results; it is an integral part of any good analytical practice.

ICH Q2 R1 – Validation of Analytical Procedure.Types of Analytical Procedures to be Validated :The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedures: - Identification tests; - Quantitative tests for impurities' content; - Limit tests for the control of impurities; - Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product. Although there are many other analytical procedures, such as dissolution testing for drug products or particle size determination for drug substance, these have not been addressed in the initial text on validation of analytical procedures. Validation of these additional analytical procedures is equally important to those listed herein and may be addressed in subsequent documents.

ICH Q2 R1 – Validation of Analytical Procedure.A brief description of the types of tests considered in this document is provided below.

1 - Identification tests are intended to ensure the identity of an analyte in a sample. This is normally achieved by comparison of a property of the sample (e.g., spectrum, chromatographic behavior, chemical reactivity, etc.) to that of a reference standard.

ICH Q2 R1 – Validation of Analytical Procedure.2- Quantitative tests for impurities' content; Testing for impurities can be either a quantitative test or a limit test for the impurity in a sample. Either test is intended to accurately reflect the purity characteristics of the sample. Different validation characteristics are required for a quantitative test than for a limit test.

ICH Q2 R1 – Validation of Analytical Procedure.3- Assay Procedures:

Assay procedures are intended to measure the analyte present in a given sample. In the context of this document, the assay represents a quantitative measurement of the major component(s) in the drug substance. For the drug product, similar validation characteristics also apply when assaying for the active or other selected component(s). The same validation characteristics may also apply to assays associated with other analytical procedures (e.g., dissolution).

1- Accuracy

2- Precisiona- Intermediate Precision b- Repeatability

3- Specificity

4- Detection Limit

PART : 2VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY

VALIDATION PARAMETERS

5- Limit of Quantitation

6- Linearity

7- Range

PART : 2VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY

VALIDATION PARAMETERS

ICH Q2 R1 – Validation of Analytical Procedure.1. SPECIFICITY Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. This definition has the following implications: 1- Identification: to ensure the identity of an analyte. 2-Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e.

ICH Q2 R1 – Validation of Analytical Procedure.Assay (content or potency): To provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.

ICH Q2 R1 – Validation of Analytical Procedure.1.SPECIFICITY

ICH Q2 R1 – Validation of Analytical Procedure.2- ACCURACY The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness.

ICH Q2 R1 – Validation of Analytical Procedure.3. PRECISION The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.

ICH Q2 R1 – Validation of Analytical Procedure.• Repeatability Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision .

• Intermediate precision Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

ICH Q2 R1 – Validation of Analytical Procedure.

• Repeatability

ICH Q2 R1 – Validation of Analytical Procedure.

Intermediate precision

ICH Q2 R1 – Validation of Analytical Procedure.• Reproducibility Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

– Transfer of technology– Compendial methods

ICH Q2 R1 – Validation of Analytical Procedure.

ICH Q2 R1 – Validation of Analytical Procedure.

4. DETECTION LIMIT The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

ICH Q2 R1 – Validation of Analytical Procedure.

4. DETECTION LIMIT

ICH Q2 R1 – Validation of Analytical Procedure.5- QUANTITATION LIMIT .The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

ICH Q2 R1 – Validation of Analytical Procedure.5- QUANTITATION LIMIT .

ICH Q2 R1 – Validation of Analytical Procedure.6. LINEARITY The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.

ICH Q2 R1 – Validation of Analytical Procedure.6- LINEARITY

ICH Q2 R1 – Validation of Analytical Procedure.7. RANGE The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

ICH Q2 R1 – Validation of Analytical Procedure.7. RANGE

ICH Q2 R1 – Validation of Analytical Procedure.8. ROBUSTNESS The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage. 1- Change in pH of mobile phase.2- Change of column3- A little bit change of temperature

ICH Q2 R1 – Validation of Analytical Procedure.System Suitability:

ICH Q2 R1 – Validation of Analytical Procedure.Scope of Method Validation:• The scope of the method and its validation

criteria should be defined early in the process. These include the following questions:

•  What analytes should be detected?

•  What are the expected concentration levels?

•  What are the sample matrices?

•  Are there interfering substances expected, and, if so, should they be detected and quantified?

ICH Q2 R1 – Validation of Analytical Procedure.Scope of Method Validation:•  Are there any specific legislative or regulatory

requirements?

•  Should information be qualitative or quantitative?

•  What are the required detection and quantitation limits?

•  What is the expected concentration range?

• What precision and accuracy is expected?

• How robust should the method be?

Changes in the

synthesis of the drug substance.

Changes in the

composition of the finished

product

Changes in the

analytical procedure

Revalidation may be necessary in the following circumstances:

Revalidation :

Revalidation is required if the scope of the method has been changed or extended, for example, if the sample matrix changes or if operating conditions change. Furthermore, revalidation is necessary if the intention is to use instruments with different characteristics, and these new characteristics have not been covered by the initial validation. For example, an HPLC method may have been developed and validated on a pump with a delay volume of 5 mL, but the new pump has a delay volume of only 0.5 mL.

Validation protocol

• Method principle / objective

• Listing of responsibilities

• Laboratories involved and their role in the validation

• Method categorization

• List of reagents (including test lots) and standards

• Test procedures to evaluate each validation parameter and proposed acceptance criteria

• Plan or procedure when acceptance criteria are not met

• Requirements for the final report

• The validation process cannot proceed until the protocol and all parties involved approve the acceptance criteria

Life Cycle Concept :As with equipment qualifications or computer system validations, method validation is not a single event. It begins when somebody wants to implement a new method in a laboratory and ends when the method is no longer in use. The process is broken down in phases because of the length of time and complexity.

A validation plan is developed, including owners, responsibilities and deliverables. The first step is to define the scope of the method. This includes the compounds with concentration range, the sample matrix, the specific equipment that should be used and the location where the method should be performed for sample analysis. Define performance characteristics, performance tests and acceptance criteria. Test protocols are then developed with all experimental details and the tests are executed according to protocols. Tests results are compared with acceptance criteria. Finally, routine method procedures are developed to verify continual system performance at the time of analysis. Tests may include system suitability testing and the analysis of quality control samples. All experimental conditions and validation results are documented in a validation report

VERIFICATIONAssessing selected analytical performancecharacteristics to generate appropriate, relevant data rather than repeating the validation process.Non-Compendial methods must be validated An �alternative method proposed for some application instead of the regulatory analytical procedure �Compendial methods can be verified Regulatory �analytical procedure in USP-NF.

VERIFICATIONUSP <1225> states: “According to these regulations [21 CFR�211.194(a)(2)], users of analytical methods describedin USP-NF are not required to validate the accuracyand reliability of these methods, but merely verify theirsuitability under actual conditions of use.” USP <1226> states:� “Users of compendial analytical procedures are not�required to validate these procedures when first usedin their laboratories, but documented evidence ofsuitability should be established under actualconditions of use.”

VERIFICATIONUSP <1226> “Verification consists of assessing selected�analytical performance characteristics, such asthose described in <1225>, to generateappropriate, relevant data rather than repeatingthe validation process.” “Users of compendial analytical procedures are�not required to validate these procedures whenfirst used in their laboratories, but documentedevidence of suitability should be establishedunder actual conditions of use.”

Validation Planning: Successful validation requires the cooperative efforts of several departments of an organization including regulatory affairs, quality assurance, quality control and analytical development.

The master plan should include: 1. Purpose and scope 2. Glossary 3. Responsibilities, such as user departments, management, QA 4. Method performance characteristics and approaches for testing 5. Steps for method validation 6. Selection of tests and acceptance criteria 7. Approach and parameters for system suitability testing

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