ICH Q2 Analytical Method Validation

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

ICH Q2 R1 – INTRODUCTION
Validation 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 – INTRODUCTION
PART A : TEXT – Q2A
PART B : METHADOLOGY
ICH Q2 A R1
TEXT AND METHADOLOGY

ICH Q2 R1 – OBJECTIVE
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 PROCEDURES
1. Introduction
2. Types of Analytical Procedures to be Validated

PART II:
VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY
INTRODUCTION
1. SPECIFICITY
1.1. Identification
1.2. Assay and Impurity Test(s)
2. LINEARITY
3. RANGE
4. ACCURACY
4.1. Assay
4.2. Impurities (Quantitation)
4.3. Recommended Data
5. PRECISION
5.1. Repeatability
5.2. Intermediate Precision
5.3. Reproducibility

PART II:
5.4. Recommended Data
DETECTIONLIMIT
6.1. Based on Visual Evaluation
6.2. Based on Signal-to-Noise
6.3 Based on the Standard Deviation of the Response and the Slope 6.4
7. QUANTITATION LIMIT
7.1. Based on Visual Evaluation
7.2. Based on Signal-to-Noise Approach
7.3. Based on the Standard Deviation of the Response and the Slope
7.4 Recommended Data
8. ROBUSTNESS
9. SYSTEM SUITABILITY TESTING

ICH Q2 R1 – Validation of Analytical Procedure.
PART 1 : TEXT
ANALYTICAL 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.

ANALYTICAL PROCEDURES
An 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/Scope
B. Apparatus/Equipment
C. Operating Parameters.
D. Reagents/Standards
E. Sample Preparation
F. Standards Control Solution Preparation
G. Procedure
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

CONTENT OF ANALYTICAL PROCEDURES
H. System Suitability
I. Calculations
J. Data Reporting
K. REFERENCE STANDARDS AND MATERIALS

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.

A. Compendial Analytical Procedures
The 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.

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 VALIDATION
Method 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.

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.

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.

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.

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).

PART : 2
VALIDATION PARAMETERS

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.

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.

1. SPECIFICITY

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.

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.

• 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.

• Repeatability

Intermediate precision

• Reproducibility
Reproducibility expresses the precision between
laboratories (collaborative studies,
usually applied to standardization of methodology).
– Transfer of technology
– Compendial methods

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

4. DETECTION LIMIT

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.

5- QUANTITATION LIMIT .

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.

6- LINEARITY

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.

7. RANGE

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 column
3- A little bit change of temperature

System Suitability:

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?

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

VERIFICATION
Assessing selected analytical performance
characteristics 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.

VERIFICATION
USP <1225> states:
†“According to these regulations [21 CFR
211.194(a)(2)], users of analytical methods described
in USP-NF are not required to validate the accuracy
and reliability of these methods, but merely verify their
suitability under actual conditions of use.”
…USP <1226> states:
†“Users of compendial analytical procedures are not
required to validate these procedures when first used
in their laboratories, but documented evidence of
suitability should be established under actual
conditions of use.”

VERIFICATION
USP <1226>
†“Verification consists of assessing selected
analytical performance characteristics, such as
those described in <1225>, to generate
appropriate, relevant data rather than repeating
the validation process.”
†“Users of compendial analytical procedures are
not required to validate these procedures when
first used in their laboratories, but documented
evidence of suitability should be established
under 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

ICH Q2 Analytical Method Validation

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