Rationale for analytical method validation

1. INTRODUCTION

The purpose of validation of analytical method is to ensure that the adopted method

meets the requirements for the intended analytical applications. The rationale of

methods validation described applies to types of analytical procedures, however, it

may not be applicable to certain unique analytical procedures for products.

2. BACKGROUND

The analytical procedures are necessary to ensure the identity, strength, quality, purity,

and potency of the drug substance and drug product, including bioavailability of the

drug product.

Methods validation is the process of demonstrating that analytical procedures are

suitable for their intended use. The analytical method is required to be validated

according to the different requirements for different analytical items.

3. TYPES OF ANALYTICAL PROCEDURES

3.1. Noncompendial Analytical Procedure

A noncompendial analytical procedure is the analytical procedure used to evaluate a

defined characteristic of the drug substance or drug product. The analytical

procedures in the CP/EP/USP/JP are those legally recognized as the regulatory

analytical procedures for compendia) items.

3.2. Compendia) Analytical Procedure

A compendia) analytical procedure is an analytical procedure proposed by the

applicant . for use instead of the noncompendial analytical procedure. A validated

compendia! analytical procedure should be submitted only if it is shown to perform

equal to or better than the noncompendial analytical procedure.

3.3. Stability-Indicating Assay

A stability-indicating assay is a validated quantitative analytical procedure that can

detect the changes with time in the pertinent properties of the drug substance and drug

product.

3. METHODS VALIDATION
 Sufficient information is required in each phase of an investigation to ensure proper

identification. quality. purity, strength. and/or potency.

4.1. o n c o m p e n d i a l Analytical Procedures

In an application, data must be submitted to establish that the analytical procedures

used in testing meet proper standards of accuracy and reliability. Methods validation

is the process of demonstrating that analytical procedures are suitable for their

intended use.

4 . 1 . 1 Analytical items that need to be validated

Some analytical items don't need to be validated. such as appearance, weight, pH.

dosage while other item need to be validated in different procedures.

The analytical items that must be validated include identification. quantification or

limit test of impurities. content determination of the active ingredient in drug

substance or drug product. etc.

4 . 1 . 2 Parameters of validation characteristics

The parameters of validation characteristics include accuracy, precision (including

repeatability, intermediate-precision and reproducibility), specificity, limit of

detection, limit of quanritation, linearity, range and ruggedness. The parameters to be

validated depend on the purpose for which the procedure is required.

Table I is a summary of the validation characteristics that should be addressed during

validation of different types of analytical procedures. The same methodology can be

used for several purposes. The validation information should support the intended

purpose of the test.

Table I Recommended validation characteristics of the various types of tests

Impurity test Assay, Dissolution Specific

Parameters Identification (Measurement Tests

. + . + +•
Accuracy

. + . + +•
Precision-Repeatabi Ii ty

Precision-Intermediate _, +•
. +' .

precrsion

+2 ..s +•
Specific it) + +
J
Detection L i m i t . . + . .
Quantification L i m i t - + - - -

Linearity - + - + -

Range - + - + -
J +4
Ruggedness + + - +

I ore:

ignifies that this characteri tic is not normally evaluated.

+ ignifies that this characteristic is normally evaluated.

In cases where reproducibility has been performed. intermediate precision is

not needed.

2 Lack of specificity for an analytical procedure may be compensated for by

the addition of a econd analytical procedure

3 May be needed in some cases.

4 May not be needed in some cases.

5 Lack of specificity for an as ay for release may be compensated for by

impurities testing.

a. Identification

Identification analytical procedures may include tests such as JR, differential scanning

calorimetry (D C), X-ray diffraction (XRD), LJV, and HPLC retention time. A

specific identification test should be included for the active ingredient whenever

possible. In cases where a nonspecific identification analytical procedure is proposed

for the acti e ingredient, two independent analytical procedures are generally

sufficient, if justified. For other identification tests (e.g., a chiral HPLC retention time

as confirmation for the presence of an enantiomer, chloride test for a counterion) a

single test is a ceptable. Th i s concept of the number of identification tests is

applicable to both the drug substance and drug product.

b. Lmpu rities

The validation characteristics under quantitative testing for impurities, as described in

Table I , apply, regardless of which methodology is used to quaruitate impurities. If

the same analytical procedure is proposed as a limit test, validation characteristics

under l i m i t testing for impurities w i l l apply.

c, Assay

!
Assay includes the content of the active ingredient, preservative (if used), and

measurement of content in dissolution and content uniformity samples.

d. Specific Tests

Specific tests to control the drug substance, excipient, or drug product can include

tests such as particle size analysis, droplet distribution, spray pattern, dissolution

(excludes measurement), optical rotation, and methodologies such as DSC, XRD, and

Raman spectroscopy. The validation characteristics may differ for the various

analytical procedures. For example, accuracy, repeatability, intermediate precision and

robustness should be evaluated for molecular size distribution gel permeation

chromatography (GPC).

4.2. Compendia! Analytical Procedures

The suitability of a compendia! analytical procedure must be verified under actual

conditions of use. Information to demonstrate that CP/EP/USP/JP analytical

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

the submission. Information on the specificity, intermediate precision, and stability of

the sample solution should be included. Compendia! assay analytical procedures may

not be stability-indicating, and this should be considered when developing the

specification. For compendial items, additional analytical procedures, such as

impurities or osmolality, may be requested to support the quality of the drug product

or drug substance. These additional analytical procedures should be validated.

5. REVALIDATION

When sponsors make changes in the analytical procedure, drug substance (e.g., route

of synthesis), or drug product (e.g., composition), the changes may necessitate

revalidation of the analytical procedures. Revalidation should be performed to ensure

that the analytical procedure maintains its characteristics (e.g., specificity) and to

demonstrate that the analytical procedure continues to ensure the identity, strength,

quality, purity, and potency of the drug substance and drug product, and the

bioavailability of the drug product. The degree of revalidation depends on the nature

of the change. When a different regulatory analytical procedure is substituted (e.g.,

HPLC for titration), the new procedure should be validated.

requirements only with repeated adjustments to the operating conditions stated in the

analytical procedure, the analytical procedure should be reevaluated, amended, and

revalidated, as appropriate.
 Transfer process for the analytical methods of new drug

R&D personnel are responsible for the following items: the implement of the

validation process for the new drug's analytical method and finishing the

report, drafting the related operation requirements (the analysis for the

intermediate and fmal product and the factors that may influence the quality of

the product, such as equipment, model, container, standard substance, reagent,

reagent solution, personnel, etc.). Trainings are held for related QC personnel.

QC check I
I

•
Vice president for quality approves
I I

The analytical method is transferred to QC

The analytical method is transferred to QC, QC formulate

the related SOP according to the management procedure .

•
R&D and QC collectively complete the validation

for analytical method .

Jfthe validation result is qualified, the

transfer is finished.