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Overview of Analytical Method Validation in Pharmaceutical Industries

Rajendra Songara1, Akabari Prakashkumar

2

1 School of Pharmaceutical Science, Jaipur National University, Jaipur, Rajasthan, India

2 Regulatory Wisdom, Food and Pharma Regulatory Consultancy, New Delhi, India

Corresponding Author: Rajendra Songara Email address: [email protected]

ABSTRACT:

Validation is an important feature in any method of measurement because it is closely related

to the quality of the results. A method of analysis is characterized by its performance parameters,

which have to be assessed if they are to provide the correct performance values. These performance

values must be in accordance with previously defined requirements that the method of analysis should

satisfy. But above all, the performance parameters depend on the type of method and its intrinsic

characteristics. So depending on what is needed, the user must choose which method of analysis will

best solve the analytical problem.

Keyword: Validation, Analytical Method Validation, ICH, FDA, PCI, ISO

http://www.regulatorywisdom.com/index.html

Vol 1:5 (2011) IJPI’s Journal of Analytical Chemistry

Rajendra Songara et al Page 10

1. INTRODUCTION

In pharmaceutical manufacturing industry Validation is very important part of Quality assurance and in Good

manufacturing Practice activities or guidelines .FDA gives special emphasis on validation, also it is one of the prime

requirement of all regulatory authorities worldwide. It is of great importance in Pharmaceutical manufacturing as well

as medical devices manufacturing industry. Validation is a process of collection of documentary evidence; it is a

process of demonstration that any of the procedure, process, method, or activity is being adapted is capable of

producing consistent and satisfactory result in terms of measurements or in terms of product quality. To demonstrate

this it is required that the systems itself and equipment are properly designed and qualified. To demonstrate that a

pharmaceutical product manufactured with any process in any pharmaceutical company it is required to validate many

procedures, processes, methods activities associated with pharmaceutical manufacturing including machinery, skills

and testing procedures, methods.

Validation is defined as follows by different agencies:

Food and drug administration (FDA): establishing documentation evidence, which provides a high degree of assurance

that specific process, will constituently produce a product meeting its predetermined specification and quality

attributes.

World health organization (WHO): Action of providing that any procedure, process, equipment, material, activity, or

system actually leads to the expected results.

European committee (EC): Action of providing in accordance with the principles of good manufacturing practice that

any procedure, processes, equipment material, activity or system actually lead to the expected results. In brief

validation is a process for effective Quality Assurance. .Validation is establishing documental evidence which provides

a high degree of assurance that specific process will constituently produce a product or result meeting its predetermined

specification and quality attributes.

2. METHOD VALIDATION

During method development, analysts establish the most suitable steps of the analytical process that will lead

to the information required: sample pre-treatment, when necessary, separation technique and the detection system,

among others. The best analytical conditions for obtaining good results are also considered. The information gathered

after the analysis may have several goals: to take decisions involving the control of the manufacturing process of a

product, to assess whether a product complies with regulatory limits, to take decisions about legal affairs, international

trade, health problems or the environment, etc. Therefore, the analytical information must be of sufficient quality,

which means that it must be reliable and match the purposes of the analysis. To meet these premises, analysts must

define the purposes of the analysis and the requirements that the method should fulfill. Therefore, the validation of the

method of analysis will provide, according to the ISO definition1 the “confirmation by examination and provision of

evidences that the particular requirements for a specified intended use are fulfilled”. Another definition given in the

Handbook for the Quality Assurance of Metrological Measurements2 states that “method validation consists of

documenting the quality of an analytical procedure, by establishing adequate requirements for performance criteria,

such as accuracy, precision, detection limit, etc. and by measuring the values of these criteria” . In general terms, then,

the requirements and performance parameters must first be defined for every analytical method and purpose of

analysis; and second, the value for these parameters must be estimated and checked to see if they really meet the

criteria. This is an essential condition if the results provided are to be used. The process of assessing the performance

criteria is closely related to the concept of „fitness-for-purpose‟, which is defined by IUPAC in the Orange Book3 as the

“degree to which data produced by a measurement process enables a user to make technically and administratively

correct decisions for a stated purpose”. Hence, it is important, first, to consider the necessary conditions related to the

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problem at hand, second to choose the method of analysis that best fits the necessities, and, finally, to validate it as is

shown in Figure 1.

Figure 1: Fitness for purpose concept, Adapted from the EURACHEM the Fitness for Purpose of

Analytical Methods.4

The EURACHEM Guide the Fitness for Purpose of Analytical Methods4 also describes how important it is for

the analytical performance and the analytical problem to be suited. It also describes the importance of method

validation, and indicates when, how and who should perform the validation, among other equally relevant statements.

Fitness for purpose also involves practicability and suitability criteria,5 which entail evaluating operational and time

constraints, as well as such other parameters as reusability or possibilities of automation. Although the users of the

method of analysis will focus the validation process on their own needs, there are some common features that all

validation procedures must have. The validation process must satisfy three requirements;4

The whole method must be validated. It is quite usual to focus on the detection technique or the instrumental

measurement, which often means that just this stage is validated. However, the previous steps of sample pre-treatment,

extraction or pre-concentration also belong to the method of analysis and are of utmost importance. So they must all be

validated.

The whole range of concentrations must be validated. It is difficult to comply with this condition because a method

may work very well in one particular concentration range but not in others.

The whole range of matrices must be validated. It is well known that the matrix can have a decisive effect on the

analysis. Therefore, and for the sake of representativeness, several matrices must be submitted to method validation.

In addition to the conditions mentioned above, it should also be pointed out that the method developed, before

it is validated, should include the various types of equipment and the locations where it will be run. That is to say, if the

analysis is always to be performed with the same equipment and in the same laboratory, then other equipment and



other laboratories need not be taken into account. Before the equipment is used, its performance must be checked with

generic standards. The analytical requirements that the analyst has defined are translated to the performance criteria of

the method of analysis. So one of the stages of method validation is to estimate and assess the values of the quality

parameters. In general terms, performance criteria can be divided into two main categories6 although some authors may

suggest other classifications. The basic parameters usually refer to the reliability of the method and are commonly

derived with statistical procedures. Some examples are trueness, precision, selectivity, sensitivity, limit of detection

and quantification. Criteria such as cost, ease of use, rapidity, etc. are considered to be complements of these. In the

Handbook of Chemometrics and Qualimetrics,7 Massart et al. state that there are two types of performance criteria:

primary and secondary. Precision, bias, accuracy, trueness and the detection limit belong to the first group while the

other parameters that can influence these primary criteria belong to the second (eg. linearity, the range of linearity, the

quantification limit, selectivity, and sensitivity or ruggedness, etc.)

3. ANALYTICAL METHOD VALIDATION

Method validation is the process by which it is established, through laboratory studies, that the performance

characteristics of the method meet the requirements for its intended purpose.8,9,10,11,12

It is a part of the overall

validation process that also includes software validation13

, instrument qualification,14,15

and system suitability.16

Typical

analytical characteristics used in method validation are highlighted in Figure 2. Although all analytical procedures or

methods used in a regulated laboratory must be validated, this chart focuses specifically on liquid chromatography.

Typical analytical characteristics used in method validation, commonly referred to as the “Eight Steps of Method

Validation.”

Specificity

Linearity

Range

Limit of detection

Limit of quantitation

Accuracy

Precision

Robustness

3.1 Specificity:

Specificity is the ability to measure accurately and specifically the analyte of interest in the presence of other

components that may be expected to be present in the sample matrix.

Identification tests

Specificity ensures the identity of the analyte of interest.

Purity tests

Specificity ensures that the method allows for an accurate statement of the impurity content (that is, in related

substances tests, heavy metals and organic volatile impurity limits)

Assays

Specificity provides an exact result for a determination of the content or potency of the analyte.

Methodology

Identification (qualitative analyses)

Specificity is demonstrated by the ability to discriminate between compounds of closely related structures, or by

comparison to known reference materials.

Assays



Specificity is demonstrated using spiked samples to show that the method results are unaffected by the presence of

impurities or excipients.

Impurity tests

Impurities available

Specificity is demonstrated by spiking the drug substance or product with the appropriate levels of impurities and

determining them with the appropriate accuracy and precision.

Impurities not available

Compare results to a second well-characterized procedure.

Include samples stored under relevant stress conditions, (for example, light, heat, humidity, acid/base hydrolysis,

and oxidation). For assay, the two results are compared. For impurity tests, the impurity profiles are compared head to-

head.

Documentation

For chromatographic procedures, representative chromatograms with peaks labeled should be included. Resolution,

plate count (efficiency), and tailing factor should be measured and documented.

Peak purity tests using advanced detection such as photodiode array or mass spectrometry should be used to show

that the response is not due to more than one component.

3.2 Linearity:

The ability of the method to elicit test results that are directly, or by a well-defined mathematical

transformation, proportional to analyte concentration within a given range.

3.3 Range:

The interval between the upper and lower levels of analyte (inclusive) that have been demonstrated to be

determined with a suitable level of precision, accuracy, and linearity using the method as written.

Methodology

Linearity

Demonstrate across the entire range of the analytical procedure.

A minimum of five concentrations is recommended.

Range

Verify that the method provides acceptable precision, accuracy, and linearity when applied to samples at the

extreme as well as within the range.

Recommended minimum Ranges:

Assay of Drug Substance or Finished Product

From 80–120% of the test concentration.

Determination of an Impurity

From 50–120% of the specification.

Content Uniformity

A minimum of 70–130% of the test concentration unless a wider or more appropriate range is justified based upon

the dosage form.

Dissolution Testing

± 20% over the specified range of the dissolution test.

Documentation

The report should include:

The slope of the regression line.

The correlation coefficient.



Y-intercept.

The residual sum of squares

3.4 Detection Limit (DL OR LOD):

Characteristic of limit tests, the LOD is defined as the lowest concentration of an analyte in a sample that can

be detected, not quantitated. It is a limit test that specifies whether or not an analyte is above or below a certain value.

Methodology

Non-instrumental methods;

Determine LOD by analyzing samples at known concentrations and establishing the minimum level at which the

analyte can be reliably detected.

Instrumental methods

LOD can be determined as a signal to noise ratio, usually 2:1 or 3:1, or,

LOD can be calculated at levels approximating the LOD according to the formula: LOD _ 3.3(SD/S)

(SD) = standard deviation of the response based on either the standard deviation of the blank, the residual standard

deviation of the regression line, or the standard deviation of y-intercepts of regression lines.

(S) = slope of the calibration curve

Documentation

Express the LOD as the concentration of the analyte.

Document and support the method used to determine LOD.

An appropriate number of samples should be analyzed at the limit to validate the level. In practice, it is almost

never necessary to determine the actual LOD. Instead, the detection limit is shown to be sufficiently low (for example,

0.1%) to be able to reliably detect at the level specified.

3.5 Quantitation Limit (QL OR LOQ):

LOQ is the lowest concentration of an analyte in a sample that can be determined (quantitated) with acceptable

precision and accuracy under the stated operational conditions of the method.

Methodology

Non-instrumental methods

Determine LOQ by analyzing samples at known concentrations and establishing the minimum level at which the

analyte can be reliably detected.

Instrumental methods

LOQ can be determined as a signal to noise ratio, usually 10:1, Or,

LOD can be calculated at levels approximating the LOD according to the formula: LOD _ 10(SD/S).

(SD) = standard deviation of the response based on either the standard deviation of the blank, the residual standard

deviation of the regression line, or the standard deviation of y-intercepts of regression lines.

(S) = slope of the calibration curve

Documentation

Express LOQ as a concentration, with the precision and accuracy of the measurement.

Documented and support the method used to determine LOD.

An appropriate number of samples should be analyzed at the limit to validate the level. In practice, it is almost

never necessary to determine the actual LOQ. Instead, LOQ is shown to be sufficiently low (e.g. 0.1%) to be able to

reliable quantitate at the level specified.

3.6 Accuracy

Accuracy is the closeness of test results to the true value.



Methodology

Drug substance

Comparison of the results with the analysis of a standard reference material.

Comparison to a second, well-characterized method.

Drug product

Evaluate by analyzing synthetic mixtures of known amounts or samples spiked with known quantities of

components.

Comparison to a second, well-characterized method.

Quantitation of impurities

Analyze samples (drug substance or drug product) spiked with known amounts of impurities. (If impurities are not

available, see specificity.)

Data from a minimum of nine determinations over a minimum of three concentration levels covering the specified

range (for example, three concentrations, and three replicates of each concentration).

Documentation

Reported as the percent recovery of the known, added amount, or as the difference between the mean and true

value with confidence intervals.

3.7 Precision:

Precision is the degree of agreement among individual test results when an analytical method is used

repeatedly to multiple samplings of a homogeneous sample.

Repeatability

Results of the method operating over a short time interval under the same conditions (interassay precision).

Generally the criteria of concern in USP procedures.

Intermediate precision (formerly ruggedness)

Results from within-laboratory variations due to random events such as different days, analysts, equipment, etc.

Experimental design should be employed so that the effects (if any) of the individual variables can be monitored.

Reproducibility

Results of collaborative studies between laboratories.

Methodology

The precision of a method is determined by assaying aliquots of a homogeneous sample to be able to calculate

statistically significant estimates of standard deviation or relative standard deviation (coefficient of variation). Assays

should be of samples that have all gone through the entire analytical procedure from sample preparation through final

analysis.

A minimum of nine determinations covering the specified range of the procedure (for example, three levels, three

repetitions each) or a minimum of six determinations at 100% of the test or target concentration is recommended.

Documentation

Precision is expressed as the standard deviation or the relative standard deviation (coefficient of variation) for a

statistically significant number of measurements and confidence interval. Statistical tables, bar charts, and other types

of graphs are commonly used to document precision.

3.8 Robustness:

Robustness is the capacity of a method to remain unaffected by small, deliberate variations in method

parameters; a measure of the reliability of a method.

Robustness should be evaluated in late development, or early in the method validation process. If the results of a

method or other measurements are susceptible to variations in method parameters, these parameters should be

adequately controlled and a precautionary statement included in the method documentation.



Robustness can be used to establish system suitability parameters.

Normally, after implementing a validated method, it can be adjusted within the confines of the robustness study

without triggering a revalidation. However, method changes, outside the range of parameters validated, would require

at least some revalidation to show equivalency of results.

Methodology

Purposely vary method parameters over a known range, and determining the effect (if any) on the method results.

Multivariate statistical experimental design can be used to control method variables (for example, Factorial,

Fractional Factorial, or Plackett-Burman designs).

Theoretical modeling software can also be used to predict robustness and then verified experimentally.

Documentation

Robustness can be illustrated by many different means, using summary tables, bar, and control charts, effect and

probability plots, and other means of result comparisons.

4. VALIDATION PROCESS

There are three accepted Validation Processes

4.1 Prospective Validation:

This is performed for all new equipment, products and processes. It is a proactive approach of documenting the

design, specifications and performance before the system is operational. This is the most defendable type of validation.

4.2 Concurrent Validation:

This is performed in two instances i.e. for existing equipment; verification of proper installation along with

specific operational tests is done. In case of an existing, infrequently made product, data is gathered from at least three

successful trials.

4.3 Retrospective Validation:

This is establishing documented evidence that the process is performed satisfactorily and consistently over

time, based on review and analysis of historical data. The source of such data is production and QA/QC records. The

issues to be addressed here are changes to equipment, process, specifications and other relevant changes in the past.

5. PHASES OF VALIDATION17

Design Qualification (DQ): the design of equipment and manufacturing facilities.

Installation Qualification (IQ): documented verification of equipment or system design and adherence to the

manufacturer‟s recommendations.

Operational Qualification (OQ): documented verification of equipment or system performance in the target

operating range.

Process Performance Qualification (PQ): documented verification that equipment or systems operate as expected

under routine production conditions. The operation is reproducible, reliable and in a state of control.

6. ADVANTAGES OF ANALYTICAL METHOD VALIDATION18

The biggest advantage of analytical method validation is that it builds a degree of confidence, not only for the

developer but also to the user. Although the validation exercise may appear costly and time consuming, it results

inexpensive, eliminates frustrating repetitions and leads to better time management in the end. Minor changes in the

conditions such as reagent supplier or grade, analytical setup are unavoidable due to obvious reasons but the method

validation absorbs the shock of such conditions and pays for more than invested on the process.



7. REGULATORY REQUIREMENTS

7.1 United States Food and Drug Administration (FDA):

Analytical method validation is essential for adherence to Current Good Manufacturing Practice (cGMP)19

and

Good Laboratory Practice (GLP) regulations. The US cGMPs spell out the requirements for validation in sections

211.165 (e) and 211.194:

165(e): “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be

established and documented. Such validation and documentation may be accomplished in accordance with 194(a)(2).

194(a)(2): Laboratory records should include a statement of each method used in the testing of the sample. The

statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper

standards of accuracy and reliability as applied to the product tested. The suitability of all testing methods used shall be

verified under actual conditions of use.

194(b): Complete records shall be maintained of any modification of an established method employed in testing.

Such records shall include the reason for the modification and data to verify that the modification produced results that

are at least as accurate and reliable for the material being tested as the established method.

The FDA GLP regulation 21 CFR Part 5820

itself does not mention the word validation but inspectors want to see

validation studies by referring to Part 58.113 which states: “Tests shall be conducted by appropriate analytical

methods”, where the word “appropriate” implies validation. Also the FDA Guidance on Validation of Bioanalytical

Methods21

defines Preclinical Toxicology as one of its scopes.

FDA‟s regulation for Bioavailability and Bioequivalence Requirements 21 CFR 32022

states in section 29: (a) The

analytical method used in an in vivo bioavailability study to measure the concentration of the active drug ingredient or

therapeutic moiety, or its metabolite(s), in body fluids or excretory products, or the method used to measure an acute

pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to measure, with appropriate

precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), achieved in

the body.

7.2 Pharmaceutical Inspection Cooperation Scheme (PIC/S) and Europe:

The Pharmaceutical Inspection Cooperation Scheme‟s (PIC/S) mission is “to lead the international

development, implementation and maintenance of harmonized Good Manufacturing Practice (GMP) standards and

quality systems of inspectorates in the field of medicinal products”.

This is achieved by developing and promoting harmonized GMP standards and guidance documents; training

competent authorities, in particular inspectors; assessing (and reassessing) inspectorates; and facilitating the co-

operation and networking for competent authorities and international organizations. As of November 2009 there are 36

participating authorities in PIC/S, including all EU member countries. Authorities from more countries have applied for

PIC/S membership, such as the U.S. FDA. Most likely new member countries that don‟t have their own GMP

regulations will accommodate PIC/S GMPs23

, which are very similar to the EU GMP directives.24

For example, the requirement for analytical method validation is stated in both documents in Part 6.1.5 with

identical text:

Analytical methods should be validated. All testing operations described in the marketing authorization should be

carried out according to the approved methods.

More details on inspectors‟ expectations are laid down in the PIC/S Laboratory Inspection Guide, section 8.7 25

. The

guide has a list of questions that inspectors should ask when inspecting quality control laboratories. They include:

Is method validation part of the validation master plan?

Is there a general SOP on method validation available and is the validation report formally approved?

Is the purpose of validation specified?

Is validation completed and documented in each protocol for parameters defined in ICH26

?



Are acceptance criteria in each protocol defined and met?

Is there an SOP for transfer of analytical methods?

7.3 International Conference for Harmonization (ICH):

The International Conference for Harmonization (ICH) was initiated in 1990 to bring together the regulatory

authorities of Europe, Japan and the United States and experts from the pharmaceutical industries in the three regions

to discuss scientific and technical aspects of product registration.

ICH publishes guidelines that are either signed into law by member countries, (for example, those in Europe)

or recommended as guidelines by national authorities such as the US FDA.

One of the most important ICH documents is the GMP Guide for Active Pharmaceutical Ingredients27

.

Requirements for method validation are specified in Chapter 12:

Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or

other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under

actual conditions of use and documented.

The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API

production process.

Appropriate qualification of analytical equipment should be considered before starting validation of analytical

methods.

7.4 Unites States Pharmacopeia (USP):

The United States Pharmacopeia (USP) develops methodology for specific applications and general chapters

on different analytical aspects of FDA-regulated industry. According to section 501 of the Federal Food Drug and

Cosmetic act, USP methodology constitute legal standards. USP has developed two general chapters related to method

validation and another one with information on allowed method changes without the need for revalidation.

Chapter <1225> on “Validation of Compendial Methods”28.

This chapter describes parameters as they are used for

validation of new methods. Recommendations can be used to validate methods developed by pharmaceutical

laboratories.

Chapter <1226> on “Verification of Compendial Methods”29

. This chapter has been written for laboratories

implementing Compendial and standard methods. The recommendations are also useful for laboratories implementing

validated methods from other laboratories.

Chapter <621> on “Chromatography”30

. This chapter has useful recommendations on how much GC and HPLC

methods can be adjusted or changed without the need for revalidation.

7.5 ISO/IEC 17025:

ISO/IEC 17025 is the most relevant ISO Standard for chemical analytical laboratories31

. It specifies general

requirements for the competence to carry out tests or calibrations or both. The standard is widely used as a quality

system in environmental, food, chemical and clinical testing laboratories. It is used to assess laboratories that seek

accreditation status.

The standard has many requirements related to the subject of this primer. The most important ones can be

found in Chapter 5.4.5:

The laboratory shall validate nonstandard methods; laboratory designed and developed methods, standard methods

used outside their intended scope, and amplifications and modifications of standard methods to confirm that the

methods are fit for their intended use.

The laboratory shall confirm that it can properly operate standard methods before introducing the tests or

calibrations.



When some changes are made in the validated nonstandard methods, the influence of such changes should be

documented and, if appropriate, a new validation should be carried out.

If standard methods are available for a specific sample test, the most recent edition should be used.

Validation includes specification of requirements, determination of method characteristics, and a check that the

requirements can be fulfilled by using the method and a statement on validity.

The following parameters should be considered for validating in-house developed methods: limit of detection, limit

of quantitation, accuracy, selectivity, linearity, repeatability or reproducibility, robustness, and linearity.

Unlike regulations, this standard is quite specific. Even though this standard is not widely accepted currently by

pharmaceutical laboratories, validation experts are advised to consult it when developing a method validation process

and take recommendations appropriate for specific applications.

8. CONCLUSION

The efficient development and validation of analytical methods are critical elements in the development of

pharmaceuticals. Success in these areas can be attributed to several important factors, which in turn will contribute to

regulatory compliance. FDA gives special emphasis on validation; also it is one of the prime requirements of all

regulatory authorities worldwide. It is of great importance in Pharmaceutical manufacturing as well as medical devices

manufacturing industry. Validation is a process of collection of documentary evidence; it is a process of demonstration

that any of the procedure, process, method, or activity is being adapted is capable of producing consistent and

satisfactory result in terms of measurements or in terms of product quality.

9. REFERENCES

(1) UNE-EN ISO 9000, Sistemas de gestión de la calidad. Fundamentos y Vocabulario, AENOR, Madrid, 2005

(2) J. K. Taylor and H. V. Opperman, Handbook for the Quality Assurance of Metrolog cal Measurements, Lewis

Publ., Chelsea, 1988.

(3) J. Inczédy, T. Lendyel and A. Ure, Compendium of Analytical Nomenc ature (The IUPAC 'Orange Book'),

M. Blackwell Science, 3rd ed., Oxford, UK, 1998.

(4) Eurachem, The Fitness for Purpose of Analytical Methods. A Laboratory Guide to Method Validation and

Related Topics, Eurachem, 1998. Available at http://www.eurachem.ul.pt

(5) International Union of Pure and Applied Chemistry, IUPAC, Harmonized Guidelines for Single-Laboratory

Validation of Methods of Analysis, (IUPAC Technical report), Pure Appl. Chem., 74, 2002, 835.

(6) R. Boqué, A. Maroto, J. Riu and F. X. Rius, Grasas y Aceites 53, 2002, 128.

(7) D. L. Massart, Data Handling in Science and Technology 20A. Handbook of Chemometrics and Qualimetrics:

Part A. Elsevier Science, Amsterdam, The Netherlands, 1997.

(8) The United States Pharmacopeia 29 / National Formulary 24 (The United States Pharmacopeia Convention,

Inc., Rockville, MD, 2006), Chapter <1225>, including Supplement 1, Official April 2006.

(9) International Conference on Harmonization, Harmonized Tripartite Guideline, Validation of Analytical

Procedures, Text and Methodology, Q2(R1), November 2005, ( www.ich.org.)

(10) Draft Guidance for Industry: Analytical Procedures and Methods Validation. U.S. Department of Health and

Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for

Biologics Division of Research, Rockville, MD, August 2000).

(11) Analytical Procedures and Method Validation: Highlights of the FDA‟s Draft Guidance. LCGC 19(1), 74–79

(2001).

(12) Swartz, M.E. and Krull, I.S., Handbook of Analytical Method Validation, Taylor and Francis, 2006, in press.

http://www.eurachem.ul.pt/

http://www.ich.org/



(13) General principles of software validation; final guidance for industry and FDA staff. U.S. Department of

Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research,

Center for Biologics Division of Research, Rockville, MD, January 2002.

(14) AAPS PharmSciTech 2004, 5(1) Article 22 (http://www.aapspharmscitech.org).

(15) Pharmacopoeial Forum, 31(5), Sept-Oct 2005, p. 1453-1463.

(16) The United States Pharmacopeia 26 / National Formulary 21 (The United States Pharmacopoeia Convention,

Inc., Rockville, MD, 2002), Chapter <621>.

(17) Michael E. Schwartz, Ira S. Krull, Analytical method development and validation; 25-46.

(18) Ravichandran V, Shalini S, Sundram K. M. And Harish Rajak, Validation of Analytical Methods – Strategies

& Importance, Int J Pharmacy and Pharm Sci, Vol 2, Issue 3, 1822.

(19) U.S. FDA, Title 21 of the U.S. Code of Federal Regulations: 21 CFR 211 Current good manufacturing

practice for finished pharmaceuticals, Revised as of April 1, 2009

(20) U.S. FDA, Title 21 of the U.S. Code of Federal Regulations: 21 CFR 58 Good Laboratory Practice for

Preclinical Studies, Revised as of April 1, 2009

(21) U.S. FDA – Guidance for Industry, Bioanalytical Method Validation 2001

(22) U.S. FDA, Title 21 of the U.S. Code of Federal Regulations: 21 CFR 320 Bioavailability and Bioequivalence

Requirements, Revised as of April 1, 2009

(23) PIC/S Guide To Good Manufacturing Practice For Medicinal Products, 2004

(24) European commission: The rules governing medicinal products in the European Union, Volume 4: Good

manufacturing practices Medicinal Products for Human and Veterinary Use, 2004

(25) PIC/S Guide: Inspection Of Pharmaceutical Quality Control Laboratories, 2005

(26) ICH Q2B, Validation of Analytical Procedures: Methodology, adopted in 1996, Geneva Q2B, in 2005

incorporated in Q2(R1)

(27) ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, update 2000

(28) USP 32 – NF 27, General Chapter 1225, Validation of Compendial Methods, 2009

(29) USP 32 – NF 27, General Chapter 1226, Verification of Compendial Meth, 2009

(30) USP 32 – NF 27, General Chapter 621, Chromatography, 2009

(31) ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories, 2005

http://www.aapspharmscitech.org/

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