farmasi analisis

8/12/2019 farmasi analisis

1/57

PHARM 462

12009


2/57

European and International regulatory bodies andtheir guidelines on different aspects of QA

Body

F ul l name Guidance on

Eurachem F ocus for Analytical Chemistry in Europe M ethod vali dation

CI TAC Cooperation of I nternational Traceabil ity inAnalytical Chemistry

Prof iciency testingQuali ty Assur ance

EA European Cooperation for Accreditation Accreditation

CEN European Committee for Normalization StandardizationI UPAC I nternational Uni on of Pure & Appli ed Chem. M ethod vali dation

I SO I nternational Standardization Organisation Standardisation

AOAC

ILAC

Association of Off icial A nalytical Chemists

I nternational L aboratory Accreditation Cooperat.

I nternal qual. ControlProf iciency testing

Accreditation

F DA US F ood and Dr ug Admini stration M ethod vali dation

USP Uni ted States Phar macopoeia M ethod vali dation

I CH I nternational Conf erence on H armonization M ethod vali dation

2 2009


3/57

M ethod Validation

Validation of analytical procedures is the process of determining the

su i t ab i l i t y o f a g iven me thodo logy fo r p rov id ing u se fu l

analytical data.

J. Guerra, Pharm. Tech. M arch 1986

Validation is the formal and systematic proof that a method compiles

w i t h t h e r e q u i r e m e n t s f o r t e s t i n g a p r o d u c t w h e nobserving a defined procedures.

G. Maldener, Chromatographia, Ju ly 1989

32009


4/57

Method validation is the process of demonstrating that analytical

procedures are suitable for their intended use and that they supportthe identity, strength, quality, purity and potency of the

drug substances and drug products

Method validation is primarily concerned with:

identification of the sources of potential errors

quantification of the potential errors in the method

An method validation describes in mathematical and quantifiable

t e r m s t h e p e r f o r m a n c e c h a r a c t e r i s t i c s o f a n a s s a y

42009


5/57

Examples of M ethods That Requi re

Validation Documentation

Chromatographic Methods - HPLC, GC, TLC, GC/MS, etc.

Pharmaceutical Analysis - In support of CMC.

Bioanalytical Analysis - In support of PK/PD/Clinical Studies.

Spectrophotometric Methods UV/VIS, IR, NIR, AA, NMR,

XRD,MS

Capillary Electrophoresis Methods - Zone, Isoelectric Focusing

Particle Size Analysis Methods - Laser, Microscopic, Sieving, SEC, etc.

Automated Analytical Methods - Robots, Automated Analysis.

52009


6/57

Considerations Prior toM ethod Validation

Suitability of Instrument

Status of Qualification and Calibration

Suitability of MaterialsStatus of Reference Standards, Reagents, Placebo Lots

Suitability of Analyst

Status of Training and Qualification Records

Suitability of Documentation

Written analytical procedure and proper approved protocol

with pre-established acceptance criteria

62009


7/57

Validation Step Define the application, purpose and scope of the method.

Analytes? Concentration? Sample matrices?

Develop a analytical method.

Develop a validation protocol.

Qualification of instrument. Qualify/train operator

Qualification of material.

Perform pre-validation experiments.

Adjust method parameters and/or acceptance criteria if necessary. Perform full validation experiments.

Develop SOP for executing the method in routine analysis.

Document validation experiments and results in the validation report.

72009


8/57

Purpose of M ethod Validation

Identification of Sources and Quantitation of Potential errors

Determination if Method is Acceptable for Intended Use

Establish Proof that a Method Can be Used for Decision Making

Satisfy FDA Requirements

82009


9/57

What is not Analytical M ethod Validation?

Calibration

The Process of Performing Tests on Individual System

Components to Ensure Proper function

For example) HPLC Detector calibration

Wavelength Accuracy/ Linear Range/ Noise Level/ Drift

92009


10/57

System Suitability

Test to verify the proper functioning of the operating system,

i.e., the electronics, the equipment, the specimens and the

analytical operations.Minimum Resolution of 3.0 between the analyte peak and

internal standard peaks

Relative Standard Deviation of replicate standard injections

of not more than 2.0%

102009


11/57

11

System Suitability

Sample

Validation

Methodnalyst

Calibration

Pump

Detector

Injector

Data System

2009


12/57

M ethod L ife Cycle

12

Validation

Development Optimization

2009


13/57

Verif ication vs. Validation

Compendial vs. Non-compendial Methods

Compendial methods-Verification

Non-compendial methods-Validation requirement

132009


14/57

Compendial Analytical Pr ocedur es

The Analytical procedures in the USP 25/NF 20 are legally recognized under

section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory

analytical procedures for the compendial items. The suitability of these

procedures must be verified under actual conditions of use. When using USP

25/NF 20 analytical procedures, the guidance recommends that information be

p r o v i d e d f o r t h e f o l l o w i n g

characteristics: Specificity of the procedure

Stability of the sample solution

Intermediate precision 142009


15/57

Published Validation Guidelines

1978 Current Good Manufacturing Practices (cGMPs)1987 FDA Validation Guideline

1989 Supplement 9 to USP XXI

1994 CDER Reviewer Guidance:

Validation of Chromatographic Method

1995 ICH Validation Definitions:

Q2A, Text on Validation of Analytical procedures

1997 ICH Validation Methodology:

Q2B, Validation of Analytical Procedures: Methodology

1999 Supplement 10 to USP 23 : Validation of Compendial Methods

1999 CDER Bioanalytical Method Validation for Human Studies

2000 CDER Draft Analytical Procedures and Method Validation 152009


16/57

Regulatory and ComplianceRequirements Review

Validation of an analytical method is the

process by which it is established, by

laboratory studies, that the performancecharacteristics of the method meet the

requirements for the intended analytical

applications

16

USP 23 GeneralInformation

2009


17/57

T h e a c c u r a c y, s e n s i t i v i t y, s p e c i f i c i t y, a n d

reproducibility of test methods employed by the firm

shall be established and documented. Such validation

and documentat ion may be accomplished in

a c c o r d a n c e w i t h 2 1 1 . 1 9 4 ( a ) ( 2 ) .

17

21 CFR PART 211 - CURRENT GOOD MANUFACTURINGPRACTICE FOR FINISHED PHARMACEUTICALS

Subpart I-Laboratory Controls

211.165 Testing and release for distribution (e)

2009
http://www.fda.gov/cder/dmpq/cgmpregs.htmhttp://www.fda.gov/cder/dmpq/cgmpregs.htmhttp://www.fda.gov/cder/dmpq/cgmpregs.htmhttp://www.fda.gov/cder/dmpq/cgmpregs.htm


18/57

The objective of validation of an analytical

procedure is to demonstrate that it is suitablefor its intended purpose

18

ICH Guideline forIndustryQ2A, Text on

Validation ofAnalytical ProceduresMarch 1995

2009


19/57

In practice, it is usually possible to design the experimental

work such that the appropriate validation characteristicscan be considered simultaneously to provide a sound,overall knowledge of the capabilities of the analyticalprocedure, for instance: Specificity, Linearity, Range,

Accuracy, andPrecision.

19

ICH Guideline for IndustryQ2B, Validation of AnalyticalProcedures: Methodology

2009


20/57

Today s Validation Requirements

20

ICH/USP

GMPs

(legal) FDA

2009


21/57

I CH /USP Validation Requirements &Parameters

Specificity

Linearity

Range

Accuracy

Precision

Repeatability

Intermediate Precision

Reproducibility

Limit of Detection

Limit of Quantitation21

ICH

Specificity

Linearity and RangeAccuracy

Precision

Limit of Detection

Limit of QuantitationRuggedness

Robustness

USP

2009


22/57

USP Data Elements RequiredF or Assay Validation

22

AnalyticalPerformance

Parameter

AssayCategory 1

Assay Category 2Assay

Category 3Quantitative Limit Tests

Accuracy Yes Yes * *

Precision Yes Yes No Yes

Specificity Yes Yes Yes *

LOD No No Yes *

LOQ No Yes No *

Linearity Yes Yes No *

Range Yes Yes * *

Ruggedness Yes Yes Yes Yes

* May be required, depending on the nature of the specific test.2009


23/57

USP Categories

Category 1: Quantitation of major components or

active ingredients

Category 2: Determination of impurities or

degradation products

Category 3: Determination of performancecharacteristics

232009


24/57

I CH Validation Character istics vs.Type of Analytical Procedure

24

Type ofAnalyticalProcedure

IdentificationImpurity testing

AssayQuantitative Limit Tests

Accuracy No Yes No Yes

Precision

Repeatability No Yes No Yes

Interm. Prec. No Yes No Yes

Specificity Yes Yes Yes Yes

LOD No No Yes No

LOQ No Yes No No

Linearity No Yes No Yes

Range No Yes No Yes2009


25/57

Specificity/Selectivity Ability of an analytical method to measure the analyte free from

interference due to other components .

Selectivity describes the ability of an analytical method to differentiate

various substances in a sample

Original term used in USP

Also Preferred by IUPAC and AOAC

Also used to characterize chromatographic columns

Degree of Bias (Used in USP)

The difference in assay results between the two groups

- the sample containing added impurities, degradation products, related chemical

compounds, placebo ingredients

- the sample without added substances

252009


26/57

Specif ici ty: I mpur ities Assay

Chromatographic Methods

Demonstrate Resolution

Impurities/Degradants Available

Spike with impurities/degradants

Show resolution and a lack of interference

Impurities/Degradants Not Available

Stress SamplesFor assay, Stressed and Unstressed Samples should becompared.

For impurity test, impurity profiles should be compared.

262009


27/57

F orced Degradation Studies

Temperature (50-60 )

Humidity (70-80%)

Acid Hydrolysis (0.1 N HCl)

Base Hydrolysis (0.1 N NaOH)

Oxidation (3-30%)

Light (UV/Vis/Fl)

Intent is to create 10 to 30 % Degradation

272009
http://my.dreamwiz.com/speed022/pds/weather/weather_04.gifhttp://my.dreamwiz.com/speed022/pds/weather/weather_11.gifhttp://www.grsites.com/webgraphics/clipart/sciencemedicine/clipart_sciencemedicine_022.gifhttp://210.220.231.208/graphic/clipart/science/prisms.gif


28/57

Linearity

Ability of an assay to

elicit a direct and

proportional response

to changes in analyte

concentration.

282009


29/57

L inearity Should be Evaluated

By Visual Inspection of plot of signals vs. analyte

concentration

By Appropriate statistical methodsLinear Regression (y = mx + b)

Correlation Coefficient, y-intercept (b), slope (m)

Acceptance criteria: Linear regression r 2 > 0.95

Requires a minimum of 5 concentration levels

292009


30/57

Range

Acceptable range having linearity, accuracy, precision.For Drug Substance & Drug product Assay

80 to 120% of test Concentration

For Content Uniformity Assay

70 to 130% of test Concentration

For Dissolution Test Method

+/- 20% over entire Specification Range

For Impurity Assays

From Reporting Level to 120% of Impurity Specification for Impurity

Assays

From Reporting Level to 120% of Assay Specification for Impurity/Assay

Methods302009


31/57

Accuracy

Closeness of the test

results obtained by the

method to the true value.

31


32/57

Accuracy Should be established across specified range of

analytical procedure.

Should be assessed using a minimum of 3 concentrationlevels, each in triplicate (total of 9 determinations)

Should be reported as:

Percent recovery of known amount added orThe difference between the mean assay result and the accepted

value

322009


33/57

Accuracy Data Set (1 of 3)

33

AmountAdded (mg)

AmountFound (mg)

PercentRecovery

0.0 0.0 ---

50.2 50.4 100.5

79.6 80.1 100.6

99.9 100.7 100.8

120.2 119.8 99.7

150.4 149.7 99.5

2009


34/57

Precision

The closeness of agreement (degree of

scatter) between a series of

measurements obtained from

multiple samplings of the same

homogeneous sample.

Should be investigated using

homogeneous, authentic samples.

342009


35/57

Precision Considered at 3 L evels

Repeatability

Intermediate Precision

Reproducibility

352009


36/57

Repeatabil i ty

Express the precision

under the same

operating conditions

over a short interval of

time.

Also referred to as

Intra-assay precision

36

Should be assessed

using minimum of 9

determinations(3 concentrations/ 3

replicates) r

Minimum of 6determinations at the

100 level.

2009


37/57

I ntermediate Precision

37

Express within-laboratory

variations.

Expressed in terms of

standard deviation,

relative standard deviation

(coefficient of variation)

and confidence interval.

Depends on the

circumstances under which

the procedure is intended

to be used.

Studies should include

varying days, analysts,

equipment, etc.

2009


38/57

Repeatabil i ty & I ntermediate Precision

Day 1 Day 2100.6 99.5

100.8 99.9

100.1 98.9

100.3 99.2

100.5 99.7

100.4 99.6

38

GrandMean = 100.0RSD = 0.59

Mean = 100.5RSD = 0.24 Mean = 99.5RSD = 0.36

2009


39/57

Reproducibil i ty

Definition: Ability reproduce data

within the predefined precision

Determination: SD, RSD and

confidence interval

Repeatability test at two different

labs.

Note: Data not required for BLA/NDA

Lab 1 Lab 2 Lab 3

Day1 Day2 Day1 Day2Day1 Day2

Man1

Man2

Man1

Man 2 Man1

Man2

3Prep

3Prep

3Prep

3Prep

3Prep

3Prep

39


40/57

Detection L imit (LOD)/Quantitation L imit (L OQ)

LOD

Lowest amount of analyte in a

sample that can be detected

but not necessarily

quantitated.

Estimated by Signal to Noise

Ratio of 3:1.

40

LOQ

Lowest amount of analyte

in a sample that can be

quantified with suitable

accuracy and precision.

Estimated by Signal to

Noise Ratio of 10:1.

2009


41/57

1. Based in Visual Evaluations

- Used for non-instrumental methods

2. Based on Signal-to Noise-Ratio

- 3:1 for Detection Limit

- 10:1 for Quantitation Limit

3. Based on Standard Deviation of the Response and

the Slope

41

LOD and LOQ Estimated by

2009


42/57

S = slope of calibration curve

s = standard deviation of blank readings or

standard deviation of regression line

Validated by assaying samples at DL or QL

42

DL =3.3s

QL =10s

S S

LOD and LOQ Estimated by

2009


43/57

43

Ybl

LOD LOQ

Statistical estimate of LOD & LOQ

LOD = 3.3 Sbl / b LOQ = 10 Sbl / b

Y = b X + a

2009


44/57

Definition: Capacity to remain unaffected by small but deliberate

variations in method parameters

Determination: Comparison results under differing conditions

with precision under normal conditionsExamples of typical variations in LC

Influence of variations of pH in a mobile phase

Influence of variations in mobile phase composition

Different columns (different lots and/or suppliers)

Temperature

Flow rate

44

Robustness

2009


45/57

Ruggedness

Degree of reproducibility of test results

under a variety of conditions

Different Laboratories

Different Analysts

Different Instruments

Different Reagents

Different Days

Etc.

Expressed as %RSD

452009


46/57

I CH /USP System Suitabili ty

ICH

Definition: evaluation of equipment, electronic,analytical operations and samples as a whole

Determination: repeatability, tailing factor (T), capacity

factor (k ), resolution (R), and theoretical Plates (N)

462009


47/57

USP 23

System Suitability Requirements

47

Parameters Recommendations

K In general k 2.0

RR > 2, between the peak of interest and theclosest potential interferent (degradant,internal STD, impurity, excipient, etc ..)

T T 2 N In general N > 2000

Repeatability RSD 2.0 (n 5)

2009


48/57

Re-validation

When Method parameters have been changed The scope of the method has been changed

Synthetic methods have been changed Impurity profile has been changed

What Preferably everything. Exceptions should be

scientifically justified

482009


49/57

H ow do we Know the expectations ofthe F DA?

FDA Form 483FDA Warning Letters

Personal Experiences

492009


50/57

483 ObservationsThere was inadequate method validation specificity

data to demonstrate that each method was capable ofdistinguishing the active ingredient from its impurities

and degradation products.

Specificity studies did not include the minimum stress

conditions of acid and base hydrolysis, oxidation,thermal degradation and photolysis, degradation

schematic for the active ingredient that identifies themajor degradation products

was not included for each product.502009


51/57

F DA Waning Letter

On addition to the example of modifying both compendialmethods and customer supplied methods, we also observedthe use of unvalidated in-house methods as well as

u n v a l i d a t e dmodifications to in-house methods.

A statement indicating that the method has not beenvalidated in the particular formulation was included in thecertificate of analysis for use of this statement does nota b s o l v e f r o m u s i n g v a l i d , a c c u r a t e , a n d

reproducible methods. (June 2000)

512009


52/57

F DA Systems Based I nspection: L aboratory System

52

MethodValidation

13

Training/Qual.

4Stability Program

21

InadequateRecords

27

Controls. General35

Feb July 2002: 212 Inspections (US)

* Reference: Albinus D Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 presentation.

2009


53/57

ICH Update:

2009 53


54/57

A Unique Approach

International Conference on Harmonisation(ICH) was created in 1990

Agreement between the EU, Japan and theUSA to harmonize different regional requirements for registration of pharmaceuticaldrug productsUnique because joint effort by regulators andassociated pharmaceutical industry tradeassociations

2009 54


55/57

ICH Objectives

Identification and elimination of the need to duplicatestudies to meet different regulatory requirementsMore efficient use of resources in the R&D process,as a consequenceQuicker access for patients to safe and effective newmedicines

2009 55


56/57

Working Groups

SAFETY EFFICACY

QUALITY MULTIDISCIPLINARY

STEERING COMMITTEEEndorses topics, guidelines and monitors progress

2009 56


57/57

Related Site

www.fda.gov

www.fda.gov/cder/

www.waters.com

www.usp.org

www.ich.org

www.aoac.org

www.pharmweb.net
http://www.fda.gov/http://www.fda.gov/cder/http://www.waters.com/http://www.usp.org/http://www.ich.org/http://www.aoac.org/http://www.pharmweb.net/http://www.pharmweb.net/http://www.aoac.org/http://www.ich.org/http://www.usp.org/http://www.waters.com/http://www.fda.gov/cder/http://www.fda.gov/

farmasi analisis

Documents

Transcript of farmasi analisis