pharm 462 12009. european and international regulatory bodies and their guidelines on different...
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PHARM 462
12009
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European and International regulatory bodies and their guidelines on different aspects of QA
Body Full name Guidance on
Eurachem Focus for Analytical Chemistry in Europe Method validation
CITAC Cooperation of International Traceability in Analytical Chemistry
Proficiency testingQuality Assurance
EA European Cooperation for Accreditation Accreditation
CEN European Committee for Normalization Standardization
IUPAC International Union of Pure & Applied Chem. Method validation
ISO International Standardization Organisation Standardisation
AOAC
ILAC
Association of Official Analytical Chemists
International Laboratory Accreditation Cooperat.
Internal qual. ControlProficiency testingAccreditation
FDA US Food and Drug Administration Method validation
USP United States Pharmacopoeia Method validation
ICH International Conference on Harmonization Method validation
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Method Validation
Validation of analytical procedures is the process of determining the
suitability of a given methodology for providing useful
analytical data.
J. Guerra, Pharm. Tech. March 1986
Validation is the formal and systematic proof that a method compiles
with the requirements for testing a product when
observing a defined procedures.
G. Maldener, Chromatographia, July 1989
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Method validation is the process of demonstrating that analytical
procedures are suitable for their intended use and that they support
the 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
terms the performance characteristics of an assay
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Examples of Methods That Require
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.
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Considerations Prior to Method Validation
Suitability of Instrument Status of Qualification and Calibration
Suitability of Materials Status 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
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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.
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Purpose of Method 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
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What is not Analytical Method
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
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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%
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System Suitability
Sample
Validation
MethodAnalyst
Calibration
Pump
Detector
Injector
Data System
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Method Life Cycle
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Validation
Development Optimization
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Verification vs. Validation
Compendial vs. Non-compendial Methods
Compendial methods-Verification
Non-compendial methods-Validation requirement
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Compendial Analytical Procedures
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
provided for the following
characteristics:
Specificity of the procedure
Stability of the sample solution
Intermediate precision 142009
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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 <1225>: Validation of Compendial Methods
1999 CDER “Bioanalytical Method Validation for Human Studies”
2000 CDER Draft “Analytical Procedures and Method Validation”152009
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Regulatory and Compliance Requirements Review
Validation of an analytical method is the
process by which it is established, by
laboratory studies, that the performance
characteristics of the method meet the
requirements for the intended analytical applications
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USP 23 General Information <1225>
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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 211.194(a)(2).
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21 CFR PART 211 - CURRENT GOOD
MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
Subpart I-Laboratory Controls
211.165 Testing and release for distribution (e)
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The objective of validation of an analytical
procedure is to demonstrate that it is suitable
for its intended purpose
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ICH Guideline for Industry Q2A, Text on Validation of Analytical ProceduresMarch 1995
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In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: Specificity, Linearity, Range, Accuracy, and
Precision.
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ICH Guideline for Industry Q2B, Validation of Analytical Procedures: Methodology
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Today’s Validation Requirements
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ICH/USP
GMPs(legal) FDA
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ICH/USP Validation Requirements & Parameters
Specificity
Linearity
Range
Accuracy
Precision Repeatability Intermediate Precision Reproducibility
Limit of Detection
Limit of Quantitation21
ICH
SpecificitySpecificity Linearity and RangeLinearity and Range AccuracyAccuracy Precision Precision Limit of DetectionLimit of Detection Limit of QuantitationLimit of Quantitation RuggednessRuggedness RobustnessRobustness
USP
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USP Data Elements Required For Assay Validation
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Analytical PerformanceParameter
Assay Category
1
Assay Category 2Assay
Category 3
Quantitative
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
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USP Categories
Category 1: Quantitation of major components or
active ingredients
Category 2: Determination of impurities or
degradation products
Category 3: Determination of performance
characteristics
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ICH Validation Characteristics vs. Type of Analytical Procedure
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Type of Analytical Procedure
Identification
Impurity 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 Yes
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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
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Specificity: Impurities Assay
Chromatographic Methods Demonstrate Resolution
Impurities/Degradants Available Spike with impurities/degradants
Show resolution and a lack of interference
Impurities/Degradants Not Available Stress Samples
For assay, Stressed and Unstressed Samples should be
compared.
For impurity test, impurity profiles should be compared.
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Forced 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
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Linearity
Ability of an assay to
elicit a direct and
proportional response
to changes in analyte
concentration.
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Linearity Should be Evaluated
By Visual Inspection of plot of signals vs. analyte
concentration
By Appropriate statistical methods
Linear Regression (y = mx + b)
Correlation Coefficient, y-intercept (b), slope (m)
Acceptance criteria: Linear regression r2 > 0.95
Requires a minimum of 5 concentration levels
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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
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Accuracy
Closeness of the test
results obtained by the
method to the true value.
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Accuracy Should be established across specified range of
analytical procedure.
Should be assessed using a minimum of 3 concentration
levels, each in triplicate (total of 9 determinations)
Should be reported as:
Percent recovery of known amount added or
The difference between the mean assay result and the accepted
value
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Accuracy Data Set (1 of 3)
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Amount Added (mg)
AmountFound (mg)
Percent Recovery
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
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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.
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Precision… Considered at 3 Levels
Repeatability
Intermediate Precision
Reproducibility
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Repeatability
Express the precision
under the same
operating conditions
over a short interval of
time.
Also referred to as
Intra-assay precision
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Should be
assessed using
minimum of 9
determinations
(3
concentrations/ 3
replicates) or or
Minimum of 6
determinations at
the 100% level.2009
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Intermediate Precision
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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
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Repeatability & Intermediate 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
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GrandMean = 100.0RSD = 0.59%
Mean = 100.5RSD = 0.24%
Mean = 99.5RSD = 0.36%
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Reproducibility
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
Day 1
Day 2
Day 1
Day 2
Day 1
Day 2
Man 1
Man 2
Man 1
Man 2
Man 1
Man 2
3 Prep
3 Prep
3 Prep
3 Prep
3 Prep
3 Prep
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Detection Limit (LOD)/ Quantitation Limit (LOQ)
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.
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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
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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
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LOD and LOQ Estimated by
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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 DL ==
3.3s3.3sQL =QL =
10s10s
SS SS
LOD and LOQ Estimated by
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Ybl
LOD LOQ
Statistical estimate of LOD & LOQ
LOD = 3.3 Sbl / b LOQ = 10 Sbl / b
Y = b X + a
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Definition: Capacity to remain unaffected by small but deliberate
variations in method parameters
Determination: Comparison results under differing conditions
with precision under normal conditions
Examples 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
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Robustnes
s
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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 %RSD452009
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ICH/USP System Suitability
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)
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USP 23 <621> System Suitability Requirements
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Parameters
Recommendations
K’ In general k’ ≥ 2.0
R
R > 2, between the peak of interest and the closest potential interferent (degradant, internal STD, impurity, excipient, etc…..)
T T ≤ 2
N In general N > 2000
Repeatability
RSD ≤ 2.0% (n ≥ 5)
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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
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How do we Know the expectations of the FDA?
FDA Form 483
FDA Warning Letters
Personal Experiences
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483 Observations There was inadequate method validation specificity
data to demonstrate that each method was capable of
distinguishing 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 the
major degradation products
was not included for each product.502009
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FDA Waning Letter
On addition to the example of modifying both compendial methods and customer supplied methods, we also observed the use of unvalidated in-house methods as well as unvalidated
modifications to in-house methods.A statement indicating that the method has not been
validated in the particular formulation was included in the certificate of analysis for…use of this statement does not absolve…from using valid, accurate, and
reproducible methods. (June 2000)
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FDA Systems Based Inspection:Laboratory System
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Method Validation
13%Training/Qual.
4%
Stability 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
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ICH Update:
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A Unique Approach
International Conference on Harmonisation (ICH) was created in 1990
Agreement between the EU, Japan and the USA to harmonize different regional requirements for registration of pharmaceutical drug products
Unique because joint effort by regulators and associated pharmaceutical industry trade associations
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ICH Objectives
Identification and elimination of the need to duplicate studies to meet different regulatory requirements
More efficient use of resources in the R&D process, as a consequence
Quicker access for patients to safe and effective new medicines
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Working Groups
SAFETY EFFICACY
QUALITY MULTIDISCIPLINARY
STEERING COMMITTEEEndorses topics, guidelines and monitors progress
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Related Site
www.fda.gov
www.fda.gov/cder/
www.waters.com
www.usp.org
www.ich.org
www.aoac.org
www.pharmweb.net
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