IVT Laboratory Compliance Week-2013
Establishing Acceptance Criteria
for
Method Validation
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
© 2013 The Lanese Group
1
Outline
• Method Validation
– Terms
– Expectations
– Impact of Process Validation Guidance
• Acceptance criteria
– Intended use
– Characterstics and Types
© 2013 The Lanese Group
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Please share
• Name
• Job
• What brought you here
• One learning point you would like to
take away.
3
Define
• Acceptance criteria
© 2013 The Lanese Group
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Why do we validate test methods?
• Good Science
• The regulations require method
validation
5
© 2013 The Lanese Group
Testing and Release for Distribution
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).
21CFR211.165(e)
6
© 2013 The Lanese Group
Validation
Documented evidence that a system
consistently performs as intended.
© 2013 The Lanese Group
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Validation of an Analytical Method
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
USP <1225>
© 2013 The Lanese Group
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What to Validate
The analytical performance parameters
listed in the USP XXII, <1225> …… can be
used as a guide for determining the
analytical parameters needed to validate
the method.
Guide to the Inspection of Pharmaceutical;
Quality Control Laboratories
© 2013 The Lanese Group
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ICH Q7
•
•
•
•
•
•
Analytical methods should be validated.
Consider ICH Characteristics
Degree of validation depends on use
Maintain records
Change control
Verify compendial methods
ICH Q7 12.8
© 2013 The Lanese Group
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Key References
• USP 1225
Validation of Compendial Procedures
• ICH Q2 (R1)
Validation of Analytical Procedures:
Test and Methodology
11
© 2013 The Lanese Group
Test method
• Analytical method
• Biological method
• Physical method
• Bioanalytical method
12
© 2013 The Lanese Group
The Impact of Process Validation
Guidance
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© 2013 The Lanese Group
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A test method is a process
© 2013 The Lanese Group
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FDA Process Validation Guidance
This guidance aligns process validation activities
with a product lifecycle concept and with
existing FDA guidance, including the
FDA/International Conference on Harmonisation
(ICH) guidances for industry, Q8(R2)
Pharmaceutical Development, Q9 Quality Risk
Management, and Q10 Pharmaceutical Quality
System.2
© 2013 The Lanese Group
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ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Technology
Transfer
Investigational
Products
Commercial
Manufacturing
Product
Discontinuance
GMP
Management Responsibilities
PQS
Elements
Process Performance and Product Quality Monitoring System
Corrective Action/Preventive Action (CAPA) System
Change Management System
Management Review
Enablers
© 2013 The Lanese Group
Knowledge Management
Quality Risk Management
ICH Q10 – 4 June 2008
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuance
• Stage 1 – Process Design: The commercial
process is defined during this stage based on
knowledge gained through development and
scale-up activities.
• Stage 2 – Process Qualification: During this
stage, the process design is confirmed as being
capable of reproducible commercial
manufacturing.
• Stage 3 – Continued Process Verification:
Ongoing assurance is gained during routine
production that the process remains in a state
of control.
© 2013 The Lanese Group
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FDA Process Validation Guidance
Process Validation
The collection and evaluation of data, from the
process design stage throughout production,
which establishes scientific evidence that the
process is capable of consistently delivering
quality products.
involves a series of activities taking place over
the lifecycle of the product and process. This
guidance describes the process validation
activities in three stages.
© 2013 The Lanese Group
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FDA Process Validation Guidance
Validated analytical methods are not
necessarily required during product- and
process-development activities or when
used in characterization studies.
Nevertheless, analytical methods should
be scientifically sound (e.g., specific,
sensitive, and accurate) and provide results
that are reliable
FDA PV Guidance
© 2013 The Lanese Group
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Test Method Validation
The collection and evaluation of data, from the
method design and development, throughout
material testing, which establishes scientific
evidence that the method is capable of
consistently delivering results that accurately
reflect the material quality attribute.
involves a series of activities taking place over
the lifecycle of the method.
© 2013 The Lanese Group
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Lanese
Product/Test Method Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Material
Testing
Method
Method
Developvalidation
ment
&
Transfer
© 2013 The Lanese Group
Product
Discontinuance
Stability
Testing
22
Product Lifecycle
Corporate Support and
Management Operations
Pharmaceutical
Development
© 2013 The Lanese Group
GMP
Technology
Transfer
Commercial
Manufacturing
23
Product
Discontinuance
Product Lifecycle
Corporate Support and
Management Operations
Pharmaceutical
Development
© 2013 The Lanese Group
PQS
Technology
Transfer
Commercial
Manufacturing
24
Product
Discontinuance
• Stage 1 – Method Design: The quality control
test is defined during this stage based on
knowledge gained during discovery and
product and method development.
• Stage 2 – Method Transfer: During this stage,
the method design is confirmed as being
capable of reproducible performance in the
quality control laboratory.
• Stage 3 – Continued Method Performance
Verification: Ongoing assurance is gained
during routine testing that the test method
remains in a state of control.
© 2013 The Lanese Group
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During development understand the
test method
• Determine intended use of the method
• Identify the method characteristics
• Identify the critical process parameters.
• Establish process controls for the critical parameters.
• Assure process controls adequate.
• Add to the product knowledge base.
• Assure that process controls are included in the test
method.
© 2013 The Lanese Group
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Effective Method Development is
dependent upon a clear set of
requirements
© 2013 The Lanese Group
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When do we identify acceptance
criteria?
© 2013 The Lanese Group
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The
The
Quality
Control
Plan
Strategy
Product Lifecycle
Corporate Support and
Management Operations
Develop
Discovery
© 2013 The Lanese Group
Commercialize
Transfer
29
Decommission
The organization knows many of the
product related acceptance criteria
the day the product is conceived.
© 2013 The Lanese Group
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Intended use
• Based on
– Customer requirements
• Product user
• Process user
– Specifications
• Regulatory
• Internal
– Product tolerances
© 2013 The Lanese Group
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As process design begins
• Tentative acceptance criteria based on:
– Customer requirements
– Marketing expectations
– Regulatory conventions
– Anticipated product specifications
– Production facilities
– Anticipated process controls
© 2013 The Lanese Group
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At product conception:
we have a good idea of:
the acceptance criteria associated
with these critical quality attributes.
© 2013 The Lanese Group
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We know
• Final product criteria
– Dosage form
– Specification range
– Uniformity of dose or homogeneity
– Microbiological limitations
• Intermediate criteria
– Support the end
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Acceptance criteria - first approximation
• Assay
specification range = 100% ± 10%
• Test Method
Measurement Uncertainty = ± 2.5%
© 2013 The Lanese Group
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Process
Design
Customer &
Marketing
requirements
Process
requirements
Critical
Quality
Attributes
Control
Parameters
Intended
use
Functional
requirements
User
requirements
© 2013 The Lanese Group
Prototype
Design
Qualification
36
Formulation
Process
Develop
Design
Design
space
Quality
Plan
When do we evaluate our process/
test method against the acceptance
criteria?
All stages
Stage 1 – Method design
Stage 2 – Method validation
Stage 3 – Continued method verification
© 2013 The Lanese Group
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During Method Design
• Continually evaluate the test method against
acceptance criteria based on the intended use
of the method.
• Acceptance criteria documented in a
document which has some revision record.
© 2013 The Lanese Group
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At Method Validation
Acceptance Criteria
 Established based on intended use
and process design knowledge.
 Identified in protocol
 Firm
© 2013 The Lanese Group
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During continued method verification
Acceptance criteria
• Initially based on criteria used in validation
• Revised based on product production and
method use experiences and trending
• Supplemented to include process capability
expectations
© 2013 The Lanese Group
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Impact of guidances
© 2013 The Lanese Group
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ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Technology
Transfer
Investigational
Products
Commercial
Manufacturing
Product
Discontinuance
GMP
Management Responsibilities
PQS
Elements
Process Performance and Product Quality Monitoring System
Corrective Action/Preventive Action (CAPA) System
Change Management System
Management Review
Enablers
© 2013 The Lanese Group
Knowledge Management
Quality Risk Management
ICH Q10 – 4 June 2008
PQS Elements
• Process Performance and Product Quality
Monitoring System
• Corrective Action/Preventive Action (CAPA)
System
• Change Management System
• Management Review
© 2013 The Lanese Group
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ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Technology
Transfer
Investigational
Products
Commercial
Manufacturing
Product
Discontinuance
GMP
Management Responsibilities
PQS
Elements
Process Performance and Product Quality Monitoring System
Corrective Action/Preventive Action (CAPA) System
Change Management System
Management Review
Enablers
© 2013 The Lanese Group
Knowledge Management
Quality Risk Management
ICH Q10 – 4 June 2008
Management
Process design
Process qualification
Continued process verification
© 2013 The Lanese Group
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ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuance
GMP
Investigational
Products
Management Responsibilities
PQS
Elements
Process Performance and Product Quality Monitoring System
Corrective Action/Preventive Action (CAPA) System
Change Management System
Management Review
Enablers
© 2013 The Lanese Group
Knowledge Management
Quality Risk Management
46
ICH Q10 – 4 June 2008
Management responsibilities
Provide the organization with a clear
definition of direction.
Including the direction of development
© 2013 The Lanese Group
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Types of methods
• Identification
• Testing for impurities
– Quantitative
– Limit
• Assay
– Dissolution measurement
– Content
– Potency
ICH Q2(R1)
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Types of methods
• Assay
• Testing for impurities
– Quantitative
– Limit
• Performance
• Identification
USP <1225>
© 2013 The Lanese Group
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Characteristics
Analytical Performance Characteristics
Parameters
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Characteristics
• Accuracy
• Precision
– Repeatability
– Intermediate precision
– Reproducibility
•
•
•
•
•
•
© 2013 The Lanese Group
Specificity
Detection limit
Quantitation limit
Linearity
Range
Robustness
51
ICH Q2(R1)
Method Validation Characteristics
Type of procedure
Accuracy
Precision
Repeatability
Intermediate
Specificity
LOD
LOQ
Linearity
Range
Ident
+
-
Impurities
Quant Qual
+
+
+
+
+
+
+
+
+
Assay
+
+
+
+
+
+
ICH
© 2013 The Lanese Group
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Typical Analytical Method Response Curve
800
700
600
500
400
300
200
100
0
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Acceptance criteria
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What are acceptance criteria?
© 2013 The Lanese Group
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Acceptance criteria
• The level of performance that a test method
must achieve if the method is to perform as
intended.
• Each method characteristic should have
appropriate acceptance criteria.
• Based on critical quality attributes for the
material under test.
© 2013 The Lanese Group
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Where do we get acceptance
criteria
From knowledge of test method
and
Intended use
© 2013 The Lanese Group
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The
The
Quality
Control
Plan
Strategy
Product Lifecycle
Corporate Support and
Management Operations
Develop
Discovery
© 2013 The Lanese Group
Commercialize
Transfer
Decommission
58
We know a lot about the testing
• Active
– Impurities
– Stability
– Degredation products
• Final product
–
–
–
–
Dosage form
Specification range
Stability
Where it will be marketed
• Intermediate
– Support the end
© 2013 The Lanese Group
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We probably know
• Where the development samples will be
tested
We may not know
Where the commercial production
quality control testing will occur
Where the marketed product stability
testing will occur
© 2013 The Lanese Group
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Test Method Validation Cycle
Product Lifecycle
© 2013 The Lanese Group
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TEST METHOD LIFE CYCLE
Start
NEW METHOD
FUNCTIONAL
REQUIREMENTS
SPECIFY
INSTRUMENT
IQ
OQ
DEVELOP METHOD
Stage 1
VALIDATE METHOD
Stage 2
Change Control
SUBMIT
IMPLEMENT
SUGGEST CHANGE
© 2013 The Lanese Group
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Stage 3
Functional Requirements
• How the test will be used
• Specifications for the material
• Where the test will be performed
© 2013 The Lanese Group
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Product 1
• API: Active A
• Possible impurities (must know if > 1ppb and
how much)
–X
–Y
–Z
• Will be used in sterile product
© 2013 The Lanese Group
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Product 1 – Quality Control Needs
• Assay for a major component – Active A
– Specification Range – 98% to 102% pure
– Specificity in presence of X, Y, Z
– Used for stability testing
• Assay for minor components X, Y, Z
– Limit of Quantitation – 1ppb
– Specificity in the presence of Active A and other
minor components
• Test for presence of microbiological organisms
© 2013 The Lanese Group
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Product 1 – Quality Control Needs
Possible tests
• Assay for low level solvents
• Assay or detection of starting materials
• Particle size
© 2013 The Lanese Group
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Product 2
• Active: L
– 0.1 mg/dosage unit
• Solid dosage form
– Capsule
• Extended release
• Excipients
–A
–B
–C
• To be marketed in Europe
© 2013 The Lanese Group
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Product 2 – Quality Control Needs
• Assay for a L
– Will be used for development, release and
stability
– Specification Range – 95% to 105% target
– Possible range of assay – 0 to 115% target
– Specificity in presence of A, B, C, Capsule
• Test for presence of microbiological organisms
© 2013 The Lanese Group
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Functional Requirements
Product 2 - Assay
• Assay for the active, L
– Accuracy and precision suitable for specification range
of target ± 5%
– Linearity suitable for defined range
– Range 0 to 115% target
– No interference from A, B, C, capsule materials and
degredation products
• Suitable for use in:
– Method Development laboratory
– QC laboratory
– Stability laboratory
© 2013 The Lanese Group
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TEST METHOD LIFE CYCLE
Start
NEW METHOD
FUNCTIONAL
REQUIREMENTS
DEVELOP METHOD
VALIDATE METHOD
SUBMIT
IMPLEMENT
SUGGEST CHANGE
© 2013 The Lanese Group
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SPECIFY
INSTRUMENT
IQ
OQ
Characteristics
•
•
•
•
•
•
•
© 2013 The Lanese Group
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
71
Characteristics
•
•
•
•
•
•
•
© 2013 The Lanese Group
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
72
Specificity
The ability to assess unequivocally the
analyte in the presence of components that
may be expected to be present. Typically
these might be impurities, degradants or
matrix materials.
© 2013 The Lanese Group
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Specificity
Required for:
• Assay for major components
• Tests for minor components
– Quantitative
– Qualitative
• Identification
Might be required for:
• Performance
© 2013 The Lanese Group
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 Nonchromatographic methods
The measured concentration
between samples with and without
possible interfering components is
not greater than the normal
technique or instrument error
© 2013 The Lanese Group
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Specificity
Acceptance Criteria
• Chromatographic methods
– The resolution between the analyte peak(s)
and any other peak is at least 2.
– The resolution between the impurity peak(s)
and any other peak is at least 2.
• if this is not possible, the difference in the assay
value with and without the interfering peak(s)
present is not greater than the normal instrumental
error for the concentration tested.
– The peak contains only one molecule.
© 2013 The Lanese Group
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Characteristics
•
•
•
•
•
•
•
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
© 2013 The Lanese Group
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Limit of Detection
The lowest amount of analyte in a
sample which can be detected, but not
necessarily quantitated as an exact
value
.
© 2013 The Lanese Group
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Limit of Detection
Required for:
• Tests for minor components
– Qualitative
Might be required for:
• Tests for minor components
– Quantitative
© 2013 The Lanese Group
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FDA Guidance
Always consider
• Accuracy and precision against the
specification range.
• Precision against system suitability
requirements.
• Limit of detection against the impurity
detection specification.
• Limit of quantitation against the impurity
level specification.
© 2013 The Lanese Group
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The method must be able to detect
the impurity at the limit
specification.
NMT
≤
© 2013 The Lanese Group
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Characteristics
•
•
•
•
•
•
•
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
© 2013 The Lanese Group
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Accuracy
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
ICH Q2(R1)
Generally expressed as:
percent recovery
percent inaccuracy compared
to the theoretical
© 2013 The Lanese Group
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Accuracy
Required for:
• Assay for major components
• Tests for minor components
– Quantitative
© 2013 The Lanese Group
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Accuracy
Acceptance Criteria
Off the top of the head
• Titration
0.5%
• Chromatography
1%
• Biological
10%
© 2013 The Lanese Group
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FDA Guidance
Always consider
• Accuracy and precision against the
specification range.
• Precision against system suitability
requirements.
• Limit of detection against the impurity
detection specification.
• Limit of quantitation against the impurity
level specification.
© 2013 The Lanese Group
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± 2%
± 5%
± 10%
Target
© 2013 The Lanese Group
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TEST METHOD LIFE CYCLE
Start
NEW METHOD
FUNCTIONAL
REQUIREMENTS
DEVELOP METHOD
SPECIFY
INSTRUMENT
IQ
OQ
VALIDATE METHOD
SUBMIT
IMPLEMENT
SUGGEST CHANGE
© 2013 The Lanese Group
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Accuracy
Acceptance Criteria
How are the accuracy acceptance
criteria used during method
development?
© 2013 The Lanese Group
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Accuracy
Acceptance Criteria
• For quantitative tests:
– Determine from the product specification tolerance
(range). The error in accuracy must be less than the
product specification tolerance.
Always consider accuracy and precision against
the specification range.
90
© 2013 The Lanese Group
Accuracy
Acceptance Criteria
A rule of thumb
A little science – based on the intended use
91
© 2013 The Lanese Group
Accuracy
Acceptance Criteria
• To estimate the accuracy criterion, divide the
product specification tolerance by 2 to 2.5.
Examples,
– if the release specification for a product is 100 ±
2%, the accuracy criterion should be ~1%.
– if it is 100 ± 5%, the accuracy specification
should be ± 2% to 2.5%.
92
© 2013 The Lanese Group
Accuracy
Suggested Acceptance Criteria
• For individual results
– ≤ ¼ Specification limits
• For the average of replicates
– 0
– From a practical prospective
Close to 0
© 2013 The Lanese Group
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GoodHealth
© 2013 The Lanese Group
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Consider
The impact of the accuracy acceptance
criterion on measurement uncertainty
© 2013 The Lanese Group
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Characteristics
•
•
•
•
•
•
•
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
© 2013 The Lanese Group
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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.
© 2013 The Lanese Group
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ICH Q2(R1)
Precision
Precision should be investigated using
homogeneous, authentic samples. However, if
it is not possible to obtain a homogeneous
sample it may be investigated using artificially
prepared samples or a sample solution.
The precision of an analytical procedure is
usually expressed as the variance, standard
deviation or coefficient of variation of a series
of measurements.
ICH Q2(R1)
© 2013 The Lanese Group
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Precision
Method Categories Requiring This
Parameter
Repeatability
Intermediate
Reproducibility
 Assay of Major Components……
Yes
Yes
Yes
 Quantitative Test for Impurities...
Yes
Yes
Yes
© 2013 The Lanese Group
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Normal instrumental and technique error
contribute to the
measurement uncertainty
© 2013 The Lanese Group
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FDA Guidance
Always consider
• Accuracy and precision against the
specification range.
• Precision against system suitability
requirements.
• Limit of detection against the impurity
detection specification.
• Limit of quantitation against the impurity
level specification.
© 2013 The Lanese Group
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What determines acceptance criteria
Measurement
Material
Best the
measurement can
do
Broadest
allowable
Based on
Derived from
experimental data Uncertainty intended use
Maximum
Demonstrated
Budget
measurement
measurement
uncertainty
uncertainty
MMU
DMU
© 2013 The Lanese Group
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What determines acceptance criteria
MMU
DMU
© 2013 The Lanese Group
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Uncertainty budget
•
How much uncertainty are we
willing to accept?
•
Uncertainty budget
•
Rule of thumb
Uncertainty budget ≤ ¼ Range
© 2013 The Lanese Group
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Range
≥ 1.33
Cp =
6MU
One sided range ≥ 1.33
3MU
One
sided
range
MU ≤
4
© 2013 The Lanese Group
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Uncertainty Budget
Range
© 2013 The Lanese Group
±10%
Uncertainty
Budget
±2.5%
±5%
±1.25%
±2%
±0.5%
±1%
±0.25%
106
Measurement uncertainty
MU = systematic error + random error
Systematic error = accuracy
Total random error = method precision
107
© 2013 The Lanese Group
What determines acceptance criteria
Measurement
Material
Best the
measurement can
do
Broadest
allowable
Based on
Derived from
experimental data Uncertainty intended use
Allowable
Demonstrated
Budget
measurement
measurement
uncertainty
uncertainty
MMU
DMU
© 2013 The Lanese Group
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Demonstrated Measurement
Uncertainty
(DME)
≤
Uncertainty Budget
© 2013 The Lanese Group
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TEST METHOD LIFE CYCLE
Start
NEW METHOD
FUNCTIONAL
REQUIREMENTS
DEVELOP METHOD
SPECIFY
INSTRUMENT
IQ
OQ
VALIDATE METHOD
SUBMIT
IMPLEMENT
SUGGEST CHANGE
© 2013 The Lanese Group
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What determines acceptance criteria
MMU
DMU
© 2013 The Lanese Group
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Precision - Total random error
Precision is related to the total random
error of the analysis
Total random error =
© 2013 The Lanese Group
√Σ
2
σ
112
Accuracy and precision
Accuracy acceptance criteria
+
Precision acceptance criteria
≤
Uncertainty Budget
(based on intended use)
© 2013 The Lanese Group
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Uncertainty Budget
Range
© 2013 The Lanese Group
±10%
Uncertainty
Budget
±2.5%
±5%
±1.25%
±2%
±0.5%
±1%
±0.25%
114
Previous guidance
 Specification range - ±5%
Accuracy ± 2% - 2.5%
Precision ± 1.5% - 2%
Uncertainty Budget discussion
 Specification range - ±5%
Accuracy + precision - ±1.25%
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Always Consider
• Accuracy and precision against the
specification range.
• Precision against system suitability
requirements.
• Limit of detection against the impurity
detection specification.
• Limit of quantitation against the impurity
level specification.
© 2013 The Lanese Group
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Characteristics
•
•
•
•
•
•
•
© 2013 The Lanese Group
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
117
Limit of Quantitation
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.
© 2013 The Lanese Group
118
ICH Q2(R1)
Limit of Quantitation
Required for:
• Tests for minor components
– Quantitative
© 2013 The Lanese Group
119
FDA Guidance
Always consider
• Accuracy and precision against the
specification range.
• Precision against system suitability
requirements.
• Limit of detection against the impurity
detection specification.
• Limit of quantitation against the impurity
level specification.
© 2013 The Lanese Group
120
Typical Analytical Method Response Curve
700
600
500
400
300
200
100
0
© 2013 The Lanese Group
121
Characteristics
•
•
•
•
•
•
•
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
© 2013 The Lanese Group
122
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.
ICH Q2(R1)
© 2013 The Lanese Group
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Range
Required for:
• Assay for major components
• Tests for minor components
– Quantitative
© 2013 The Lanese Group
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Range - Guidance
For the assay of a drug substance or a finished
(drug) product: normally from 80 to 120 percent
of the test concentration;
ICH Q2(R1)
Specification Limits
Validation Range
80%
© 2013 The Lanese Group
90%
100%
125
110%
120%
Range - Guidance
For content uniformity: a minimum of 70 to 130
percent of the test concentration, unless a wider
more appropriate range, based on the nature of
the dosage form (e.g., metered dose inhalers), is
justified;
ICH Q2(R1)
Specification Limits
Validation Range
70%
© 2013 The Lanese Group
90% 100%
126
110%
130%
Range - Guidance
• for dissolution testing: +/-20 % over the
specified range;
ICH Q2(R1)
Time (hr)
1
3
6
9
12
© 2013 The Lanese Group
% Released
20%-40%
40%-75%
50%-80%
60%-90%
>80%
Range:
0% to 120%
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Characteristics
•
•
•
•
•
•
•
Specificity
Accuracy
Precision
Linearity
Range
Limit of Detection
Limit of Quantitation
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128
Linearity
The ability (within a given range)
to obtain test results which are
directly proportional to the
concentration (amount) of analyte
in the sample.
ICH Q2(R1)
© 2013 The Lanese Group
129
Linearity
may be demonstrated directly on the drug
substance (by dilution of a standard stock
solution) and/or separate weighings of
synthetic mixtures of the drug product
components, using the proposed
procedure.
ICH Q2(R1)
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130
Linearity
Required for:
• Assay for major components
• Tests for minor components
– Quantitative
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 Linear regression analysis
 Coefficient of variation
 Major analyte - ≥ 0.999
 Minor analyte - ≥ 0.98
 Intercept = zero
 95% confidence
 Visual analysis
 Straight line
 Zero intercept
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IVT Laboratory Compliance Week-2013
Establishing Acceptance Criteria
for
Method Validation
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
© 2013 The Lanese Group
133
Contact Information
Jerry Lanese
Ph.D.
The Lanese Group,, Inc.
12401 Catalina
Leawood, KS 66209
913 491 9234
jerry@lanesegroup.com
www.lanesegroup.com
© 2013 The Lanese Group
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