Horacio N. Pappa, Ph.D.

Principal Scientific Liaison

USPs Validation and Verification General
Chapters: Current and Proposed
Prescription/Non-Prescription Stakeholder
Forum
Meeting #4 for 2010-2015
Thursday, J une 27, 2013
<1225> Validation of Compendial Procedures
Developed in late 1980s
Define Analytical Performance Characteristics
No validation acceptance criteria

<1226> Verification of Compendial Procedures
Required at the time of implementation
Focus in matrix interference and lab variability
Lack of specific directions

<1224> Transfer of Analytical Procedures
Applicable were verification is not appropriate
High level information
Statistical approaches are not fully described (<1010>?)

Validation to Measure Variability
Validation & Verification Expert Panel
<1200> Requirements for Compendial Validation
<XXXX> Statistical Tools for Procedure Validation
Elemental impurities / Spectroscopy chapters
USP initiatives
3
Validation & Verification Expert Panel
4
The primary objective of the Expert Panel is to develop a
consistent approach to validation, verification and related
topics, from a compendial perspective, which is
requirements driven, supported by appropriate statistical
tools and will provide guidance which will add value to
industry.
Allen Templeton
Anne K. McCasland-Keller
Christopher Burgess
David LeBlond
David P. Thomas
Elisabeth Kovacs
Gregory Martin (Chair)
Gyongyi S. Gratzl
Membership
J ane Weitzel
J oachim Ermer
J oerge Herrmann
J ohn P. Hammond
Kimber Barnett
Lucinda Buhse (FDA)
Paul Curry, J r.
Phil Nethercote
Rosario LoBrutto
Deliverables
Lifecycle Management of Analytical Procedures:
Development, Performance Qualification, and
Performance Verification
Scheduled for PF 39(5) 2013
Introduces integrated lifecycle concept, Analytical Target Profile

Revised core USP Chapters
<1225> Validation to be updated and expanded
<1226>, <1224> may no longer be necessary
Informational chapter to provide guidance
Establishes the types of data that the USP is expecting to see
in order to determine the acceptability of a procedure prior to
its inclusion in the USP-NF.
Include measurable parameters and clear criteria
Acceptability of a procedure is evaluated by means of six
standardized studies: PrecisionAccuracy, Specificity, Range,
Accuracy, Precision, and Detectability.
Eliminates LOQ and Linearity
<1200> Requirements for Compendial Validation
7
Precision and Accuracy Study
When properly combined Precision and Accuracy yield a
probability of passing.


Bias-%CV Tradefoff, 98%-102% limits, True Value = 100, Prob'y Passing 0.95
0
0.2
0.4
0.6
0.8
1
1.2
2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00
Bias
%
C
V
This chapter, intended to be a companion to <1225> Validation of Compendial
Procedures, provides appropriate statistical methods and examples to aid
method validation. Analytical performance characteristics that are discussed
from a statistical perspective in the sections that follow are:
Accuracy
Precision
Detection Limit
Quantitation Limit
Linearity
Range

<XXXX> Statistical Tools for Validation
9
Elemental Impurities / Spectroscopy Chapters
10
Equivalent or Better Concept
Option Name Demonstrating Comparison
to official
procedure
Number of
characteristics
considered
1 Acceptable Procedures Acceptable No Many
2 Performance Equivalence
Equivalent or
Better
Yes

Many

3 Results Equivalence Equivalent
Yes

One
4 Decision equivalence Equivalent
Yes

One
Reproduced from Acceptable, equivalent or better approaches for alternatives
to official compendial procedures by W. Hauck et al. PF35(3), 2009
Elemental Impurities / Spectroscopy Chapters
11

Include Validation/Verification acceptance criteria in
the chapter
<233> Elemental impurities - Procedures
<852> Atomic Absorption Spectroscopy
<854> Mid-Infrared Spectroscopy
<857> Ultraviolet-Visible Spectroscopy
<853> Fluorescence Spectroscopy


Summary
USP is revisiting validation concepts
Introducing concepts of QbD and ATP
Including validation acceptance criteria where appropriate