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Huber_1_Method_Validation
Huber_1_Method_Validation
Validation
Ludwig_huber@labcompliance.com
Today’s Agenda
• Lifecycle management of analytical
FDA 2014
procedures: development, validation
and routine use
• Using principles of Quality by
Design to get most robust methods FDA 2013
• Defining validation parameters,
acceptance criteria and test
procedures
• Templates and examples for efficient
and consistent documentations NATA 2013
www.fdawarningletter.com
© Copyright Ludwig Huber - LabCompliance Slide
Slide6
6
Method Validation Parameters for
different Method Tasks (ICH Q2)
Identifi- Impurity Impurity
Analytical Task Assay
cation Quantitative Qualitative
Accuracy No yes No Yes
Precision
Repeatability No Yes No Yes
Intermediate No Yes No Yes
Reproducibility No Yes No Yes
Precision
Repeatability Minimum of 9 determinations over the specified range
Intermediate Over 3 days, 2 operators, 2 instruments,
Reproducibility Only required if testing is done in different laboratories
Specificity Prove with specific methods: HPLC, DAD, MS, dif. columns
• Controlled transfer
Routine Operation • Regular review
• Controlled changes & Revalidation
Method
Control Strategy for
Qualification
CMAs
(ICH Q2)
System Suitability
Factor 1 3 3 2 18
Factor 2 2 1 3 6
Method UV
col. %organic
Parameter flow rate pH Wave-
temp. phase
Method Attributes length
LOQ 1 2 1 3 2
Linearity 2 1 1 3 2
Repeatability 2 1 1 2 3
Accuracy 2 3 1 3 1
Specificity 3 1 1 3 2
Risk Priority
10 8 5 14 10
Number (RPN)
Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 26
Simple DoE Example for HPLC Method
- Impact on Selectivity -
%
Run # pH Col. Temp Column Flow Rate
Org.Phase
1 -1 -1 +1 +1 +1
2 -1 +1 +1 -1 +1
3 -1 +1 -1 +1 +1
4 +1 -1 +1 -1 -1
5 +1 -1 -1 +1 -1
6 +1 +1 -1 -1 -1
Precision
Repeatability <4 % RSD (up to 15% at LOQ)
Intermediate <5.0 % RSD (higher at LOQ)
Reproducibility < 6% RSD (higher at LOQ)
Peak resolution >1.5 (related substances)
Specificity or >2 (main peak)
Peak purity check with UV DAD or MS
Limit of Detection N/A
Column Temp. ±2 C R for all peaks >1.5 R for all peaks >2.0
Mobile Phase ±2 % R for all peaks >1.5 R for all l peaks >2.0
Robustness
Sample extraction time -20 % Recovery in spec. Recovery in spec
Compound stability 6 days <3% degradation <2% degradation
Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 35
Industry Barriers to QbD
• Current guidelines not in line with QbD approaches
• Registration currently not based on method performance but on method
conditions
• Low motivation to change
• Only little experience in the industry
• Requires new tools and skills for analysts
• Implementation Challenges
– Collaboration between functions
– Experience with new concepts
– Workload and resource limitations
Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 36
FDA-EMA Collaborative Research on
QbD for Analytical Methods: Q&As
Question
•What are the Agencies’ views with respect to the use of analytical
target profile (ATP) for analytical methods?
Answer
•In general, an analytical process profile (ATP) can be acceptable
as a qualifier of the expected method performance by analogy to
the QTPP as defined in ICH Q8 (R2).
•However, the Agencies would not consider analytical
methods that have different principles (e.g.,HPLC to NIR)
equivalent solely on the basis of conformance with the ATP. An
applicant should not switch between methods without appropriate
regulatory submission and approval