Points to Consider in QC Method Validation and Transfer for Biological Products

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Points to Consider in QC
Method Validation and
Transfer for Biological
Products
Weijun Li, Ph.D.
Bayer, Quality Control
Berkeley, CA, USA

The contents of this presentation are based upon the
opinion and experience of the presenter. The statements
and information do not represent the official position of
Bayer. The actual results may differ materially from the
contents presented due to proprietary consideration. The
presenter and Bayer have no obligation to update the
contents contained in this presentation.
Disclaimer

Overview
Consider analytical validation and transfer as part of
analytical lifecycle management
Fit-for-purpose concept in validation design
Case study – Spiking material for SEC validation
Analytical transfer is risk-based and confirms the
validation status
Case study – Practice run to identify potential issues
prior to the transfer
Case study – Operator interview for transfer
troubleshooting
Summary

Consider
Validation and
Transfer as Part
of Analytical
Method Life Cycle

Analytical Method Life Cycle
Analytical
Development
Method
Procedure
Validation/
Transfer
Method
Improvement
Analytical
Target
Profile

Consider Fit-for-
Purpose Concept in
Method Validation

Fit-for-Purpose Validation Approaches
Graduated Validation
from development to commercialization
Generic Validation
when the method is not product-specific
Co-Validation
Full Validation per ICHQ2(R1)
Compendial Verification

Case Study 1: Creating Fit-for-Purpose
Spiking Material for SEC Validation
Spiking study is required for the SEC validation
Spiking material should fit-for-purpose: represent the size of
Aggregates or Low Molecular Weight (LMW) impurity in SEC
Challenge - difficult to obtain stable and enough quantity of the
impurities for the study.
Options:
Stability/forced degradation
Purification cut-off impurities
Chromatographic fractionation
Chemical reaction

Creating Aggregates and LMW by Chemical
Reaction
min2.5 5 7.5 10 12.5 15 17.5
mAU
0
100
200
300
400
500
MWD1 A, Sig=280,8 Ref=330,8 (XMZ040915A 2015-04-09 12-21-47033-0401.D)
min6 7 8 9 10 11
mAU
0
20
40
60
80
min2.5 5 7.5 10 12.5 15 17.5
mAU
0
100
200
300
400
500
600
min10 10.5 11 11.5 12 12.5 13 13.5 14 14.5
mAU
0
10
20
30
40
Aggregates LMW

SEC Spiking Study (Aggregates)
Linearity, R = 1.00; Accuracy, %Recovery 90% to 100%

Linearity, R = 0.99; Accuracy, %Recovery 80% to 100%
LMW1:
R = 0.993, %Recovery
62% to 100%
LMW2:
R = 1.000, %Recovery
100% to 103%
min10 10.5 11 11.5 12 12.5 13 13.5 14 14.5
mAU
0
10
20
30
40
SEC Spiking Study (LMW)

Spiking Study May Reveal Potential
Method Issue
Red: SEC Method 1; Blue: SEC Method 2
Both Methods showed good linearity/accuracy by linear dilution study, but
different responses to spiking study

Consider Analytical
Transfer Is Risk-
based and Confirms
the Validation Status

Globalization of Biotech Industry Requires
Analytical Transfer
Bioprocess International WEST 2015, Weijun Li
CMC Development
GLP Study Facility
Drug Substance Manufacturing
Drug Product Manufacturing
Stability Program
Contract Testing Lab
Capacity Expansion/Replacing Aging Facilities
…

Risk-based Transfer Approaches
Compendial Verification (receiving lab)
Co-Validation (two or more labs)
Transfer Waiver
Side-by-Side Comparative Test (two labs)
Non-Compendial Verification (receiving lab)
when the lab has similar method established
Full Validation (receiving lab)

Validation Characteristics per ICH Q2(R1)
Validation
characteristics
Identification
Test
Testing for Impurities
Assay:
• Dissolution test:
(measurement only)
• Content/potency
Quantitative
Limit
(Qualitative)
Accuracy - + - +
Precision:
Repeatability
- + - +
Precision:
Intermediate
- + (1) - +
Specificity (2) + + + +
Detection Limit - - (3) + -
Quantitation
Limit
- + - -
Linearity - + - +
Range - + - +
- signifies that this characteristic is not normally evaluated; + signifies that this characteristic is normally evaluated
(1) in cases where reproducibility (see glossary) has been performed, intermediate precision is not needed
(2) lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s)
(3) may be needed in some cases

Typical Risk-based Transfer Characteristics (Red)
Validation
characteristics
Identification
Test
Testing for Impurities
Assay:
• Dissolution test:
(measurement only)
• Content/potency
Quantitative
Limit
(Qualitative)
Accuracy - + - +
Precision:
Repeatability
- + - +
Precision:
Intermediate
- + (1) - +
Specificity (2) + + + +
Detection Limit - - (3) + -
Quantitation
Limit
- + - -
Linearity - + - +
Range - + - +
- signifies that this characteristic is not normally evaluated; + signifies that this characteristic is normally evaluated
(1) in cases where reproducibility (see glossary) has been performed, intermediate precision is not needed
(2) lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s)
(3) may be needed in some cases

Lessons Learned
- Analytical transfer between different sites
Key Topics Points to Consider
Team building The providing and receiving sites may be
culturally different
Method transfer overall plan Define the work flow, options, general
requirements, roles and responsibilities in a
written document
Transfer protocols and reports Define the template prior to the start of
transfer
Samples and reagents Material plan, shipment, expiration date
Review process Defined review cycle from identified
stakeholders (QC and QA)
Data management systems Consider the difference in LIMS, CDS and
electronic document approval system

Side-by-Side Comparative Test
Precision
assessment
Accuracy
assessment
Start
Cause investigation
Transfer is
successful
Determine MAD, sample size and
precision acceptance criteria, and
define the method transfer protocol
Execute the method transfer protocol
and collect and verify data
Test for
each lab’s precision
acceptance
PASS
PASS
FAIL
EqualTest for
variance equality
in two labs?
Test for
equivalence of means
assuming unequal
variances
Test for
equivalence of means
assuming equal
variances
FAIL
Unequal
FAILPASS

•An appropriate sample size and mean allowable difference (MAD) is
determined by considering the product specification, method historical
variation (%CV) and product mean from the historical process data.
Transfer Acceptance Criteria
(Side-by-Side Transfer)
Product Mean
MAD
(Method ±nSD)
Product Specification

Equivalence Test
(Side-by-Side Transfer)
• Equivalence Test is also called ‘two one-sided t-tests’
(TOST).
Mean difference in results between two labs
0 321-1-2-3
Not Equivalent
Equivalent
Mean difference (white diamonds) and 90% confidence intervals (horizontal lines)
±MAD

Case Study 2: Consider Practice Run prior to
Method Transfer with Mock Samples
Practice Run Result
Lab 1
(providing)
Lab 2
(receiving)
Mean (ppm) 3.05 3.41
N 6 6
SD 0.07 0.20
%CV 2.4% 5.8%
Putative Lab to Lab
MAD
0.31 ppm (10% of Lab 1 mean)
Lab to Lab Actual
Difference
0.36 ppm (12%)
Outcome
Practice Run Failed the TOST
Analysis

Troubleshooting the Practice Run
Method
• Analysis of a
process-related
small molecule
impurity
• RP-HPLC
• UV 220 nm
Standard
• Establish standard
curve using 1, 5,
10, 25 and 50 ppm
for calibration
• Diluted from 1000
ppm stock standard
Sample/control
• Direct injection
• No sample or
control dilution
• Control at 20 ppm
Potential problems:
Difference in stock standards and/or standard curves (prepared
by each lab)

Difference in Stock Standards
The stock standard lots from the two labs were diluted
to 50 ppm by one operator and then read on one
UV/Vis spectrophotometer.
<1% difference was found (not an issue).
Absorbance (220 nm)
Reading Lab 1 Lab 2
1 1.1557 1.1476
2 1.1557 1.1487
3 1.1545 1.1419
Average 1.1553 1.1461
%Difference 0.8

Difference in Standard Curves
Standard Curve Pipette slope y-intercept R2
Lab1, SC1 Lab1 0.0228 0.0010 0.9999
Lab1, SC2 Lab1 0.0227 0.0050 0.9999
Lab1, SC3 Lab1 0.0226 0.0013 1.0000
Lab1, SC4 Lab2 0.0226 0.0027 0.9999
Lab1, SC5 Lab2 0.0227 0.0080 0.9998
Lab1, SC6 Lab2 0.0225 0.0091 0.9998
Lab2, SC1 Lab2 0.0226 0.0102 0.9999
Lab2, SC2 Lab2 0.0229 0.0087 1.0000
Lab2, SC3 Lab2 0.0227 0.0097 0.9999
Lab2, SC4 Lab1 0.0232 0.0083 0.9997
Lab2, SC5 Lab1 0.0230 0.0142 0.9998
Lab2, SC6 Lab1 0.0231 0.0076 0.9997
Second investigation assessed the effect of standard curve
on sample results

Variation in Standard Curves Preparation
Resulted in Larger %CV of Mock Samples at
Low Concentration
(N=6 standard curves for each sample in each lab)

The putative MAD was based on 3xRSD of an old control at 20 ppm.
However, the sample concentration is lowered to < 5 ppm in
transfer. Therefore, a larger MAD should be acceptable for the low
concentration samples in the final transfer protocol.
Consider Precision Change at Different
Concentration in Setting Acceptance Criteria
(Bill Hall, AOAC, 2008)

Case Study 3: Consider Operator Interview in
Transfer Troubleshooting
In one investigation of transfer failure, we interviewed the
operators in two labs and found an unexpected difference in
the SOP interpretation.
Sample 1 Vortex Sample 2 Vortex Sample 3 Vortex
Sample 1 Sample 2 Sample 3 Vortex
SOP was updated to emphasize immediate vortex for each
sample.

Post-Transfer Considerations
Alignment on the method performance monitoring and
trouble-shooting
Qualification and management of critical reagents,
controls and standards to support multiple sites
Change management related to QC methods

Analytical Method Life Cycle
Analytical Target Profile
Identity
Impurity
-Quantitative
Impurity
-Limit
Content
/Potency
Development and Qualification
Analytical Validation
Monitoring, Improvement and Change
Commercial
Transfer
Standard Control,
Critical Reagent
Stability Specification
Process Validation and Licensure
Early-Stage
CMC
Development
Late-Stage
CMC
Development
Commercial
Production
Commercial Method Life Cycle
Maintenance Transfer
Periodic
Review
OOS
Investigation
Post-Approval
Change
Performance
Trending
Re-
Validation

Summary (Points to Consider)
Method validation and transfer are integrated activities of
analytical lifecycle management. Validation and transfer
should be revisited if significant change is made to the
method in the lifecycle.
The parameters to be validated and study design should
fit for purpose in method validation.
Method transfer is to confirm the validation status of the
method in a different lab. The transfer approach and
design should consider the risk of method consistency.
Validation and transfer are effective activities to identify
potential issues and enhance our understanding of the
method performance.

References
FDA Guidance (2015): Analytical Procedures and
Methods Validation for Drugs and Biologics
ICH Q2 (R1): Validation of Analytical Procedures
PDA Technical Report 57: Analytical Method Validation
and Transfer for Biotechnology Products
USP <1224>: Transfer of Analytical Procedures
The USP General Chapters – Chemical Analysis
Expert Committee (2016): Stimuli to the Revision
Process: Proposed New USP General Chapter: The
Analytical Procedure Lifecycle <1220>

Acknowledgement
Lisa Regan
Anita Bawa

Points to Consider in QC Method Validation and Transfer for Biological Products

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