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1
The Analytical Method Transfer Process
PDA AMD-AMV Workshop Baltimore, MD
7-8 October 2013
Stephan O. Krause, Ph.D.
Principal Scientist, Regulatory Science, Development
MedImmune
2
The Analytical Method Transfer Process
Agenda:
Introduction to Analytical Method Transfer (AMT)
Mapping out the Overall Product Development and Tech Transfer Process
Method Types and Acceptance Criteria
Analytical Platform Methods vs. New Methods
AMT Example
Krause/PDA, 2012
3
The Analytical Method Life Cycle
Krause/PDA, 2012
An
aly
tica
l Me
tho
d D
ev
elo
pm
en
t
A
na
lytic
al M
eth
od
V
alid
atio
n
(Po
st-V
alid
atio
n) L
ife
Cy
cle
Ste
ps
Select and Design – Establish Intended Use of Analytical Procedure
Development and Optimization
Performance Review, Qualification
Validation Acceptance Criteria
Validation
Post-Validation Life Cycle Steps
Transfer of Methods
Validation Prerequisites Assessment
IdentityImpurity
LimitImpurity Quantity
Assay / Potency
Tech Transfer
Resource Assessment
Standards and Controls
StabilityVerify Product Specifications
Maintenance Transfer Comparability Study
OOS/Valiation Failures
CQA Development, CMC Changes, Specifications
4
FTIH POC BLA
Tox StudiesPhase 1
Phase 2Phase 3
Clinical ResupplyMfg/Formulation Change(s)
Specifications Revision(s)
Target Quality CriteriaCommercial
Specifications
Negotiations, Final Commercial Specifications
QTPP
Final CQAs & Control Strategy Approval
Potential CQAsProduct & Process Design
Life-CycleManagement
POST-APPROVALCHANGES
PHASE 3PHASE 1/2Pre-IND
CQ
A D
evel
op
men
t(Q
bD
Pro
cess
)S
pec
s L
ife
Cyc
le
Mg
mt
CM
C a
nd
Tec
h
Tra
nsf
er P
roce
ss Analytical
Manufacturing
Strategic or Tactical Changes
Method qualification
Dose change
Delivery Device
PQ lots
Setting of Initial Specifications
Specifications Review/Confirmation
Mfg Transfer
Method validation
Method transfer
Formulation Change
Process Verification
Method Maintenance
Global Supply
Method transfer
5
The Five General AMV/AMT Classes
AMV Class Description Typical Risk /
Uncertainty Level (1=Low, 5=High)
Suggested Prospective AMV Studies
AMV Class No.
Analytical MethodProduct /
Process Sample
A New New 4-5 Full Validation
B New Old (Validated) 3-4(1) Full Validation Plus AMR(2) Studies
CAnalytical Platform
Technology (not validated “as run”)
New 2-3 Partial Validation
D Old (Validated) New 1-2Partial Validation or
Verification
E Compendial New 1-2Verification per USP
<1226>
(1) If a new analytical method (forced method replacement) is needed due to supply reasons, the risk level can be generally considered higherbecause no other option may exist. Unforced test method replacements can be considered to be a lower risk level as more time may be availableto optimize the method performance.
(2) AMR = Analytical Method Replacement. A study to confirm that a new analytical method can perform equally or better than the existing one.
From Krause, PDA/DHI 2007.
6
Risk-Based AMT Protocol Acceptance Criteria
Specifications
Consider Type of
Specifications
Acceptance Criteria
Existing Knowledge
One-Sided Specifications(NMT, NLT, LT)
Two-Sided Specifications
(Range)
Regulatory Requirements
Historical Method
Performance
Historical Data from this
Product and Process
Knowledge from Similar Product and
Process
Krause/PDA, 2012
7
General AMT Strategy
Krause/PDA, 2012
Co-validation/Co-qualification – this may be used early in the life cycle of a test method when appropriate.
Comparative study – AMT study performed concurrently by sending and receiving laboratories. Acceptance criteria determine the equivalence of the two laboratories. Historical and validation data may be used when appropriate for parts of the method transfer study. The sending laboratory typically has collected a significant amount of historical data for test method performance results in addition to test results for the samples to be tested at the receiving laboratory.
Performance Verification - The receiving laboratory may already perform the method for a similar product or for another type of sample for the same product. In this case, a formal method transfer may not be required. Any reduced prospective study considered should be properly justified.
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Retrospective and Prospective Use of Data for AMV Studies from other Processes Prior to AMV – New Method
Method Qualification
(AMQ)
Method Validation (AMV)
Method Transfer (AMT)
AMQ Studies
ICH Q2(R1) AMV
Studies
PVFTIH BLA
Historical Data - SU
Assay Control
Tech Transfer
Interm. Precision & Reprod.
Historical Data - RU
Assay Control
“Approved” Method
Platform Method
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Retrospective and Prospective Use of Data for AMV Studies from other Processes Prior to AMV – Platform Method
Method Qualification
(AMQ)
Method Validation (AMV)
Method Transfer (AMT)
(Less)AMQ
Studies
“Verification” Focus on: Accuracy, Specificity
PVFTIH BLA
Historical Data - SU
Assay Control
Tech Transfer
(Less) Interm.
Precision & Reprod.
Historical Data - RU
Assay Control
“Approved” Method
10
“Fixed” vs. “Variable” AMT Execution Plan
A fixed execution plan does not integrate test method result variation and the minimum number of test replicates needed to obtain a desirable statistical confidence in the transfer results. A fixed execution matrix can be more advantageous when transferring multiple products to/from multiple locations.
A variable execution plan does consider test method result variation and may require a larger data sets, especially for test methods with relatively high result variation. For example, a variable execution plan may be advantageous when transferring bioassays with an expected high degree of test result variation.
Krause/PDA, 2012
11
Typical “Fixed” AMT Execution Plan for Late-Stage/Commercial Products
Laboratory Day Analyst Instrument Replicates Sending 1 1 1 3 Sending 1 2 2 3 Sending 2 1 1 3 Sending 2 2 2 3 Sending 3 1 1 3 Sending 3 2 2 3 Receiving 1 1 1 3 Receiving 1 2 2 3 Receiving 2 1 1 3 Receiving 2 2 2 3 Receiving 3 1 1 3 Receiving 3 2 2 3
From Krause, PDA/DHI 2007.
12
Analytical Method Transfer (AMT) Example
A validated analytical method for potency is to be transferred from the original QC laboratory to another QC laboratory to release drug product (DP). The analytical method generates potency (dose) results for lyophilized DP.
The vials are available in three nominal doses between 500 – 2000 IU/vial using an identical formulation. Release testing is performed using three replicate preparations from each of three vials.
Before analysis the content of a vial is reconstituted with 5.0 mL of WFI water and the potency is measured in IU/mL (100 – 400 IU/mL).
The samples and a product-specific reference standard are prepared similarly. The analytical method procedure and statistical evaluation are performed with the parallel-line concept.
The “variable” AMT execution plan is used.
13
AMT Study Design and Acceptance Criteria
Characteristics Evaluated
Accuracy/Matching:The relative difference between lab means should at 90% confidence not be less than -Θ= 10% and not more than +Θ = 10%. The 10% difference limit was set with consideration of product specification.Intermediate Precision:RSD 6 % for all sample types, with appropriate homoscedasticity throughout the potency range (from validation results). This means that any RSD from a sample of n=8 should not exceed 9.43 %
Number of Replicates
Nreplicates = at least 23 independent replicates
The confidence interval for the lab-to-lab difference for N determinations to less than the [10%, +10%]. As above the 10% difference limit was set with consideration of product specification.
Samples to test Nlevel = 3
The range of potency/dosing results is covered by: Lowest dose 500 IU/vial or 100 IU/mLMedium dose 1000 IU/vial or 200 IU/mLHighest dose 2000 IU/vial or 400 IU/mL
Testing design, each sample
Number of operators, n = 2Number of days, n = 2Number of replicates per day per operator, n = 2N = 8 in each lab for each of n= 3 potency levels. Results are converted to “% recoveries vs. expected” to allow pooling Total NTotal = 24 individual observations will be recorded for each laboratory. N=24 individual
observations are needed as N=23 is the minimum number of replicates calculated.
14
AMT Results from Sending and Receiving Labs Theoretical
Potency Level in IU/mL
Operator Day Replicate
Sending lab Receiving lab
Experimental Potency in IU/mL
%Recovery vs. Theoretical
Potency
Experimental Potency in IU/mL
%Recovery vs. Theoretical
Potency
100 1 1 1 103 103.0 95 95.0
100 1 1 2 104 104.0 99 99.0
100 1 2 1 108 108.0 104 104.0
100 1 2 2 101 101.0 103 103.0
100 2 1 1 94 94.0 93 93.0
100 2 1 2 99 99.0 96 96.0
100 2 2 1 102 102.0 92 92.0
100 2 2 2 104 104.0 100 100.0
200 1 1 1 212 106.0 208 104.0
200 1 1 2 208 104.0 192 96.0
200 1 2 1 191 95.5 199 99.5
200 1 2 2 201 100.5 195 97.5
200 2 1 1 204 102.0 208 104.0
200 2 1 2 206 103.0 211 105.5
200 2 2 1 198 99.0 203 101.5
200 2 2 2 200 100.0 183 91.5
400 1 1 1 375 93.8 383 95.8
400 1 1 2 401 100.3 401 100.3
400 1 2 1 408 102.0 389 97.3
400 1 2 2 388 97.0 391 97.8
400 2 1 1 402 100.5 408 102.0
400 2 1 2 415 103.8 421 105.3
400 2 2 1 406 101.5 415 103.8
400 2 2 2 410 102.5 403 100.8
15
AMT Result Summary from Sending and Receiving Labs
(1) Raw data was used unrounded. Upper and lower 90% CIs were calculated using equation below .
(2) N=24 data points are not independent.
Separate and Pooled Potency Levels Evaluated
Sending lab Receiving lab
Statistical Parameters
%Recovery vs. Theoretical
Potency
Statistical Parameters
%Recovery vs. Theoretical
Potency
TOST with acceptance criteria [-10%, +10%] (1)
N1 24(2) N2 24
Mean1 101.1 Mean2 99.3
SD 3.5(2) SD 4.2
RSD 3.4 RSD 4.2
Pooled SD(2) 3.9
Mean1-Mean2 1.8
t-value 1.679
Upper 90% CI limit(1) 4 (3.6)
Lower 90% CI limit(1) 0 (-0.1)
Transfer Acceptance Conclusion Pass
212,2121
11)(
21 nnstxx pnn
16
Graphical Representation of Potency Results Per Potency Level Between Laboratories
The boxes represent the 25th – 75th percentile distribution of the results for the two laboratories. Medians (line in the box) and means (cross in the box) are approximately centered while the medians are equidistant from the box hinges, providing a visual indication for a normal data distribution(s) among data points within each laboratory set.
One potential outlier (lower open circle outside of the whiskers) is observed in the sending lab, however, this does not change the overall interpretation for the demonstration of lab-to-lab equivalence.
The variation in the test results (wider 25th – 75th percentile boxes) appears to be higher in the receiving laboratory which may be attributed to less test method execution experience.
80
90
100
110
120
Sending lab Receiving lab
%R
eco
very
ver
sus
theo
reti
cal
po
ten
cy (
in%
)
17
Graphical Representation of the Combined Percent Recoveries Between Laboratories for all Concentration Levels
18
Summary
AMTs may occur at different product development stages.
AMT study execution matrix and the acceptance criteria should be developed based on risk(s).
Many thanks to:• Rashmi Rawat (Product Quality Reviewer, CDER)
• Pat Cash (Sr. Director, Analytical Biochemistry, MedImmune)
• Mark Schenerman (VP, Analytical Biochemistry, MedImmune)
• Martin Van Trieste (SVP, Quality, Amgen)
• Rich Levy (SVP, PDA)
• Pierre Douette, Ph.D., Eurogentec S.A., Belgium
• Michael Warncke, Ph.D., Bayer HealthCare, USA
• Earl K. Zablackis, Ph.D., Sanofi Pasteur, USA
Krause/PDA, 2012
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