Inter-Laboratory Method Transfer
RACI Conference - Chemical Analyses
Dr. Ludwig Huber
Ludwig_huber@labcompliance.com
Overview
• Regulatory expectations
• Four approaches for analytical method transfer
• Experiments and acceptance criteria for
comparative testing
• •Effective planning, execution and documentation
of method transfer
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Ludwig Huber - LabCompliance
Slide 2
Occurrence of Method Transfer
• Sponsor company to contract lab
• Analytical development to QC labs
• Across different sites
– The same lab conditions
– Different lab conditions
• Existing to new instrumentation
– With different specifications
– With different technology
• Supplier of material to client
• Transfer to new instruments with different
instrument characteristics
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Ludwig Huber - LabCompliance
Slide 3
Transfer of Analytical Procedures
Definition According to USP <1224>
• The transfer of analytical procedures (TAP), also
referred to as method transfer, is a documented
process that qualifies a laboratory (the receiving
unit) to use an analytical test procedure that
originated in an other laboratory (the transferring
unit, also referred as the sending unit),
• Thus ensuring that the receiving unit has the
procedural knowledge and ability to perform
the transferred analytical .procedure as
intended.
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Ludwig Huber - LabCompliance
Slide 4
Why Controlled Method Transfer
• Expected by agencies
– The suitability of all testing methods used shall
be verified under actual condition of use
• Reduces failure rate
• Improves the quality of the testing at
the new place
Problems can come up due to different
equipment, different analysts and lab environment
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Ludwig Huber - LabCompliance
Slide 5
FDA CGMP Regulation 21 CFR Part 211.194 (a) (2)
• Laboratory records shall include a statement of
each method used in the testing of the
sample.
• The statement shall indicate the location of
data that establish that the methods used in
the testing of the sample meet proper
standards of accuracy and reliability as applied
to the product tested
• The suitability of all testing methods used shall
be verified under actual condition of use.
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Ludwig Huber - LabCompliance
Slide 6
FDA Warning Letter
• The firm failed to perform finished product test
method transfers for 34 products (W-187)
• The firm has failed to perform method validations,
method verifications, or method transfers for
any of the laboratory test methods used to
test active pharmaceutical ingredients (W-187)
Ref: www.fdawarningletter.com
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Ludwig Huber - LabCompliance
Slide 7
Warning Letter
• Failure to establish and document the
accuracy and reproducibility of test
methods employed. (W-186)
• For example, methods that were
validated at one facility and transferred
to xxx site are being used without a
methods transfer or revalidation
protocol. (W-186)
Ref: www.fdawarningletter.com
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Ludwig Huber - LabCompliance
Slide 8
USP Chapter <1224>; Risk Based Approach
for Transfer of Analytical Procedures:
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Concept Paper Published in Pharmacopeial Forum, Nov 2009
Draft Chapter published in Pharmacopeial Forum , Jan 2011
Final chapter for USP 35 (May 1, 2012)
Content
– Focus on risk based approach
– Discussion of 4 types of analytical transfer
– Elements recommended for transfer of analytical procedures
– Emphasizes importance of transfer protocol
– The analytical procedure and report
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Ludwig Huber - LabCompliance
Slide 9
USP Chapter <1224>; Risk Based
Approach for Transfer of Analytical
Procedures
• The tests that will be transferred, the extent of the
transfer activities, and the implementation strategy
should be based on risk analysis that considers the
– previous experience and
– knowledge of the receiving unit
– the complexity and
– specifications of the product, and
– the procedure
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Ludwig Huber - LabCompliance
Slide 10
Options for Method Transfer
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Comparative Testing
Co-validation
Complete or partial validation or revalidation
Omission of formal transfer (waiver)
Criteria: type of method (simple, complex), experience
and capabilities of receiving lab
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Ludwig Huber - LabCompliance
Slide 11
Co-validation
• Receiving lab is part of original method validation
• Transferring and receiving lab conduct the same
validation experiments
• Useful for methods not (fully) validated
• Must be based on pre-approved validation protocols
and acceptance criteria
• Should challenge all USP or ICH validation parameters
• Include receiving lab in validation through interlaboratory tests.
• Ensures harmonization of method at both sites
A site that performs validation studies is
qualified to run the method
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Ludwig Huber - LabCompliance
Slide 12
Full or Partial Revalidation
• Received lab repeats some or all of the validation
experiment
• Done after initial method validation
• Validation parameters depend on the method e.g.,
– Limit selectivity and limit quantitation for
impurities
– Precision for content uniformity assays
Similar process as verification of compendial methods
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Ludwig Huber - LabCompliance
Slide 13
Transfer Waivers
• Method is used without dedicated transfer testing
• Reasons should be well justified and documented
– The new product’s composition is comparable to that of
an existing product and/or the concentration of active
ingredient is similar to that of an existing product and is
analyzed by procedures with which the receiving unit
already has experience
– The analytical procedure transferred is the same as or
very similar to a procedure already in use
– The personnel in charge of the development, validation or
routine analysis of the product at the transferring unit are
moved to the receiving unit
– Transfer of compendial methods (refer to USP <1226>)
Waiver should be well justified and documented
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Ludwig Huber - LabCompliance
Slide 14
Comparative Testing
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Most frequently used
The same tests are carried out by both labs
Should only be performed with validated methods
Based on pre-approved transfer protocol (TAP)
Predetermined number of samples of the same lot
Well defined test procedures and acceptance
criteria, including acceptable variability
• Results are compared with a set of predetermined acceptance criteria
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Ludwig Huber - LabCompliance
Slide 15
Prerequisites
for Successful Method Transfer
• Analytical method validated
– Includes ruggedness testing
– Includes robustness testing
• Scope well defined
– Sample, matrix
– Performance characteristics, acceptance
criteria
– Equipment
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Ludwig Huber - LabCompliance
Slide 16
Required Documents
• Transfer Master Plan (TMP) used as frame work
• Transfer project plan or method transfer protocol
(MTP)
– Approach for controlled transfer and
justification
• SOPS for step-by-step implementation
• Templates and forms for efficiency and
consistency
• Analytical procedure
• Original validation report
• Historical data on method reliability and
performance (to identify greatest causes of
variance)
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Ludwig Huber - LabCompliance
Slide 17
Transfer Plan or MT Protocol
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Reason and purpose of the transfer
Scope of the plan and method transfer
The approach
Description of transfer process
Responsibilities
– Transferring, receiving labs, project owners, QA
• Assumptions
– E.g., Analysts in the receiving lab not familiar with
the method
• Training details
• Test Plan
MTP = Method Transfer Protocol
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Ludwig Huber - LabCompliance
Slide 18
Test Plan
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Tests to be performed and test parameters
Rational behind tests
Description of materials and samples
Description of equipment
Number of lots, batches replicates, injections
Pitfalls that may be encountered
Test schedule
Acceptance criteria
Documentation, approvals
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Ludwig Huber - LabCompliance
Slide 19
Responsibilities Project Owners
• Transferring lab
– Develops transfer plan
– Develops for procedures for comparative testing
– Arranges equipment for training and testing
– Arranges for people for training and testing
– Arranges for preparation of test sample(s)
– Documents comparative sample testing
• Receiving Labs
– Arranges for equipment for training and testing
– Arranges for people for training and testing
– Documents comparative sample testing
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Ludwig Huber - LabCompliance
Slide 20
Responsibilities of Analysts
• Transferring lab
– Train analysts in receiving laboratories
– Perform and document comparative sample testing
– Sign test results
– Share experience with test method
• Receiving Labs
– Get trained on method
– Perform comparative sample testing
– Sign test results
– Give feedback on test method
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Ludwig Huber - LabCompliance
Slide 21
Other Responsibilities
At transferring and receiving lab
• Lab supervisor
– Designate project owner
– Provide resources for testing
– Review and approve validation documents
• Quality Assurance
– Review and approve transfer plan
– Review and approve validation documents
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Ludwig Huber - LabCompliance
Slide 22
Steps for Comparative Testing
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Develop and approve a test plan
Order missing equipment and materials
Training
Concurrent execution of the protocol
Evaluation of test results
– Compare with acceptance criteria
• Resolution of deviations, if there are any
• Gather all required documents
• Write method transfer report (MTR)
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Ludwig Huber - LabCompliance
Slide 23
Considerations for Testing
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Number of samples (1-3)
One or more concentrations (1-3)
Number of repetitive analysis / sample (4-6)
One or more analysts? (1-2)
One or more days? (2-5)
Equipment from one or more
manufacturers? (1 - all)
Ludwig Huber - LabCompliance
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Evaluation of Test Results
Direct comparison with acceptance criteria
• Based on product release criteria
• Based on criteria for method validation
– Accuracy, precision, specificity
Use of statistics will build objectivity into the test
result and allow unbiased comparison of data sets
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Slide 25
Example: API in Finished Drugs
Sample Amount
% of test
concentration
Measure
Acceptance as
% of target
50%
Accuracy
3 replicates
All 97 - 103
100%
Accuracy
3 replicates
All 98 - 102
150%
Accuracy
3 replicates
All 98 -102
Results
#1: 98
#2: 99
#3: 99
#1: 101
#2: 100
#3: 101
#1: 101
#2: 99
#3: 100
System Suitability Tests must pass
• Resolution between two most critical compounds >2
• Precision of amounts based on 6 sample runs: RSD < 1% for 100% of test
concentration
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Example: Quantitative Impurities
Sample Amount
Measure
Acceptance as
% of target
At LOQ
= 0.5 x specification
limit
Accuracy
3 replicates
All 85 - 115
At 5 x LOQ
Accuracy
3 replicates
All 94 - 106
At 20 x LOQ
Accuracy
3 replicates
All 96 -104
Results
#1: 96
#2: 98
#3: 108
#1: 98
#2: 103
#3: 99
#1: 101
#2: 99
#3: 100
System Suitability Tests must pass
• Resolution between two most critical compounds >2
• Precision of amounts based on 6 sample runs: RSD < 4% for 5x LOQ
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Ludwig Huber - LabCompliance
Slide 27
Check Variability by Operator,
Instrument and Day
Two instruments, two operators, three days
Sample
Instrument
Operator
Day
100% conc. (3x)
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1
1
100% conc. (3x)
1
2
2
100% conc. (3x)
1
3
3
100% conc. (3x)
2
1
2
100% conc. (3x)
2
2
3
100% conc. (3x)
2
3
1
Example: API in finished drugs, 100% of test concentration
• Acceptance: RSD < 2%
Ludwig Huber
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Page 28
Review and Approvals
• Transfer plan and result has to be accepted by
both laboratories
• Approval of the result by at least
– The test person
– Technical supervisor
– QA
• Review and acceptance by all responsible people
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Ludwig Huber - LabCompliance
Slide 29
Recommendations for
Deviations
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If the tests don’t pass acceptance criteria, identify
the source of the problem
Develop corrective action plan
– Provide additional training
– Use other equipment
Update the procedure
Repeat the tests
If successful, document initial results, corrective
actions and final results
If not successful, develop alternative procedure
Ludwig Huber - LabCompliance
Slide 30
Method Transfer Report
Report items and format to be specified in the study
transfer plan
• Summary of method familiarization results
• Detailed results of transfer study
• Description of any deviations and from expected
results and how they have been resolved
• Signatures of individuals responsible for transfer
studies
• Copies of supporting material, e.g., chromatograms
and spectra
• Conclusion and assessment of the transfer study
results
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Ludwig Huber - LabCompliance
Slide 31
Thank You
I would like to thank
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All attendees for your attention
•
Agilent Technologies for invitation and organizatopn
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