Analytical Method Transfers: Practice and...
-
Upload
truongcong -
Category
Documents
-
view
240 -
download
3
Transcript of Analytical Method Transfers: Practice and...
Analytical Method Transfers: Practice and Pitfalls
11/23/2015 Product and Process Variants & Impurities
1
Wayland Rushing, Ph.D.
Senior Scientific Advisor, ABC
Definitions
11/23/2015 2
• Analytical method transfer Documented process to qualify a laboratory on a validated method originating from a separate laboratory
• Sending unit (SU) Laboratory which the method originates from
Development lab, routine QC lab, etc.
Originating lab, sending lab, transferring lab
• Receiving unit (RU) Laboratory which is being qualified on the validated method
CRO, CMO, commercial unit, etc.
Receiving lab, transfer site
Method Transfer
11/23/2015 3
R&D Lab QC Testing Lab
Contract Lab CMO/CRO
Manufacturer
Guidance/Best Practices
11/23/2015 4
• USP <1224>
• PDA TR57
• PDA TR65
• WHO guideline, No.961 Annex 7
• FDA Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics
Transfer Team
11/23/2015 5
• Project Management
• Operations
• Quality Assurance/Quality Control
• Upper Management
• Finance
• Legal
• Regulatory Affairs
• EH&S
Transfer Process
11/23/2015 6
•Project Plan
•Documentation Sharing/Risk Assessment
•Methods, instruments, SOPs, data, etc.
•Transfer Protocol
•Reviewed and approved by both units
•Training
•Provided by the sending unit
•Transfer Execution
•Evaluate results
•Transfer Report
•Reviewed and approved by both units
Site Responsibilities
11/23/2015 7
Sending Unit Receiving Unit
Readiness assessment Review transfer package
Compile data/history Evaluate internal gaps
Organize training Define training requirements
Prepare transfer package Provide resources
Draft protocol/set acceptance criteria Perform transfer and evaluate site results
Provide samples Provide data to SU
Provide troubleshooting support Approve transfer report
Compare RU data against SU data
Approve transfer report
Transfer Package
11/23/2015 8
• Analytical method
• Method development/validation reports
• Previous transfer reports
• Relevant SOP’s
• Data Example chromatograms
Trends
QC/stability data
Spreadsheets/calculations
• List of known issues
Tips for Documentation
11/23/2015 9
• Analytical method Is it written for internal use or external use? Are there any assumptions in the method? Does the method reference any other documents or rely on other documents for performance?
• Gather bench chemist observations What do they commonly observe? i.e. solution starts cloudy but becomes clear is normal How often are issues/failures observed? What are they?
• RU: don’t be afraid to ask More data, unclear instructions, etc. No such things as a stupid question
Site Evaluation
11/23/2015 10
• Regulatory compliance Quality agreement
• Scientific background resources
• Differences between sites Equipment (brands, models, etc.) Lab infrastructure/environment Reagents, solvents, water sources Analyst training/requirements Cleaning/maintenance procedures HPLC column usage Dedicated/common use Data systems
Types of Transfers – USP <1224>
11/23/2015 11
Comparative Testing
Co-Validation
Re-Validation
Waiver
Which Transfer should we do?
11/23/2015 12
Timing
Cost
Logistics
Strategic
Method Status
Comparative Transfers
11/23/2015 13
• Analysis of the same set of samples between the two sites • Multiple samples
Multiple lots and/or multiple replicates Aged Samples Spiked samples
• Timing Samples at both sites tested within a reasonable timeframe
• Predetermined acceptance criteria for comparison of results
i.e. Assay results within 1%
• Evaluate other parameters which may be impacted
Co-Validation
11/23/2015 14
• Multi-site validation
• Receiving unit participates in the validation of the method
• Validation protocol
Reproducibility testing
Other tests as deemed necessary
• Can impact timing for finalizing validation
Revalidation
11/23/2015 15
• Receiving unit revalidates or partially revalidates the method
• Validation criteria expected to be impacted Accuracy, Precision, Linearity
Robustness (instruments)?
Solution Stability?
• Method change Instrument variance
• Strategic Sponsor may not want originating lab to know
Waiver
11/23/2015 16
• Compendial methods Still require method verification
USP <1226>
• Methods not impacted by sample Receiving lab has significant experience in performing
ID tests
UV-Vis, FTIR, NMR
Physical tests
LOD, Melting point, etc.
• Risk assessment/justification should be documented
Training Approaches
11/23/2015 17
Remote
Onsite
Dual Onsite
Remote
11/23/2015 18
• RU trains staff based solely on information provided by SU
• Most commonly used approach
• Pros
Logistically easy
Financially is the cheapest
• Cons
Highest failure rate
Training based solely on quality of transfer package
Onsite
11/23/2015 19
• SU staff provides onsite training at the RU
• Pros
Hand’s on training leading to low failure rate
Can help identify critical areas not well documented
• Cons
Logistically can be complicated
Additional cost
Timing can be extended
Dual Onsite
11/23/2015 20
• Usually reserved for complex/problematic methods RU sends staff to SU for training
Then RU and SU staff return to SU for training/completion of transfer
• Pros Lowest failure rate
Can aid significantly in complicated/tricky methods
• Cons Logistically the most complicated
Costly to perform
Significant time investment
Transfer Protocol
11/23/2015 21
• Typically drafted by the SU
• Should contain
Test method
Parameters to be assessed
Sample origins/preparation
Performance parameters
Statistical evaluation
Pre-defined acceptance criteria
Approval by both the SU and RU
Acceptance Criteria
11/23/2015 22
• Need to be meaningful
Based on historical performance
Validation/QC results
Careful to use same criteria in the validation
• Need to watch out for bias
Variance should be random (normal distribution)
If all high/low should evaluate
• Allow for evaluation of the transfer results beyond simple pass/fail.
Transfer Report
11/23/2015 23
• Drafted by SU or RU
Comparative/Co-validation – typically by SU
Re-validation/Waiver – typically by RU
• Reviewed and approved by SU and RU
Communication is KEY
11/23/2015 24
• “Those specific instrument settings are set by SOP, so we didn’t list them in the method, did you need them?”
• “Our internal SOP allows for variance of the method conditions as long as system suitability is met”
• “The chromatograms in the method really are not representative of what we commonly see, attached are more common examples”
Common Issues
11/23/2015 25
• Unclear method instructions
Prepare a 1 ppm solution
Gravimetric or volumetric?
Prepare a 60% methanol solution in water
600mL + 400 mL
600mL in grad cylinder and fill to 1L volume
by volume or weight?
• Your common practice may not be their common practice
Common Issues
11/23/2015 26
• Method is missing key details or relies on other internal documents
• Bias not evaluated
• Solution Stability
Different solvent/water sources
Difference “ambient” conditions o Temperature, humidity, light
• Relative Response Factors
Don’t assume they will remain the same.
Common Issues
11/23/2015 27
• Non-robust methods
• Using routine/clean samples for comparative testing
• Ignoring failed system suitability runs
• Setting arbitrary acceptance criteria
• Accepting release results from SU for comparative testing
• Executing transfer based on paper training only
Case Study 1
11/23/2015 28
• UV/Vis derivitization method • Method was validated
Ran at SU for many years in Europe
• RU could not duplicate standard or sample results Variable recoveries
• SU sent individuals to study performance of the method at the RU and vice versa – no major performance difference
• Test tubes/stoppers were determined root cause Method specified size but not brand/source RU always used one brand not available in the US
Case Study 2
11/23/2015 29
• HPLC Assay and Impurity
Transfer package was detailed
Method was “standard”, nothing out of the ordinary
• RU could not reproduce the chromatography
Failed resolution criteria
• Traded MP/Standards/columns etc.
• RU met criteria when used the SU column
SU common lab practice was to only use columns that met a specific column efficiency rating
Case Study 3
11/23/2015 30
• Impurity HPLC method Transfer package was detailed Method was “standard”, nothing out of the ordinary
• During execution of transfer RU observed new impurity Impurity had not been observed at the SU Failed transfer criteria
• Traded MP/Standards/columns etc. • Investigation included a 3rd lab • Final determination was that impurity was being formed
on column • Method had to be optimized and re-validated
Case Study 4
11/23/2015 31
• HPLC Assay Transfer package was detailed
Method was “standard”, nothing out of the ordinary
• RU passed the transfer
• RU failed first batches of API AC set to +/- 1.0%
RU results were -0.8% for all results
Transfer deemed success and finalized
Assay results historically averaged 98.5%
• Bias in the method was traced to weighing techniques
Case Study 5
11/23/2015 32
• ELISA Assay Transfer package was detailed
Method was “standard”, nothing out of the ordinary
• RU could not reproduce standard curve Curve was flatter with poor inflection points
• SU visited RU No discrepancies noted
SU scientist produce identical results to that of RU
SU determined that RU had been sent a different sub-lot of Ab. When sent the same sub-lot the proper standard curve was obtained
Summary
11/23/2015 33
• Most transfer failures are preventable
• Communication is KEY
• Establish a defined plan with defined roles/responsibilities
• Don’t treat as check box/routine
Thank You
11/23/2015 34
Questions? Ask ABC