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Analytical Method Transfers: Practice and Pitfalls

11/23/2015 Product and Process Variants & Impurities

1

Wayland Rushing, Ph.D.

Senior Scientific Advisor, ABC

Definitions

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• 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

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R&D Lab QC Testing Lab

Contract Lab CMO/CRO

Manufacturer

Guidance/Best Practices

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• 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

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• Project Management

• Operations

• Quality Assurance/Quality Control

• Upper Management

• Finance

• Legal

• Regulatory Affairs

• EH&S

Transfer Process

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•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

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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

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• 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

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• 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

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• 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>

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Comparative Testing

Co-Validation

Re-Validation

Waiver

Which Transfer should we do?

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Timing

Cost

Logistics

Strategic

Method Status

Comparative Transfers

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• 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

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• 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

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• 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

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• 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

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Remote

Onsite

Dual Onsite

Remote

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• “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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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Questions? Ask ABC