Establishing Analytical Comparability For Manufacturing Process Transfer

Christina Vessely, Ph.D., Senior Consultant, CMC/Analytical, Biologics

Consulting Group, Inc.

Importance of Analytical Comparability

• From ICH Q5E:“The goal of the comparability exercise is to ensure the quality, safety and efficacy of drug product produced by a changed manufacturing process, through collection and evaluation of the relevant data to determine whether there might be any adverse impact on the drug product due to the manufacturing process changes”

• Analytical Comparability is used for the determination of whether confirmatory non-clinical/clinical studies are required

Steps to establish Analytical Comparability

• Analytical Method transfer– In-process and release methods

• Process transfer

• Formal Comparability Exercise– Pre-defined acceptance criteria

– Evaluation of critical quality attributes across the manufacturing process

– Evaluation of product quality/potency at release and in stability/forced degradation studies

Analytical Method Transfer

• What is the status of the analytical method prior to transfer?

– Validated? Qualified? Fit for purpose?

– Have forced degradation studies been performed?

• How will you know if method transfer was successful?

– Predefined acceptance criteria, often based on validation/qualification data

Analytical Method Transfer, cont.

• How can you increase the probability of success?

– Risk assessment prior to transfer

• Similarity of instrumentation

• Availability of key reagents

– Robustness studies

• Know the sensitive steps of your assays

– Setting up a transfer team

• Regular communication

• Face to face transfer for more complicated methods

– Laboratory technique

– Integration or other data analysis

Process Transfer

• Risk assessment/Facility Fit– Similarity of equipment– Appropriate infrastructure (water systems, etc)– Availability of key raw materials

• What is the status of the process?– Validated? Operating ranges established?

• Well defined CQA’s– What impurities are critical to product safety?– What levels have been established clinically?

• Communication with Analytical to understand method variability– What level of difference in the data would be considered

significant?

Formal Comparability Exercise

• Comparability Plan– How many lots– Retrospective comparison for in-process data

• Assumes consistency in methods across processes• Focus on Critical Quality Attributes (CQA’s)

– Retrospective vs. side by side testing for analytical evaluation at release• Retrospective is preferred for general methods

– pH, concentration, appearance, osmolality, microbial quality,

• Side by side is helpful for purity/impurity methods– Evaluation of chromatographic profiles for samples from the same

analytical run» Reduces questions regarding shifts in retention time or column to

column differences that may be observed otherwise

Formal Comparability Exercise, cont.

• Extended characterization studies– What additional methods are needed to support claims of

comparability?

• Pre-defined Acceptance Criteria– Evaluation of historical data

• What ranges were typically observed with the original process

– Evaluation of method capability/variability• Don’t set acceptance criteria of ± 2% if the method shows

precision of ± 5%

• Evaluation of product quality/potency at release and in stability/forced degradation studies– Comparable trends– No new impurities/degradation pathways

Reference Materials

• Bridging to the past

– Establish ties between the original process/facility and transferred process

– Preliminary indicator of changes in analytical methods

• Sudden loss of impurity species typically seen in the standard can be an indication of bad column, reagents, etc.

• Method drift

• Opportunity to investigate/explain aberrant results

We have our process transfer plan!

What could possibly go wrong?

Failure of Method Transfers

• Acceptance criteria for method transfer are typically set based on assay qualification or validation– Depending on project stage, qualification data may be limited

• Intermediate precision is important for successful transfers!

• Inadequate SOP’s– Not enough detail for the average analyst to perform successfully– “Lost in translation” (more to come on this topic)

• Training– Methods may not perform the same in the hands of an analyst who is

less familiar with the method

• Environmental factors– An assay that performs well in a laboratory in Colorado may perform

differently than at a laboratory in Texas• Differences in ambient temperature• Differences in humidity

Differences in impurity profiles

• Variability in O2 levels in different fermenters

• Differences in reagents

• Inadequate understanding of process variability vs. analytical method variability

• Inadequate batch records– “lost in translation”

– Insufficient training of operators

– Process is not sufficiently robust to accommodate small variations

“Lost in Translation”

• Especially problematic in transferring from one region to another

• All analytical methods, batch records, SOP’s, etc. should be translated into the native language at the location of the new facility– Requires formal GMP translation, not just a “Google”

translation– Operators from both sides to communicate with

translator to confirm that the wording is clear– Operators from originating site to observe

performance at transfer site

“Lost in Translation”, cont.

• Precise Communication is required

– Avoid Euphemisms

• Phrases like “lets get our ducks in a row” or “knock on wood” may mean nothing (or something completely different) in another culture

• Continuous communication is required

– Lines should remain open even after initial process transfer appears complete

Internal vs. External

• Different processes may be in place at a CMO compared to internal company systems

– How are deviations handled at a CMO?

– How much control do you have over activities and decisions?

– Does the CMO include the company in conducting laboratory investigations? To what level?

• Inform after investigation complete vs. include in the investigation process

Case study: Process Transfer to Increase Manufacturing Capacity

• Internal company site in Switzerland, external CMO in the US

– Both sites were to continue to manufacture supplies to produce adequate supplies to support market and ongoing clinical studies

– Due to distance/issues with shipping, it was not feasible to have a central location for all analytical testing

Harmonization between sites

• Compendial methods

– Are the same methods run across sites? What controls are in place to show consistency?

• In-process method differences

– Downstream concentration measurements by UV vs. RP-HPLC

• Show equivalence of methods/explain why different methods were chosen

• Adequate description of process and methods in BLA

Differences in Integrations

• Upstream samples

– Integration across whole peak including shoulders

– Integration to exclude shoulders from calculations

– Results in slight differences in calculated yields

Inadequate Change control systems

• Modifications to analytical methods in one laboratory were not communicated to all relevant laboratories

– Changes to methods occurred at site level

– Project lacked technical / regulatory assessment across sites

– Resulted in differences in methods between sites

– non-GMP sites working on process improvements, using outdated methods

Cultural Differences

• Differences in holidays – Specific example: 5 contractors from US were planned to

be on site to do work on a Monday in September. The day happened to be Assumption day. This holiday is not celebrated in the US, but access to the site was not permitted due to mandate by the canton.

• Differences in work habits/schedules– Is it socially acceptable to work through lunch?– Are there maximum numbers of hours that an operator

can work within a week?

• Resistance to change– Different requirements in one region compared to another

can complicate harmonization efforts

Lessons Learned

• Risk Assessment– Thorough review of potential problems areas prior to initiation of

transfer improves probability of success

• Communicate– Need to communicate on all aspects of transfer

• Representatives from analytical and process in the same room/same conversations

– Rapid reporting of problems and strategies for remediation

• Systems need to be set up for success– Discuss up front how to deal with change control and other potential

stumbling blocks

• Build a team– People at each site should know their counterparts well– Inclusive discussions

Conclusions

• Process transfers may be necessary over the course of a development program

• Establishing analytical comparability is key to success

– Minimize risk of differences in quality / safety of material produced at the new site

• Communication is key to a successful transfer