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Comparability: Issues and Experiences

Comparability: Issues and Experiences. Examples of Changes Recombinant Therapeutic Enzyme Production. Post Phase 3 Composition of seed train cell culture medium Post Marketing Bioreactor operations (dO 2 and temperature set-points, perfusion strategy)

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Comparability: Issues and Experiences

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  1. Comparability: Issues and Experiences

  2. Examples of ChangesRecombinant Therapeutic Enzyme Production • Post Phase 3 • Composition of seed train cell culture medium • Post Marketing • Bioreactor operations (dO2 and temperature set-points, perfusion strategy) • Bioreactor hardware (number and type of impellers, liquid level control system) • Chromatography column diameters • Cell separation filter train • Intermediate pH adjustment step (temperature control, titrant composition, modified filter train)

  3. Components of a Successful Approach • Upfront discussion with FDA • Agreement with agency on nature of changes and expected level of characterization • Bundle proposed changes when appropriate • Internal assessment of each change and how they may interrelate • Understand the economic benefit associated with a given change. • Assess impact upstream changes may have on downstream steps and intermediates • Impurity clearance (i.e. host cell protein, DNA, virus) • Need for re-validation and/or comparability of a specific intermediate

  4. Commitment to Thorough Characterization • Goes beyond the scope of release testing • It is essential to already understand your protein. • Enzyme kinetics (KM and kcat) • Receptor binding kinetics • Stability profiles under specific/extreme conditions • Degradation profiles in response to various challenges • Allows for the design of relevant characterization assays. • Understand the challenges that may be associated with the use of “research” assays • Used infrequently, may be outsourced, usually not validated • i.e. analytical ultra-centrifugation to evaluate aggregates

  5. Timing • Depends on the motivation for process change • Act sooner if related to supply chain: • Capacity: difficulty meeting market demand • Robustness or reproducibility problems • More flexibility exists if driver is purely economic • Still need to assess impact to supply chain • In some cases multi-product considerations are warranted • Timing is also dependent on how many regions the product is approved in. • US, Europe, Japan, and ROW.

  6. Key Issue Yet to be Addressed • Need for a harmonized process • A proposed change is a variation in Europe, while it may be a pre-approved comparability protocol in US. • Creates a strategic issue when considering process changes for a product distributed to multiple regions.

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