When the process changes, keep it equivalent: Comparability in manufacturing discussed by regulators and industry

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Process changes during manufacturing of regenerative medicine products occur often. They can be caused by a process-based change, such as changes in the manufacturing process (eg. new formulation, new purification column, new equipment) or they can be material-related, caused by such reasons as donor or raw material changes (eg. new resin, new Master Cell Bank, etc.).

In such cases, the FDA – as well as international regulatory agencies – dictate that cell therapy and regenerative medicine manufacturers must demonstrate that any manufacturing changes do not affect safety, identity, purity, or potency.

In their own words, the FDA specifies:

The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and postchange product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact on safety or efficacy of the drug product.

When it comes to biologics, the FDA has been active this year. Earlier in 2016, the FDA updated its guidance for Comparability Protocols for the first time in 13 years. The new guidance, officially titled Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information, places, for the first time, a particular emphasis on QbD (Quality by Design), PAT, and Process Validation principles, which are now more significantly emphasized.

Such guidances were also reflected internationally, particularly in Europe.

In response to a recent publication by members of the Committee for Advanced Therapies at the EMA, which emphasized that demonstrating comparability in cell therapy manufacturing following process changes may be “difficult for cell-based medicinal products,” a UK-based panel published a response following a workshop held last year. The panel, it should be emphasized, focused on pluripotent stem cell-based products.

The workshop was held September 15-16, 2015 at Cambridge Unversity in Cambridge, United Kingdom, while the resulting opinion paper came out earlier this month.

Titled “Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop” and authored by a contingent of scientists, researchers and industry professionals, the paper highlights considerations that arise when “comparability” is to be maintained in the cell therapy manufacturing process.

Issues of “automation vs. mechanization” and “interchangeable manufacturing” are addressed, with the manuscript mentioning that “there is still a need for the manufacturing community to convince other stakeholders of the value of the application of automation and mechanization approaches to control variation.”

These ongoing conversations are important as the regenerative medicine industry advances to wider commercialization of products and technologies while addressing challenges that are unique to bringing these products to market.

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