Submitting Critical Manufacturing Changes to FDA in eCTD Format for Pharmaceutical Manufacturer

Problem: Several manufacturing changes for the biologic drug substance and drug product were necessary, including new primary and working reference standards, a new ELISA method for host cell protein determination, widening of the vacuum pressure range for the lyophilization drying process, expansion of the building where drug substance was manufactured, and creation of a new working cell bank.

The original filing was submitted in paper format by the previous license holder. The client wanted to submit the changes to FDA in eCTD format packaged in several prior approval supplements.

Solution: The changes were reviewed to identify which modules and supporting documentation would be required for each supplement and to determine supplement submission order. The reference standards supplement was submitted first, because several analytical methods used for the reference standards were also used for the drug substance and drug product.

Subject matter experts provided supporting documentation, such as Certificates of Analysis, specifications, and revised analytical methods and standard operating procedures. The original submission, annual reports, and supporting documentation were used to create the modules (reviewer’s guides, Module 2, and Module 3).

Five amendments were submitted within 15 months, and the entire submission now conforms to eCTD format. Three of the five amendments were approved with no questions from the health authority.

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