Which manufacturing changes have the least potential to adversely affect product quality? That’s the question the FDA has attempted to answer in a new draft guidance released this week.
FDA released the draft guidance in response to an increase in the number of postapproval manufacturing supplements it has received in recent years. Specifically, industry has sought FDA recommendations on the types of changes that can be documented in an annual report, rather than in a supplement.
The changes FDA is recommending be included in such an annual report are focused on five areas: Components and composition; manufacturing sites; manufacturing process, batch size and equipment; specifications and container closure systems.
Many of the changes included in the appendix and to be documented in an annual report are either slight modifications or those that would have no impact on the current risks of the manufacturing.
For instance, FDA says a change on a manufacturing location can be considered minimal if the manufacturing area is already listed in an approved BLA, the steps are part of a nonsterile production process, and the new location will have no impact on product quality or will lower the risk of contamination or cross-contamination (e.g., “improved air classification, better process flow, enhanced segregation of pre- and post-viral inactivation steps,” FDA says).
In addition, changes to batch sizes can be considered minimal if they do not involve the use of different equipment, for example, an “increase in roller bottle number, minor increases in fermenter volume or minor increases in load volumes for chromatography columns.”
The agency says that for sterile products, a change from a qualified sterilization chamber (ethylene oxide, autoclave) to another of the same design and operating principle can be considered minimal when the new chamber and load configurations are validated to operate within the previously validated parameters. However, the agency notes, “This does not include situations that change the validation parameters.”
Changes in the container closure system for the storage of a nonsterile drug substance can be considered minimal when the proposed container closure system has no increased risk of leachable substances, FDA says, and the new container “offers equivalent or greater protection properties from air and moisture.”