FDA Explains What Is a Minor Change in Biologics Manufacturing: Core Principle for All GMP Process Changes

The manufacturing process for any given FDA-regulated product could go through several changes, each of which needs to be reported to the FDA on a schedule based on the scope of the change. Manufacturers play it safe by sending most changes immediately which clogs the FDA reviewers’ time. This week FDA released a guidance to instill common sense in the process of reporting manufacturing changes. Per the regulations, all changes to FDA-approved manufacturing processes must be grouped into three categories based on the potential impact of the change on the safety of the product: minor, moderate and major. The major changes require FDA pre-approval, moderate changes can be implemented 30 days after informing FDA, while minor changes can be implemented immediately and reported in the annual report. A lot of the changes in manufacturing processes are minor but end up getting reported as moderate. Many changes in the product, production process, quality controls, equipment, facilities, or responsible personnel do not affect the quality or safety of the product and could be classified as minor changes reportable in the annual report. The best part of the guidance is a list of changes that would likely be minor per the FDA. Some of these seem obvious while others would be surprising to more conservative facilities. Examples of minor changes include revising the batch formula to reduce or eliminate overages, change in testing or packaging sites, moving manufacturing steps around a registered facility, making improvements to the facility, increasing or duplicating process chain to increase the batch size without changing equipments, replacing equipment with similar equipment, and common low impact changes to the container closure systems. Some seemingly surprising minor changes included on the list are changes to analytical procedures, tightening of acceptance criteria, addition of in-process tests, changes in mixing times, and manufacture of additional products in the same facility that produces another approved product. The key principle being propagated here is that the manufacturers must conduct a risk-based review of the changes being planned and make decisions about when to submit to FDA based on the impact of the change. The burden of responsibility resides with the manufacturer regarding when FDA is informed of a given manufacturing process change. FDA also states that if a manufacturer submits change information as a moderate or major change that is later deemed by FDA to be a minor change, FDA will notify the applicant and ask to submit later again in the annual report. This is similar to the process announced earlier for drugs. Overall, this provides manufacturer a reasonable flexibility and additional responsibility to appropriately inform the FDA of manufacturing changes.