Final Word: Should You Need FDA Approval to Make Manufacturing Changes?

The pharmaceutical industry is well aware that FDA is trying to take a risk-based approach to enforcing the current good manufacturing practices (cGMP) regulations. This approach is driven by an economic reality: FDA simply does not have the resources to inspect every facility every other year. The organization doesn't even have the resources to inspect facilities every three years. Likewise, it is not cost-effective for our companies to carry out a complete, documentation-oriented revalidation for every process change, regardless of its significance or risk.

John T. English

So judgments have to be made and risk is the metric of choice. FDA has convoked a public meeting for February 7 to consider changes to 21 CFR 211.314.70, "Supplements and other changes to approved applications." The text of the regulation requires the applicant to notify the agency before any change and get prior approval:

"370.70 (a) Changes to an approved application. The applicant shall notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully...."

The current regulation does not distinguish between well developed processes from mature companies and novel formulations being produced by start-ups. The agency believes that the section can be changed so that it does recognize such differences, as well as companies' implementation of quality systems and risk-based approaches based on manufacturing process understanding, including prior knowledge of similar products.

For several years, FDA has been encouraging manufacturers to increase their understanding and control of their manufacturing processes by using longstanding methods (e.g., design of experiments) and new technologies (e.g., process analytics). At the same time, the agency has been asking companies that have gained such process knowledge to share it with the regulators, trying to convince them that they will be rewarded, not punished, for their openness.

Now FDA is taking the next big step, by considering a way to take these approaches from policy to regulation. Before doing so, they are asking the industry to comment on the change mechanism. Can companies indeed be entrusted to make changes under their own internal controls without agency preapproval? This sounds like an easy question to answer with a strong "Yes!" This would recognize the reality of the situation—that FDA can't effectively monitor all manufacturing operations and that as a result, companies are taking de facto responsibility for the quality of their product and the safety of the public.

The next questions are, How well do we understand the change process within our own structures? Are these mechanisms strong enough to accept the responsibility for this without agency backup? And if such permission is granted, will the pace of change increase based on economic, rather than quality drivers?

Everyone in the industry, even if not planning to participate in the meeting, should be interested in following the output from it. The long-term consequences should lead companies to either strengthen their change control systems in anticipation of greater autonomy, or streamline them so that they can be used efficiently and considered a part of normal operations.

FDA recognizes that companies need to view change not just as a way to deal with production failures or as a futile exercise in documentation for "the quality department," but for what it is: an opportunity to improve manufacturing operations.

John T. English is manager of computer systems validation at BE&K BioPharm, 302.452.9048, englishj@bek.com