The No. 1 Most Common Problem in FDA GMP Inspections

COVID-19 had a dramatic impact on the inspectional activities of the U.S. Food and Drug Administration (FDA). The number of good manufacturing practices (GMP) inspections that could be completed understandably decreased and the agency found itself relying more on remote methods. While FDA oversight now looks quite different than before the pandemic, the biggest problem in FDA GMP inspections hasn't changed.

When it comes to pharmaceutical manufacturing, year after year, the same problem is at the top of the list for both FDA warning letters and Form 483s — issues involving quality responsibilities and procedures.

FDA Warning Letter and Form 483 Data

Data from FDA warning letters and Form 483s is readily available on the FDA's website.¹ According to data from the FDA, the most common observations in FY2021 were:

1. 21 CFR 211.22(d) — Responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed].
2. 21 CFR 211.192 — Failure to review a discrepancy of the failure of a batch or its components to meet specifications.
3. 21 CFR 211.100(a) — No written procedures for production and process controls.

Warning letter data from The FDA Group from FY2017-FY2021² lists the most common citations as:

1. 21 CFR 211.22(d) — Responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed].
2. 21 CFR 211.192 — Failure to review a discrepancy of the failure of a batch or its components to meet specifications.
3. 21 CFR 211.160(b) — Scientifically sound laboratory controls.

The top two reasons for FDA warning letters and Form 483s are the same. As stated above, this is a trend. So, why the consistent problem with standard operating procedures (SOPs) related to quality control? The answer likely lies in a company's document control.

Importance of a Document Control Software

In a regulated environment, everything has to be documented and SOPs are no exception. SOPs record how you do things in your organization. Writing them out in the first place and getting them approved is hard enough. Updating them is much harder. Especially if you aren't storing and updating them using document control software.

Document control is much easier when it's done electronically. An electronic document management system (EDMS) makes managing and updating SOPs considerably easier. Of course, document control is even more cohesive when it's part of an electronic quality management system (eQMS). The connection between SOPs, training, and audits makes it much easier to stay compliant and avoid a potential warning letter from the FDA.

Other FDA GMP Issues

The SOPs are the evidence that a pharmaceutical company is following GMPs. This ensures the safety, efficacy, and purity of drugs being produced. When an inspector determines that a manufacturer isn't following GMPs, a Form 483 can be the result. Significant violations can result in a warning letter. While the problem with procedures is the most common citation, it's important to be prepared for other common issues.

The second reason for regulatory problems relates to manufacturing and reviewing the batch record. Reviewing the batch record can greatly slow down product release, especially if there's a problem. And this is the scenario that the FDA cites as a common problem. Similar to document control software, enterprise software can be used to solve this issue. Electronic batch records let quality teams use review by exception to find and solve issues sooner in the process.

Conclusion

Problems with SOPs keep popping up in FDA warning letters and Form 483s. This trend is likely to continue until the majority of the industry embraces digitization and adopts an eQMS to manage their quality processes, including documents. While there has been some progress in this area, and COVID-19 sped up digitization, there's still a long way to go before these problems become a thing of the past.

Sources:

1. “Inspection Observations,” U.S. Food and Drug Administration.
2. “FDA Warning Letter & Inspection Observation Trends [Updated 2022],” The FDA Group, Feb. 15, 2022.