At the 2021 PDA/FDA Joint Regulatory Conference, FDA Director for the Division of International Drug Quality Carmelo Rosa provided a regulatory perspective on quality systems, including key inspection trends in this area.

[Related: Prepare for your next FDA inspection by downloading a FREE analysis of FDA Warning Letters from FY2020 and FY2021 by GMP Consultant Barbara W. Unger.]

Warning Letters FY2020 and FY2021

In looking at the most common Warning Letter citations for finished drug product manufacturers from FY2018 to FY2020, the No. 1 citation concerned process validation/process control and investigations of discrepancies. The second most frequently cited issue falls under 211.84, components not tested for identity. Other common citations include inadequate stability testing and failure to test finished product.

Similar findings can be seen when reviewing the most common cGMP deviations listed in Warning Letters issued to API manufacturers within the same timeframe. 

“Failure to investigate out-of-specification (OOS) results continues to be among the top citations,” Rosa said.

The common factor with all of these? The quality system.

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Strong Quality Systems Require Sustainable Compliance

But how do FDA investigators determine that a company’s quality system is robust? Rosa went on to explain that many times when companies respond to a 483 or Warning Letter, the responses address the particular issue but do not “include a comprehensive assessment of the system.”

“That is a challenge for us to see if there is a good indicator that the firm is operating in sustainable compliance with CGMPs,” he said. “What are the tools that are being used by companies? And have these companies implemented or been using appropriate quality risk management (QRM) strategies?” 

Rosa pointed to batch failure investigations, one of the most frequent citations in the last 30 years, as an example.

“Because we continue to see it, it just leads us to the conclusion that there is something missing in that quality system that has been unable to identify the root causes or to systemically improve problems related to the corrective actions implemented,” he said. 

Failure to investigate out-of-specification (OOS) results continues to be among the top citations

Further, “we often see test methods that are criticized in a Warning Letter and when we get the responses, that test method has been validated, but we go back to a facility and we find that other test methods have not been reexamined.”

Other quality system areas of concern by FDA investigators include:

  • Quality management
  • Supplier qualification
  • Adequacy of the change control program

“It all boils down to, how do I demonstrate sustainability?” the regulator said. “The emphasis we are giving in our recent letters has to do with senior management, commitment, and responsibility.

“We, as regulators, connect the dots and we expect companies to do the same. It is interesting that we do an inspection for four or five days at a facility, and we are able to connect the dots. We look at the complaints, we see how these complaints are related to investigations, and we see impurities. Then, we start connecting to cleaning procedures, to complaint issues, or to development issues, or to any incident or situation that gives us information to show that there may be a bigger picture that a company might be missing here. Being reactive versus being preventive—that is a common issue that we see.”

Warning Letters FY2020 and FY2021

Rosa pointed to impurities as an example of “connecting the dots,” pointing to situations he has seen where an “impurity is found and detected, but no further work is done to understand the associated risk.”

Another key signal is transparency. Does a firm wait for FDA investigators to point issues out? Or does a company attempt to limit regulators’ access to information? Rosa described his experience with a company that employed an alternative quality system to address OOS results found during manufacturing operations.

Addressing Consultant Recommendations

Rosa explained FDA regulators also examine how companies respond to recommendations from consultants.

“How are you using the information that consultants are providing?,” he asked. “One important point in this regard is that a consultant can add value to a company’s assessment, but it is ultimately the firm’s responsibility of executing what the consultant recommends.”

It all boils down to, how do I demonstrate sustainability?

While companies can disagree with a consultant’s recommendations, FDA regulators want to see a document that explains why the firm disagrees with a consultant’s recommendations.

The regulator concluded his talk by explaining how a company’s quality system should look to FDA investigators. 

“It is essential for a pharmaceutical quality system to continue operating in compliance with cGMP and then to remain in a sustainable state of control. This desired state requires a quality commitment mindset, necessary resources, and a QRM approach. It is a dynamic state that includes process and product understanding, which are essential to moving from a reactive to a proactive approach and to enable it for continual improvement.”

Additional Resources

FDA on Cross-Contamination, Sustainable Compliance, and Contract Ops

ICH Q9: Quality Risk Management Revision Focuses on Six Topic Areas

GMP Inspection Case Study Focuses on Inadequate Deviation Investigations

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