FDA Inspection Trends Update

Across the world and across the various review divisions at the FDA, COVID-19 has had profound impacts on how inspections have taken place—or not, as the case often has been over the past 2 years. The top warning letter themes include departures from the following regulations:

Sec. 211.22
Responsibilities of quality control unit. Especially subpart (d): “The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.”

Sec. 211.192
Production record review. Especially related to investigation of discrepancies: “Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up.”

Sec. 211.160
[Laboratory Controls] General requirements. Specifically, subpart (b): “Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.”

Sec. 211.100
Written procedures; deviations. Esp. subpart (a): “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.”

Sec. 211.25
Personnel qualifications. Most frequently, subpart (a): “Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.”

Slopes versus trends

I should note that two data points don’t make a trend. A “change” from one data point time period to another may not represent an actual change at all. But from two points we can draw a line in between and calculate a slope. Looking at a slope and interpolating or extrapolating imaginary data architecture is a lazy person’s “trend.” But nevertheless, remember that a slope from two points is not a trend (Figure 1). Statistically defined, a trend would be 6 or more consecutive points ascending or descending* to describe a characteristic adjustment in a process. News stories love wielding this nonsense: A one month-to-the-next increase of 8.4%, for example, in commodity pricing as evidence for a trend; it’s not.


Takeaway: Small decreases or increases in FDA’s Warning Letters against different regulations from one timepoint to the next isn’t necessarily evidence for a trend in the agency’s inspection or enforcement activities.

Insulate against what matters most, but this Pareto has a long tail

Even though it’s smart money to look after the most-frequently cited issues as where to protect your company next (or to shore-up where you may be deficient), I’d be remiss if I didn’t mention that when we plot the most frequent Warning Letter findings on a Pareto chart, there is a very long right-skewed tail to the distribution (Figure 2).

This means that while the elements above provide a “Most Wanted” list for the FDA, there are many other sections and subparts in 21 CFR which also garner a lot of airtime and pixel space with regard to organizations receiving Form 483 Observations and Warning Letters. It’s not enough to just go after a “Top Few” items—though ensuring your Top Few elements are robust is certainly a good way to start.

Insulate yourself from risk as best as possible, that’s the most effective and repeatable way to achieve success in your FDA inspections. There are experts who can help you to prepare better; don’t leave your company’s situation to chance. 

*The basis for this exists in the Western Electric run rules and alternatively in the Nelson rules for control charts. It is highly statistically improbable to have 6 or more data points consecutively increasing or decreasing unless a specific characteristic process behavior exists.

References

• U.S. Food & Drug Administration. (2022). CFR – Code of Federal Regulations Title 21.
• Montgomery, D. (2005), Introduction to Statistical Quality Control (5 ed.), Hoboken, New Jersey: John Wiley & Sons.

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Ben Locwin
Contributing Writer, Industry Executive

Dr. Ben Locwin, contributing editor, is a healthcare executive, philanthropist and investor. Aside from work in public health and clinical settings, he has trained FDA inspectors, and provided help to organizations who need to get inspection-ready. Inspectorate activities are ramping-up worldwide, and this is good impetus to ensure that your organization is similarly ready.