Trends in FDA Inspection Observations

What are the top 5 citations from FDA inspections for the past 3-years (2018-2020)?

#1

For each of the past 3-years 21 CFR 211.22(D) has been the most frequent observations in FDA inspections.  The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.  According to the FDA citations often the responsibilities are not defined, documents, or fully followed.

#2

In 2 of the last three years the second most frequent citation has been 21 CFR 211.192.  All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. 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. FDA citations identify that often there is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed.

#3

In 2 of the last three years the second most frequent citation has been 21 CFR 211.160(b).  This portion of the CFR addresses Laboratory controls. 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. Laboratory controls shall include:

(1) Determination of conformity to applicable written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.

(2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.

(3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified.

(4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.  As cited by FDA, Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity.

#4

For each of the past 3-years 21 CFR 211.100(a) has been in the 4th most frequent citation.  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. However, during FDA inspection often there are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

#5

In the 5th spot, for 2 of the last three years the most frequently cited item is 21 CFRF 211.67(a).  Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. FDA citations identify that often Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product.

As reported in the inspection observations FY 2020, the above 5 citations accounted for 22% of the total number of citations issued during the FY, while the top 10 citations accounted for one third of all citations noted.

Over the past 3-years the FDA inspections identify consistency with 67% (or more) of the citations occurring at the same position year to year. For a summary of the top 10 FDA Inspection Observations for the past 3 years see table 1.

Noe 1:  The inspection Observations for each FY are available for download from the FDA at the following link.