FDA’s Top Ten Drug GMP Inspection Citations for FY 2016

By Brent Conatser, Senior Consultant - Regulatory Surveillance and External Engagement, Elanco

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At the FDA/Xavier University PharmaLink conference at Xavier University in Cincinnati, Ohio, in March 2017, Robert Tollefsen and Dell Moller presented FDA’s top ten drug GMP inspection citations for FY 2016.

Tollefsen is an FDA National Expert Investigator – Drugs/Computers, Pharmaceutical Inspectorate/Level III Certified in Drugs, Medical Products and Tobacco Program Operations Branch.

Moller is FDA Cincinnati District Supervisory Investigator.

Also on the panel was Elanco QA Compliance and Auditing Regulatory Surveillance and External Engagement expert N. Brent Conatser.

Below is the top ten list from the presentation. Each finding includes a brief comment/analysis on the finding. Additional comments or clarifications, if any, follow in italics. The comments are from Moller unless otherwise noted.

Following the top ten analysis is additional information regarding inspection trends and other inspection findings.


1. Responsibilities and procedures for the QA Unit are not in writing or fully followed.

Analysis: Does QA have the responsibility and authority to carry out their job effectively?

Frequently it is a lack of authority that is responsible for QA unit ineffectiveness.


2. Laboratory controls do not include the establishment of scientifically sound and appropriate specs/standards/sampling plans/methods to assure drug products conform to specs/standards.

Analysis: The expectation is you rely on good science so why is this still being observed?

We are just looking for good science.


3. Failure to thoroughly review any/all unexplained discrepancy or failure of batch/components to meet their specsWHETHER OR NOT the batch HAS BEEN DISTRIBUTED.

Analysis: The firm is responsible to assure that all deviations are properly investigated and that all affected batches are included and evaluated.

We are looking for looking for a pattern or practice.  We are not looking for isolated incidents unless they are really bad. The firm needs to ID the scope of the problem and how each batch may be impacted.


4. No written SOPs for production/process controls designed to assure the drug products meet their necessary attributes.

Analysis: A properly written procedure provides sufficient information to assure the activity can be performed consistently and correctly each time.

We see this especially in batch record issues, inadequate procedures for in-process, incoming, and final materials. You must maintain a validated process. Following SOPs, even if they are not the best, is important. Conatser: Some SOPs can be too complex to execute, in which case you are setting yourself up for failure. People find workarounds if they cannot execute a procedure as written.


5. Aseptic processing areas are deficient regarding environmental monitoring.

Analysis: The firm must be familiar with the requirements for the drug they are manufacturing. Environmental monitoring reflects the actual environment drugs are being manufactured in.

Sometimes we see folks documenting actions as done when they have not been done. We also see screens to keep out bugs, and operators sanitizing hands before doing glove testing.


6. Routine calibration/inspection/checking of automated/mechanical/electronic equipment is not performed according to a written plan.

Analysis: Manufacturer of drugs needs to assure that cGMP equipment used is suitable for its intended use.

If most firms are doing it, it is considered current, CGMP. We have seen issues with good validation plans. Tollefsen: The process control system does not know when the calibration is incorrect.


7. Lab testing does not include appropriate determination of satisfactory conformance to meeting spec BEFORE release.

Analysis: Products released and shipped prior to all required analysis being completed. What factors have allowed this to occur?

All tests must be completed before the product ships. It does not matter if it “always” passes. Tollefsen: The product must not go outside firm's control until everything passes and all investigations are complete.


8. SOPs for sterile products are not followed.

Analysis: Manufacture of Sterile Drug Products require sophisticated controls. Failure to follow all procedures could lead to someone getting injured from using Sterile Drug Product.

We see firms with good SOPs, but they are not being followed.


9. Equipment/utensils are not cleaned/maintained or sanitized at appropriate intervals.

Analysis: Includes establishing dirty and clean hold times in addition to identification of status of equipment and utensils. Why is this issue still being observed?

Operators have finished the process and are moving on, sometimes forgetting about the utensils. Do you have a dirty/clean hold times? I have seen both dirty and clean items stored on the same shelf. Their status needs to be clear. Tollefsen: This is an area that is often overlooked, as firms are more focused on risk evaluations for control. Even if it is less of a risk, you need to assure that they are clean. Conatser: Running equipment to failure is not good. Equipment is part of validated system that is running in a validated state.


10. No stability program, methods are not stability indicating, or they are not tested when pulled or tested within a reasonable time.

Analysis: Failure to demonstrate methods are stability indicating. Inadequate or no degradation challenges performed. Stability testing schedules not adhered to. Why did internal audits not capture and correct these issues before the FDA inspection?

Requalification or periodic review does not negate the validated state of the associated facility, process, or equipment, but may call into question the relevance of the validation.  Tollefsen: Test whenever you get a chance, regardless of what the time point was supposed to be.

Tollefsen suggested studying the top ten observations and looking at them in the context of practices at your company.

“My goal is not to write 483 observations,” he asserted. “My goal is to go into a firm and not write anything. You are going to make my life easier if you correct these things before I walk through the door. One of the reasons we are here is to try to give you that opportunity.”


After completing the top ten portion of the presentation, Moller presented additional analysis of FY 2016 data and compared it to previous years.

The Cincinnati District Supervisory Investigator commented that the same citations are frequently observed from year to year on inspections. While the “specifically” or “for example” may be different, the root citation for these observations often remains the same.

He presented a color-coded table showing CFR citations from the last three years, along with a comparison to FY 2006 data:


Moller noted “a point of interest” that for FY 2016 the total number of 483 citations issued was 918, and that the top three were issued 406 times.

He proceeded to go into other common findings:

  • Regular use of trial injections of samples for HPLC analysis. Trial injections are HPLC injections of samples performed prior to official analysis. This allows for test failures to go unreported and not investigated
  • Data acquisition systems allowing files to be manually saved rather than automatically saving to designated locations with repeatable naming schemes
  • Not having the audit trail turned on/reviewed during the laboratory analysis review
  • Analysts having Administrator rights
  • Computer systems (either OS or data acquisition software) not locked down and the ability to delete/copy/rename data files
  • The data acquisition system allowing files to be manually saved rather than automatically saved to a specific location with a repeatable naming scheme

“You should not run trial injections,” Moller stressed. “You cannot trace them. It leads to data integrity issues.”

He further commented, “There is nothing wrong with doing a test shot on your system to know that it is working correctly. But what are you putting on the column? Is it your standard, which you know is good, and know what you should be getting? Or is it your product? If it is product, you have to keep that record and you have to show that record.”


Moller pointed to the importance of the laboratory system and how it can impact other systems.

He said that he had received a question asking why he was in the lab on an inspection when he was not doing a lab system inspection.

“Systems are interrelated,” he pointed out. “They are interdependent on each other. So how the laboratory operates directly affects how production operates, which directly affects how the materials systems operates, which directly affects how quality operates.”

[Editor's Note: For a similar review of the top ten FDA 483 drug GMP observations for FY 2017, click here.]