Guest Column | September 4, 2019

FDA Analysis Of The Top Drug GMP Inspection Citations In FY2018

By Jerry Chapman

Top 10

At the FDA/Xavier PharmaLink conference at Xavier University earlier this year, FDA Supervisory Consumer Safety Officer Dell Moller presented the agency’s top 10 drug GMP inspection citations for its 2018 fiscal year (FY2018) and participated in a panel discussion that provided insight into the observations.

Joining Moller on the panel were FDA Office of Pharmaceutical Quality Operations (OPQO) Division 3 Program Director Art Czabaniuk and OPQO Division 3 Investigator Lindsey Schwierjohann.

This two-part article series will count down the top 10 list from Moller’s presentation, in descending order. Part 1 will unveil citations #10 through #6, and Part 2 will cover citations #5 through #1. For each citation in the list, its rank from FY2017, the related Code of Federal Regulations (CFR) Title 21 reference, and a brief analysis provided by the FDA featured on the presentation slides are included. Additional comments from the panelists follow in italics.


#10 (FY2017 rank: #6) – Prior to release, testing and release of drug product for distribution does not include appropriate laboratory determination of satisfactory conformance to the either final specifications, or is a missing an identity or strength of an active ingredient. [21 CFR 211.165(a)]

FDA Analysis: This does not assure the drug product “in the bottle” is what it is as it is intended to be.

FDA Panelist Comments:

Dell Moller: This could also mean missing a test and pushing it through.

Art Czabaniuk: The key word is “appropriate.” It could be a range of things — for example, a significant change to procedure that has not been validated. As a chemist you can see that the change you made will work from a scientific perspective, but you do not see it from a regulatory perspective. That occasionally happens.


#9 (FY2017 rank: #9) – Routine calibration or inspection of automatic or electronic equipment is not performed according to a written program designed to assure it is operating properly. [21 CFR 211.68(a)]

FDA Analysis: Not calibrating a piece of equipment on time or performing a requalification/preventive maintenance task on equipment just because it is operating fine or because “we haven’t had any issues with it” is not a good strategy. Are the calibration/maintenance program and personnel reactive or are they not proactive or not doing the job they need to be doing?

FDA Panelist Comments:

Moller: This applies to the laboratories as well — for example, HPLCs.

If we find a piece of equipment out of calibration, everything you used it for from the last time it was calibrated forward is now suspect. That goes for any piece of equipment in the laboratory or in production, if it is critical.

Lindsey Schwierjohann: The stickers on your equipment showing qualification and calibration are not only for us when we are doing a walk-through, but also for your operators. They should be checking those prior to use and verifying that they are up to date.


#8 (FY2017 rank: not in the top 10) – Control procedures are not established which monitor the output or validate the performance of manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. [21 CFR 211.110(a)]

FDA Analysis: Are those procedures to manufacture the drug product complete and accurate for what is currently going on — not 2 years ago, but now?

FDA Panelist Comments:

Moller: If you have modifications to procedures or processes, were they approved and does everyone know about them? Are your procedures up to date?

With all the advancing equipment and emerging technologies, I have seen a lot of good training of operators on how to use the equipment, but the corresponding procedures are not always updated to reflect how the equipment is actually being run.

Czabaniuk: This citation sometimes points to validation. A number of years ago we inspected a firm making a solid oral dose. Approximately 80 percent of the finished dose was API (active pharmaceutical ingredient). They completed their validation. But they failed to measure breakage once it was in distribution. There was a significant amount of breakage. This was the firm’s biggest complaint for this product. The company made a significant number of changes to keep the product from breaking in shipping. In the end, there were so many changes that the process turned out to be significantly different than what they validated. They needed to go back to the beginning of the process and revalidate.


#7 (FY2017 rank: #5) – Written procedures are not established or followed for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. [21 CFR 211.67(b)]

FDA Analysis: This is similar to what we have seen in the past. Often equipment is not properly cleaned and/or sanitized and there is residue or cleaning solution remaining in the equipment. Is this a case of not following the procedure or a procedure that can be written better?

Equipment tagged “ready to use” with some type of leftover/remaining residue/solution in equipment could be an indication of the pre-operative inspections needing more time or better training/more expertise to conduct properly.

Some equipment is found cleaned and tagged ready to use in a closet. Could it be that the pre-op people didn’t catch it or the sanitation people? Training? Expertise? Time? Cleaning and pre-op may run into issues, but production starts anyway.

FDA Panelist Comments:

Czabaniuk: This citation is about procedures. Make sure your procedures are easy to understand. Some of the best procedures I have seen had pictures in them, making them more visual instead of a lot of words on a page. Is the cleaning not being performed properly because the procedure is too hard to understand? Or are they missing a step? Does it go back to training? Make sure the procedure is adequate and the employees can follow it.

Schwierjohann: There should always be a second check. There should always be someone who comes in and verifies. What does that verification entail? Are they just looking at a document? Or are they going out and truly verifying that the cleaning was performed?


#6 (FY2017 rank: #7) – Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. [21 CFR 211.68(b)]

FDA Analysis: Changes to any “quality” document (master batch or production batch record, deviation record, incoming material record, lab worksheet, etc.) without QA approval run through an approved change control process causes unauthorized changes to the system.  Even an apparent minor change can affect the downstream if not evaluated and no one knows about it until FDA catches it.

Even adjusting mixing times can be an issue, because over time there is production drift and properly documenting the actual mixing time. But the actual mixing time then does not equal the batch record mixing time.

FDA Panelist Comments:

Moller: If someone makes a tweak to a process, then next week, next month, next year they tweak it a little more because it seems to make the process run better, that is not a place you want to be. If you have a proper change control system and properly trained employees, they will recognize that the changes need to be approved. It may very well be that the tweaks to the system will have no impact on the quality of the product and can be signed off. But that formal review process has to be established and followed to ensure changes made have been evaluated for risk to the product.

Production drift is a big thing. My colleagues who inspect devices see this often, where a succession of tweaks to the process makes what used to look like a square now look like a triangle.

How does this look when it gets audited? Not if it gets audited, but when should be the mindset.

Schwierjohann: You need to be sure that the changes are documented and can be audited, and whether they are impacting established parameters.

Czabaniuk: Some examples of this that would result in citations would include technicians being able to change the date and time on a lab system, or if they are using the same shared login on the HPLC systems, or if the HLPC system has an audit trail function that has been turned off.

Schwierjohann: For computer systems you want to make sure that you have established roles such as user, operator, and admin, with the admin function being independent of the working area.

Czabaniuk: I suspect this is an area that we are going to continue to focus on. It is a data integrity issue. As more of our investigators get more experience in this area there will be a greater focus on it.

Stay tuned for Part 2 of this two-part article, which will count down citations #5 through #1 and also discuss inspection trends, other common inspection findings, and how FDA investigators get a sense for the quality culture of an organization during an inspection.

Editor's Note: For a similar review of the top 10 FDA 483 drug GMP observations for FY2017, click here.

The PharmaLink conference is one in a series of drug, medical device, artificial intelligence (AI), combination product, and EU Medical Device Regulation (EU MDR) conferences sponsored annually by Xavier Health. Read a review of how Xavier’s conferences are unique and engaging, written by Rob Wright, chief editor of Life Science Leader magazine, here.

About The Author:

Jerry Chapman is a GMP professional with nearly 40 years of experience in the pharmaceutical industry. His experience includes numerous positions in development, manufacturing, and quality at the plant, site, and corporate levels. He designed and implemented a comprehensive “GMP Intelligence” process at Eli Lilly and again as a consultant at a top-five animal health firm. Chapman served as senior editor at International Pharmaceutical Quality for six years and is now senior GMP quality consultant at FDAzilla.