EDITOR'S NOTE: This is the first of a two-part series counting down the FDA's top 10 drug GMP inspection citations from fiscal year 2017.
At the U.S. Food and Drug Administration (FDA)/Xavier PharmaLink conference at Xavier University in Cincinnati, Ohio, in March 2018, Dell Moller and Nicholas Paulin presented FDA’s top ten drug GMP inspection citations for FY 2017 and participated in a panel discussion that provided insight into the observations. Moller is an FDA supervisory investigator based in Columbus, Ohio. Paulin is a drug specialist and pre-approval manager at the FDA’s Cincinnati district office.
Also on the panel were Art Czabaniuk, FDA Division of Pharmaceutical Quality Operations Division 3 program director, and Brent Conatser, Elanco Animal Health senior consultant.
Below is the top 10 list from Moller and Paulin’s presentation, in descending order. Each finding includes the Code of Federal Regulations (CFR) Title 21 reference and a brief analysis provided by the FDA featured on the presentation slides. Additional comments from the panelists follow in italics. Following the top 10 analysis is additional discussion regarding inspection trends, other inspection findings and advice on interacting with FDA investigators.
#10 — “No written stability program, methods are not stability indicating, or they are not tested when pulled or within a reasonable time (chronically late testing). (FDA 21 CFR 211.166 (a)).”
Analysis: Failure to demonstrate methods are stability indicating. Inadequate or no degradation challenges performed. Stability testing schedules not adhered to. Too many samples for the lab’s capacity. Why did internal audits not capture and correct these issues before the FDA inspection?
Paulin: “The citation could also be given when the firm has no data to support expiration dating.”
#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. (FDA 21 CFR 211.68 (a)).”
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.
Paulin: “I check calibration stickers during inspections on equipment that is running.”
Moller: “Missing a 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 or the qualification process itself.”
Moller said that at one company he inspected he was told, “The equipment is working. We do not see any negative trends with the system working or over time. So why do we need to take that piece of equipment out of production to make sure that it is working OK?”
#8 — “Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are either not established or written or not followed. ( FDA 21 CFR 211.113 (b)).“
Analysis: Many times, the procedures are solid and well-written, but they are not followed. Other times, there are gaps in procedures that leave it up to the production associate/employee to decide what to do.
Paulin: “One example is in a sterile system with a remote access barrier system, or RABS. I have seen tears or pinholes in gloves and the operators are still using them. Another example would be operators opening a RABS barrier door, adjusting it and removing vials from the line with their bare hands instead of using gloves. It is mostly about poor aseptic practices.”
Moller: “It points to the quality culture in the organization and whether management really has control. How does something simple like this happen? Is nobody monitoring? Is it the culture? Senior management can promote or derail a quality culture.”
Conatser: “Do the people who are executing these procedures, who have been trained on them, know why they are doing what they are doing? Do they know the impact of not following that procedure? It has been my experience that when someone is asked why they are doing something, it is because the SOP [standard operating procedure] says so. No. Why do you do that? Do you understand the reason why you are doing it? Training should be ‘Read, understand, demonstrate, and execute.’”
Czabaniuk: “In one case I recall, the procedure was too complex, too long and hard to understand from the operator's point of view. They were trained on it, but there was just too much there. To address it, the firm simplified the procedure and created a work instruction as an addendum, which covered the critical portions of the SOP. It allowed the operator to better understand what the critical requirements were. It did solve the problem that we cited.”
#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. ( FDA 21 CFR 211.68 (b)).”
Analysis: Changes to master batch or production batch records or incoming material records, for example, without QA approval or a formal change control process review causes unauthorized changes to the system, and no one knows about it. Mixing times adjusted because, over time, there is production drift and the batch record time isn’t long enough.
Paulin: “This specifically talks about batch records, but can be carried over into other areas of documentation control. Eventually, the product will drift out of spec. This can also include: deletions and alterations of electronic raw data; manipulation of the date and time setting; analysts using shared logins on lab systems; and an HPLC (high-performance liquid chromatography) system used for testing with the audit trail turned off.”
#6 — “Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the either final specifications or are missing an identity or strength of an active ingredient, prior to release. (FDA 21 CFR 211.165 (a)).”
Analysis: Assuring that the drug product is what it is, that the identity and strength on the label is in the bottle and it is as it is intended to be.
Paulin: “A firm released product without testing for the identity and strength of the active ingredients. Without that testing, the firm has no scientific evidence if it is in spec prior to release.”
#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. (FDA 21 CFR 211.67 (b)).”
Analysis: Often times, 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 residue/solution in that equipment could be an indication of the pre-operative inspections needing more time or expertise to thoroughly conduct.
Paulin: “I look at equipment tagged as clean. I have found residue of the previous product made on that line still on the equipment that is tagged as clean. The company needs to look at how it was cleaned, and at the analytical method used. The cleaning procedure may be inadequate. Sometimes, the cleaning procedures are not well-written as to who is responsible, what the cleaning schedule is and what the cleaning agents are. Is there a sanitizer used? What is it rinsed with?”
#4 — “No written SOPs for production/process controls designed to assure the drug products meet their necessary attributes. (FDA 21 CFR 211.100 (a)).”
Analysis: A properly written procedure provides sufficient information to assure the activity can be performed consistently and correctly each time and appropriately documented for production, QA and regulatory review. This includes what to do if something does not go quite right.
Paulin: “As an example, I see operators taking note of what they are doing, when they are adding an ingredient. Then, I check the procedure or batch record, and I do not see where this is called for or recorded. There should be specifications for everything that is added into the batch. Everything should be following a procedure or batch record.”
Moller: “Some of the better procedures I have seen, like for gowning, have fewer words and more pictures in them.”
The remainder of the top 10 observations along with commentary and analysis continues in Part 2 of this blog post.