EDITOR'S NOTE: This is the second part of a two-part series about a presentation by U.S. Food and Drug Administration (FDA) experts Dell Moller and Nicholas Paulin at the FDA/Xavier PharmaLink conference at Xavier University in Cincinnati, Ohio, in March 2018, about the agency's top 10 drug GMP inspection citations for FY 2017. 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.
#3 — “Failure to thoroughly review any/all unexplained discrepancy or failure of batch/components to meet their specs – WHETHER OR NOT the batch HAS BEEN DISTRIBUTED [emphasis added by the presenter]. (FDA 21 CFR 211.192).”
Analysis: The firm is responsible to assure that all deviations are properly investigated and documented, and that all affected batches are included in the evaluation but also appropriately dispositioned.
Paulin: “A firm failed to investigate a stability testing failure concerning a couple of batches of their drug products. The product failures included viscosity and appearance. During stability testing the firm also discovered packaging defects. It did not initiate investigations for these drug quality issues. When the firm did investigate, it failed to review the batch record and failed to identify a root cause or corrective action. [The] FDA wants to see root cause and corrective actions. We would rather see an investigation than find a problem and ask if an investigation was performed and find out that it was not.”
Moller: “For findings three and four, we at the FDA understand that things are not going to go perfectly every single time. What we expect is that you appropriately handle things when they do not go right, every single time. That includes the investigation and the disposition of the product.”
#2 — “Laboratory controls do not include the establishment of scientifically sound and appropriate specs/standards/sampling plans/methods designed to assure drug products conform to specs/standards, etc. (21 CFR 211.160 (b)).”
Analysis: The expectation is you rely on good science, so why is this still being observed? This includes laboratory investigations having a sound investigation strategy and not just retesting or testing into compliance, and proper application and use of the outlier test.
Paulin: “As an example, lab test procedures are not validated. The FDA has a guidance document for investigating out of spec test [OOS] results. Whenever we are looking at OOS investigations, we are looking to see if you found the root cause of the OOS. When you reject a batch, you still need to perform an investigation on those rejected batches.”
#1 — “Responsibilities & Procedures for the QA Unit are not in writing or fully followed. (21 CFR 211.22 (d)).”
Analysis: Does QA have the responsibility and authority to carry out their job effectively and efficiently?
Paulin: “As an example, a firm has not established procedures for numerous functions, including complaints, deviations, change control, supplier qualification or batch release. If so many are overlooked, that points to the quality unit. Are they really performing their job effectively, efficiently and to the best of their ability?
“As another example, when a firm has a quality agreement with their customer, they must notify their customer within a certain amount of days if their product is going to have a FAR [field alert report]. We noticed that a firm did not notify their customer within that time frame. There had been multiple complaints on leaky and defective vials. If there is a quality or patient risk, that is also an issue. That points back to the quality unit and whether it was effective in carrying out its duties and responsibilities. The main thing for all these under number 1 is that quality is an umbrella of everything at a pharma company, no matter what system we are covering.
“Quality should have its hands in everything the firm is doing. They should have oversight of everything going on in their facility. Patient safety is the number one priority. When I perform an inspection, I always ask myself if I would feel safe taking this product, if I would feel safe having my family taking this product. I should always be able to say ‘yes.’”
Czabaniuk: “The people not following procedures are probably doing that because management is not monitoring them, and management is not enforcing the requirements.”
Moller presented a color-coded illustration of the top five 483 citations issued over the last four fiscal years, along with the same data from FY 2006 for comparison, noting the similarities over time (below).
“What we found,” Moller said, “were that the same citations are frequently observed from year to year on inspections. The ‘specifically’ or ‘for example’ may be different, but the root citation for these observations often remains the same. While major improvements have been made in industry over the years, we are seeing recurring themes.”
After the presentation of the top 10 483 findings, Czabaniuk asked, “Of the violations we talked about today, which are the most egregious and could result in some sort of a regulatory action?” He pointed to three findings, which, from his perspective, fit that criterion.
There is nothing more basic to GMP compliance than testing finished products and making sure they meet the specs, Czabaniuk said. “And if you do not have any of the other GMP controls in place, then how comfortable is the agency going to be with the finished product that is in distribution? Not too comfortable. And if it is a narrow therapeutic index drug or a sterile drug, we are going to take action quickly.”
The second serious violation he singled out is not having procedures to prevent microbial contamination. “That is an incredible risk,” Czabaniuk said. “The manufacturing processes for sterile products are incredibly complex. There are a lot of controls that are required to make sure that the finished product is in fact sterile. That is another observation that would push a case to the violative category.”
Lastly, Czabaniuk cited issues with product stability. “If you are doing forced degradation studies and your methods are not stability-indicating, that data is useless. That means that the product that is in distribution is of an unknown quality. We would expect the firm to take prompt action to look at the quality of product in distribution. Our expectation is that they would move quickly to develop stability-indicating methods.”
Moller noted that there is “multi-level review” of each 483 warning letter at the agency after the inspection to determine if compliance actions need to be taken.
Other common findings, Moller pointed out, are in the area of data integrity in the laboratory. These include:
• Computer systems not locked down and users (analysts and reviewers) have the ability to copy, rename or even delete files.
• Data acquisition system settings allowing files to be manually saved to locations by analysts rather than automatically being saved to a specific locked down location with a pre-determined repeatable naming convention.
• Analysts having administrator rights.
• Not having the audit trail turned on.
The audit trail, for example on lab chromatography equipment, “needs to be functional and utilized,” Moller emphasized. “We have seen where the audit trail is not reviewed at any level in the lab or by QA.”
When the audit trail is turned off, it allows the analyst or the reviewer the potential to either change data, delete data, or move data to a folder that is not reviewed or does not go through the QA process.
“We understand in some development processes the analyst needs to have some expanded roles and rights," Moller said. "But as soon as they are done with that, take it away. Lock it down. That gives you and the analyst a good out. ‘I did not do it. I do not have the rights.’”
Czabaniuk provided his perspective on interactions with FDA investigators during inspections.
“Challenge the investigator if you feel that an observation is not correct,” he recommended. “Do not feel like there will be some bad follow-up as a result of challenging the investigator.”
“Our investigators want to be right. We want to be right. We do not want to make mistakes. Engage with the investigator on the observations.”
Czabaniuk noted that the investigator should have close-out meetings with the firm to discuss what has been found, either daily or at some frequency. That provides the opportunity to discuss any concerns.
“I was wrong about some observations early in my career,” Czabaniuk commented. “And I only found that out through those discussions [that] it is critical that you engage the investigator and have those conversations.”