At the FDA/PharmaLink conference earlier this year, representatives from the Russian State Institute of Drugs and Good Practices, UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and U.S. FDA shared their top ten pharma company inspection findings from FY2019, revealing many similarities and a few differences (more about these similarities and differences can be read here).
In addition, each also shared their agency’s processes for how it evaluates and escalates inspection findings to determine if regulatory action is needed, which are reviewed here.
[Related: Download the author’s Oct. 29 presentation on this topic, which includes additional analyses, here.]
FDA: Possible Center Review
Director of Investigations Branch in the division of Pharmaceutical Quality Operations 3 within FDA’s Office of Regulatory Affairs Lieutenant Commander Jeffrey Meng discussed what he called the “stereotypical regulatory process for a CGMP warning letter,” (Figure 1).
The process begins with an FDA investigator performing an inspection and issuing a 483 to the firm’s management that contains the investigator’s observations. The investigator then completes the Establishment Inspection Report (EIR) with the supporting evidence.
“There is a supervisory review process in which someone like me—a Director of Investigations Branch— will have input into whether the case will proceed or not,” Meng explained. “If the management review within the investigation branch determines that a case should be put forward, it will be sent to a compliance officer for a first-line technical review and legal review. Typically, a Director of Compliance Branch or DCB also provides input.”
If the case is deemed significant—and at this point a firm’s response is also taken into consideration— the case might be submitted to a Center, e.g., the Center for Drug Evaluation and Research (CDER) or the Center for Veterinary Medicine (CVM), for example. And there will be a Center Compliance Officer review of the case, as well as decisions made by Center management that consider current policy and legal assessment.
“If all those things play out properly and there are no mitigating factors, the Warning Letter might be issued,” Meng said.
MHRA: A Teamwork Approach
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) GMDP Senior Inspector and GMDP Operations Manager Graham Carroll explained his agency’s processes for classifying inspection findings and its use of Compliance Management and Inspection Action Group Processes.
Carroll began his explanation using a few inspection finding examples. He started with a case in which an investigation of a deviation did not contain sufficient detail to describe the nature of the deviation, the assessment of the impact on products, or the identification of a root cause. During this same inspection, the investigation also found failure to follow existing deviation procedures—a repeat finding from an earlier inspection.
“The nature of these observations would be an instant referral to what we call our Compliance Management Team,” he explained.
In another example, an MHRA investigation found the management of out of specification investigations deficient. Summary reports were not sufficiently comprehensive. The reports had come from a contract lab and were lacking in detail. The manufacturer failed to secure additional information nor provide a suitable justification for conclusions drawn.
“The second finding is going to be considered significant and would be raised to the compliance management team at a minimum.”
Carroll shared MHRA’s Compliance Management Process overview (Figure 2).
Carroll explained that the process is non-statutory and is managed within the inspectorate by senior and expert inspectors, operations, and unit managers. The team meets monthly or ad hoc as required.
“Really, the aim of this group is to escalate cases where we can help direct companies to a state of compliance before they are directly putting public health at risk. The aim is to avoid regulatory action and maintain supply of medicines,” Carroll explained.
A different group, the Inspection Action Group (IAG) (Figure 3) “comes into play whenever there is a potential need for us to take regulatory action,” Carroll said. “It is a cross-functional team that encompasses expertise from across the agency, and external bodies where needed.”
Sites are referred to the IAG typically for one or more critical deficiencies found during an inspection. But referrals can also come from other causes such as refusal to accept an inspection and lack of/poor responses or other quality issues, such as a large or significant recall.
“After an inspection, sites will be told at the closing meeting that a referral to IAG is likely. Company management will be provided with a link to more information to help them understand the potential outcomes and support their accurate and timely communication with the inspector and the inspection action group,” Carroll said.
That group meets every two weeks routinely but does hold emergency meetings for urgent referrals.
Carroll explained that there are different possible outcomes between UK sites and those not in the UK due to different licensing arrangements and other factors. The different possible outcomes are listed in Figure 4.
“It’s worth bearing in mind that in both cases, the IAG does have the power to prevent supply to the UK and EU markets, and also can also prevent or impact supply to Mutual Recognition Agreement (MRA) partner markets, where we make a recommendation that products coming out of that facility are not safe,” Graham noted.
Russian SID&GP Process
Joining the FDA/Xavier PharmaLink conference in 2020 was Nadezhda Arkhipova, Deputy Head of Expertise, Department of State Institute of Drugs and Good Practices of the Ministry of Industry and Trade, Lead GMP Inspector in the Russian Federation Ministry of Health.
When asked about the Russian Federation’s system for making decisions on how to deal with inspection findings and potential escalations, Arkhipova said, “Our system is not all that different from the one MHRA has. If we identify critical or major issues, we will provide those to the company in an inspection report. Of course, the company must provide some proof they have made progress on fixing their problems, and then we inspect them again. We do not issue any letters based on our findings in our final inspection report.”
[Editor’s Note: To learn more about Russian SID&GP FY2019 inspection findings, read the earlier article from the author.]
[Related: Download the author’s Oct. 29 presentation on this topic, which includes additional analyses, here.]
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