HHS OIG: US FDA Inspection Manual Revision Could Reduce Unannounced Inspections Abroad
Executive Summary
Poor inspection history was dropped as a criteria for unannounced inspections, OIG says in an audit report, even as support grows for surprise inspections of poor quality sites. An exhaustive review of foreign for-cause inspections shows the FDA reorganization has sped up a process that must go faster still. Meanwhile, whatever happened to experienced investigators’ training records?
A change to US Food and Drug Administration inspection procedures could reduce the number of unannounced foreign inspections, the Health and Human Services Department’s Office of Inspector General warned in an audit report.
The change comes even as the agency responds to political pressure for more unannounced inspections abroad by pilot-testing the concept. (Also see "Surprise US FDA Facility Inspections Resume In India" - Pink Sheet, 24 May, 2022.)
Meanwhile, a 2017 enforcement initiative did not accelerate the agency’s response to foreign for-cause drug inspection findings as much as intended, the OIG audit concluded.
The realignment of the FDA’s Office of Regulatory Affairs by center and its subsequent Concept of Operations agreement with the Center for Drug Evaluation and Research sped up a lot of activities, but some did not met the new timelines.
The OIG also criticized the agency for failing to ensure lead investigators were fully trained before they conducted inspections, which the FDA said it is already working to fix.
IOM Revision Seen As Overly Broad
The OIG said in a 24 June report that after it completed the audit, the FDA revised its Investigations Operations Manual so that it no longer required the agency to consider a site’s inspection history when deciding whether it would be appropriate to announce an inspection of the site.
The manual’s 2018 version had required such consideration for all commodity types, including drugs and devices.
The 2017 FDA Reauthorization Act added section 704(h) to the Food, Drug and Cosmetic Act, which required all medical device inspections to be announced, whether foreign or domestic, unless they were for cause.
But the OIG said the FDA implemented that requirement with a much broader revision of the manual, which “eliminated the requirement to consider a facility’s inspection history when determining whether to announce an inspection for all types of facilities.”
The OIG said “this revision could potentially result in fewer unannounced inspections at foreign drug facilities.”
Giving Facilities ‘Plenty Of Time’
The FDA announces most foreign inspections 10 to 12 weeks in advance to allow for travel arrangements such as obtaining visas for US-based investigators.
The OIG report quotes Sen. Chuck Grassley, R-IA, saying during a 2 June 2020 Senate hearing that “12 weeks, common sense tells us, is plenty of time to doctor up a facility to make sure that it passes inspection.”
The agency announces some within just five days of inspection if investigators based in foreign offices conduct them.
There is no prior notification for unannounced inspections, which the FDA might conduct based on tips from informants, for example.
Announcement History Unclear
The OIG was unable to determine how announcement affected the inspections it audited because the FDA did not know whether all of the inspections were announced.
The FDA requires establishment inspection reports to say whether the inspections were announced, but that information was missing from some of the reports the OIG reviewed, including eight of 68 post-ConOps EIRs.
The OIG was going to recommend a fix, but in the meantime the FDA added a required field to its inspection tracking system for reporting whether inspections were announced, resolving the issue.
In any case, the government auditor observed that the FDA announced 54 of the 68 post-ConOps foreign for-cause inspections it reviewed, including 32 inspections of facilities that had been classified as OAI.
The OIG raised the concern that “if FDA announces an inspection, a facility could prepare for that inspection by correcting or concealing deficiencies or destroying records prior to the inspection. If that occurs, investigators may not identify deficiencies and recommend correction action that would aim to achieve continued compliance with CGMP.”
The audit agency went on to note similar concerns raised by members of Congress and its congressional counterpart, the Government Accountability Office.
Post-ConOps Improvements
The OIG compared foreign for-cause drug inspection trends in the 15 months before and after a major restructuring and reprogramming effort that was expected to increase the timeliness of the FDA’s drug inspection program.
The FDA conducts for-cause inspections of facilities it has reason to believe may have serious quality problems. In recent years, there have been continuing concerns about the quality of foreign drug manufacturing sites, particularly in India and China.
The agency began realigning ORA from a geography-based to a program-based model in May 2017. (Also see "FDA Aligns New Pharmaceutical Inspectorate Into Six Divisions" - Pink Sheet, 16 May, 2017.)
For the pharmaceutical quality program, additional changes began in June 2017 based on a “Concept of Operations” agreement, or ConOps, between ORA and the FDA’s Center for Drug Evaluation and Research. (Also see "FDA Accelerates Inspection Process With New Concept Of Operations" - Pink Sheet, 25 Aug, 2017.)
ConOps gave ORA 45 days to deliver establishment inspection reports, evidence and site classification recommendations to the office that assigned the for-cause inspection, which gets an additional 45 days to classify the site, for a total of 90 days.
The OIG Reviewed 132 Inspections
For the audit, the OIG:
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reviewed all 64 foreign for-cause inspections that the FDA conducted in the 15 months from January 2016 through March 2017;
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did not review any of the 35 foreign for-cause inspections conducted during a nine-month organizational and operational transition period from April through December 2017; and
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reviewed all 68 foreign for-cause inspections the agency conducted in the 15 months from January 2018 through March 2019.
The reviews focused on timing of key steps in the enforcement process.
Key Findings On Enforcement Acceleration
Foreign for-cause drug inspection timeframes generally improved with the program changes, the OIG said.
The agency initiated announced for-cause inspections and held regulatory meetings in two thirds of the time, while classifying inspections in nearly half the time.
However, the inspections themselves did not go any faster. Also, it took 62% longer to issue import alerts and 40% longer to conduct follow-up inspections at sites not covered by import alerts. These delays may have meant longer exposure in the US to risk from adulterated products.
Deadlines Were Still Missed
Although classification of inspected sites went much quicker overall after ConOps set a 90-day deadline for it, the OIG complained that the FDA nevertheless missed the deadline in 40% of foreign for-cause drug inspections.
Of the 27 foreign for-cause inspections that required extra time to classify, nine took an extra week or less, another six took up to two weeks extra and another seven took up to a month extra. There were outliers: 51, 116, 406 and 442 extra days beyond the 90 allotted. One site never received a final classification.
Asked by the OIG about the delays, FDA officials attributed them to family emergencies, computer problems, other inspection priorities, resource constraints, furloughs and government shutdowns.
Some Warning Letters Were Still Late
ConOps calls for the agency to issue any warning letters or other inspection follow-up actions within six months of inspection.
Of the 68 post-ConOps foreign for-cause inspections the OIG reviewed, nine resulted in warning letters, but three of those warning letters were late; one by just a few weeks, another by three months and the third by five months.
The OIG raised the concern that such delays leave consumers and other stakeholders unaware of quality issues at facilities even as they continue to produce drugs for the US market.
Nevertheless, warning letter issuance timelines had vastly improved since fiscal year 2015, when they were taking nearly a year on average. (Also see "FDA Promises Shorter, Quicker Drug GMP Warning Letters" - Pink Sheet, 30 Jun, 2016.)
Most Regulatory Meetings Were On Time
Rather than issue a warning letter, sometimes the agency requests regulatory meetings with the responsible officials. ConOps calls for these meetings to occur within six months of inspections. The FDA met that goal for 18 of the 20 regulatory meetings it scheduled in the post-ConOps period the OIG studied.
One of the meetings took longer while the FDA consulted with microbiology experts. The other took extra preparation because it covered multiple sites.
The OIG observed that “delays in holding regulatory meetings could result in facilities not correcting deficiencies at their facilities in a timely manner.”
Problems Seen Documenting Investigator Training
The OIG found that the FDA had not documented that all lead investigators completed required training.
FDA uses a system called Pathlore to track completion of training requirements.
The OIG reviewed training records of the 65 lead investigators for the 132 foreign for-cause inspections it reviewed and found that two of the investigators had not completed their training before conducting the audited inspections.
One completed an inspection in August 2018, but was not certified until June 2019. The other completed an inspection in May 2016, but did not complete training until the following year.
The OIG also found that the FDA could not document that six of the lead investigators had completed the required training or passed a Level 1 performance audit and obtained a Level 1 investigator certificate.
Five were highly experienced investigators whose training was apparently in the distant past. The FDA explained that their training records may have been misplaced because since 2002 it had moved hard copy records several times and changed its electronic training systems.
The sixth may have been qualified under a different training program funded through the generic drug user fee program.