FDA CDER Compliance Office Answered Pandemic With Fewer Inspections, Greater Discretion
Executive Summary
Fewer inspections but more warning letters, import alerts and drug-shortage discretions were seen as office sought to ameliorate COVID-19 impacts.
Inspections were down, warning letters were up and import alert activity increased in fiscal year 2020 as the Office of Compliance in the US Food and Drug Administration’s Center for Drug Evaluation and Research coped with the COVID-19 pandemic, according to the office’s annual report.
The report highlighted coronavirus responses that came to dominate the office’s activities during the latter half of the fiscal year:
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Efforts to protect US consumers from unsafe hand sanitizer contaminated with methanol or 1-propanol.
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Efforts to prevent or mitigate potential drug shortages the agency identified through intense monitoring of the global pharmaceutical supply chain as it buckled under the strain of rising demand and uncertain supply due to the pandemic.
The office made 45 decisions to exercise enforcement discretion to ease supplies of critical medications like remdesivir, heparin, albuterol, etomidate midazolam and propofol. It also exercised discretion on compounding of drugs for treating COVID-19 patients, repackaging propofol and exempted COVID-19 drugs from burdensome anti-counterfeiting requirements.
Half The Inspection Classifications
The compliance office only sent 113 facility inspection classification letters to drug manufacturers in FY 2020, down 49% from 232 the previous year.
These are the letters that convey to pharmaceutical companies whether the agency believes inspections identified serious problems, minor problems or none at all.
The center had committed to issuing such letters within 90 days of surveillance inspections as part of its second five-year generic drug user fee agreement in 2017 but decided to apply the policy to all such inspections.
The FY 2020 decline was a consequence of the sharp reduction of surveillance inspections during the COVID-19 pandemic.
After the pandemic curtailed travel in the middle of the fiscal year, the agency relied heavily on inspection alternatives like remote records assessments and trusted foreign regulators’ assessments that do not involve issuing inspection classification letters. (Also see "Preparing For The Return Of US FDA Inspections" - Pink Sheet, 5 Feb, 2021.)
Median time to warning letter was down to 6.3 months in FY 2020 from 12.2 months in FY 2016, the last full year before the June 2017 concept of operations agreement between the FDA’s center for drugs and the agency’s Office of Regulatory Affairs set a goal of issuing such letters within six months of inspections. (Also see "FDA Accelerates Inspection Process With New Concept Of Operations" - Pink Sheet, 25 Aug, 2017.)
The office issued 238 warning letters across compliance programs, up from 166 the year before.
Good clinical practice inspections held nearly steady at 114 compared to 120 in FY 2019.
A Dropoff In GMP Declarations
In FY 2019, the agency had issued 33 letters to foreign regulators declaring the GMP compliance status of US sites referenced in foreign drug applications, six of them related to a GDUFA II commitment.
In FY 2020, there were no such declaration letters.
The FDA began offering to write the letters in 2018 after the US/EU mutual recognition agreement on pharmaceutical inspections took effect and the EU sharply reduced inspections of US facilities.
The idea was to provide manufacturing facilities something akin to the three-year EU GMP certificates they used to get. (Also see "FDA Offers New ‘cGMP Declarations’ That Could Fill US Gap In EU GMP Certificates" - Pink Sheet, 2 Oct, 2018.)
Import Alerts Were Up
The CDER compliance office collaborated with ORA to add 209 drug manufacturing facilities to various quality-related import alerts, up from 153 in FY 2019.
The main difference: 57 facilities added to a new import alert 66-78 for product adulteration determined by FDA testing. The import alert category, which the FDA created during the pandemic, allowed the agency to reject methanol-tainted hand sanitizer manufactured in Mexico and detained at the border.
The number added to the drug GMP import alert, 66-40, was down to 34 from 41 the previous year. Similarly, just 20 were added to the inspection refusal import alert, 99-32, compared to 32 in FY 2019, and just 80 to the import alert for unapproved new drugs, 66-41, down from 97 the year before.
One crude heparin manufacturer was added in FY 2020 to import alert 55-03, established in February 2012 as part of an effort to prevent another heparin adulteration crisis like the one in 2008. (Also see "Is Another Heparin Crisis Looming? Congress Raises Alarm, Demands US FDA Briefing" - Pink Sheet, 5 Aug, 2019.)
Notably, the office did not remove any facilities from such import alerts in FY 2020, compared to 13 in the previous year. Removals are generally contingent upon reinspection.
FY 2020 Drug Recalls
Type Events Drugs
Class I 48 110
Class II 235 828
Class III 78 100
FY 2019 Drug Recalls
Type Events Drugs
Class I 36 513
Class II 242 1,505
Class III 83 150
Drug Recalls Focused Less on Nitrosamines
There were 21 nitrosamine-related drug recall events in FY 2020, down from 41 in FY 2019. The issue of nitrosamine impurities arose with valsartan in June 2018, expanded to other angiotensin II receptor blockers and then to other drug products including ranitidine. The decline could continue as drug manufacturers implement tighter controls on release of nitrosamine-contaminated drugs.
There was an increase in the number of serious Class I drug recall events, but a decline in the number of drugs involved, probably a consequence of the proliferation of methanol-contaminated alcohol hand sanitizers from Mexico.
Class II and Class III drug recall events held steady, though the number of drugs involved declined.