While the number of drug GMP warning letters declined by about 30% in FY2019, the number of import alerts, regulatory discretions, and regulatory meetings increased dramatically through July 2020 compared to FY2019. 

At the 2020 PDA/FDA Joint Regulatory Conference held virtually in September, Director of the Office of Manufacturing Quality (OMQ) in CDER’s Office of Compliance Francis Godwin gave an update on his office’s activities in 2020 and discussed why the increase took place in several of OMQ’s compliance activities.  He also discussed a program known as Concept of Operations (ConOps) and a new import alert instituted by the agency in July.

Godwin noted that as part of CDER’s Office of Compliance, OMQ’s mission is to shield patients from poor quality, unsafe and ineffective drugs through proactive compliance strategies and risk-based enforcement action.  OMQ accomplishes this primarily by evaluating compliance via current good manufacturing practice requirements for drugs.  Most of its cases are based on inspection reports and evidence gathered by FDA investigators in the Office of Regulatory Affairs.

OMQ also develops and implements compliance policy, and takes regulatory actions to protect the public from adulterated drugs in the U.S. market.  

“When I say adulterated, I am using a legal term,” Godwin explained.  “Drugs can be adulterated for various reasons, which can range from unsanitary conditions—think of Upton Sinclair’s The Jungle in terms of a facility of being filthy and the potential for contamination.  But the bulk of our cases stem from a citation of failure to conform with current good manufacturing practices.”

Other provisions that lead to citations include:

  • 501(b) for a drug that differs from its compendial standards
  • 501(c) for a drug that is labeled to contain one thing but contains less or more of it and its strength is not accurate
  • 501(d) applies to a mixture or substitution with another substance
  • 501(j) applies if a facility denies an FDA inspection; if this happens, the drugs are deemed adulterated

FY2020 Regulatory Actions

During fiscal year 2019, October 2018 through September 2019, Godwin explained, “we issued almost a hundred warning letters.  We had 44 regulatory meetings.  We put 57 firms on import alert.  And we issued about 50 regulatory discretions when dealing with drug shortage situations.  We also had an untitled letter, an administrative detention, and a consent decree.  This was the landscape in 2019 (Figure 1).”

FIGURE 1 |OMQ Enforcement and Advisory Actions FY2019-FY2020

In fiscal year 2020 through the end of July, OMQ issued 69 warning letters.  The Office also held 64 regulatory meetings and issued 81 import alerts.

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“So far this fiscal year, we have put more firms on import alert than we did all last fiscal year. And so far this year we have issued 82 regulatory discretions.”

One reason for the differences is the COVID-19 pandemic, which has caused quite a strain on the United States, particularly on drug supply chains.  This is evidenced by a breakdown of regulatory discretions that OMQ has granted by month, starting from fall of last year through July (Figure 2).

FIGURE 2 | OMQ Reviewed Regulatory Discretions

Regulatory discretions were averaging a few a month—then suddenly in April, May, and June, the number of regulatory discretions granted grew.  The ones related to COVID drugs appear in red in Figure 2.  COVID drugs are therapies that are related to patients being treated.  For example, if a COVID patient needs to be intubated, there are certain drugs needed to support intubation.

The bulk of our cases stem from a citation of failure to conform with current good manufacturing practices

“As COVID spread around the world, the drug supply chain had to ramp up to meet demand,” Godwin explained. “So, we granted regulatory discretions to help ensure that the supply of necessary drugs was ready to go in terms of the COVID pandemic in the hospital systems.”

Inspection Program and ConOps Update

Godwin gave updates regarding the inspection program for human drugs and the Concept of Operations.

“For those of you that are familiar with drug GMP inspections, there were two things that came in with the Generic Drug User Fee Act (GDUFA 2),” Godwin explained.  “One was to issue a 90-day classification letter, which we have done. And the other part comes from the Concept of Operations—for facilities that are considered Official Action Indicated, or out of compliance with CGMP, we have committed to having the regulatory actions completed within six months of the closing of the FDA inspection.

Over the past six years, the timeframe between inspection and the regulatory action has been decreasing even while the number of warning letters has increased dramatically (Figure 3).

Figure 3 Agency Progress Toward Six-Month Compliance Actions
FIGURE 3 | Agency Progress Toward Six-Month Compliance Actions

In 2015, there were 19 warning letters issued with a median time between the inspection and the regulatory action of nearly a year, whereas so far in 2020 the median time is just over six months.  This is because FDA has been putting resources into the Concept of Operations to ensure that facilities get classified quickly after an FDA inspection.  And if violative conditions are observed, the ensuing regulatory action occurs quickly.

The reason for the massive increase in warning letters is a result of FDA inspecting the uninspected over the past three years.  There are a lot of firms—primarily non-application, over the counter drug manufacturers—that had not been inspected before and were inspected and found to be noncompliant. Most of those firms were issued warning letters, but many were also placed on import alert to bar their drugs from coming into the United States.  They were typically failing fundamental GMPs such as not testing their product prior to release, poor stability, and not testing raw materials—things that make FDA question the quality of drugs from those facilities.

Import Alerts Increasing

Import alerts are a tool used by FDA to inform its field staff and the public that the agency has enough evidence to allow for Detention Without Physical Examination (DWPE) of products that appear to be in violation of the FDA’s laws and regulations.  This means that the products will be stopped at the U.S. border and denied entry based only on the name of the company and address it is being shipped from. The violations leading to an import alert could be related to the product, manufacturer, shipper, and/or other information.

OMQ uses several import alerts, as listed below with Godwin’s commentary (Figure 4).

Figure 4 Number of Import Alerts by Type
FIGURE 4 | Number of Import Alerts by Type FY2016-FY2020

Import Alert 99-32
Import Alert 99-32 applies when a company refuses to allow an FDA inspection. “If a company registers to ship drugs to United States, FDA will provide notice to the firm that we plan to inspect.  If the firm says it does not want to be inspected by FDA, we will place them on import alert thus preventing their drugs from coming into the United States,” Godwin explained.

Import Alert 66-40
Import Alert 66-40 is used when FDA conducts a physical inspection of a facility and finds violations of CGMPs that would warrant banning the drugs produced at the facility from coming into the United States.  This alert is used frequently.

Import Alert 55-03
Import Alert 55-03 is specific for heparin. It was put in place to alert the agency and the public to the discovery of adulterated heparin, whether it is from an inspection, from a heparin manufacturer refusing inspection, or through other evidence of contamination. “This also helps to ensure that manufacturers that purchase heparin raw materials for manufacturing know who is on import alert and who they might want to avoid” Godwin said.

Import Alert 55-05
Import Alert 55-05 is an import alert that OMQ has used for several years.  It is related to FDA testing of imports or other samples that show gross microbial contamination.  “We have had instances of diaper rash cream contaminated with fungus,” Goodwin revealed. “We have had sterile drugs test for sterility and fail [meaning they are contaminated].  We use this import alert to block drugs from facilities that do not have control over the microbiological standards of their products that would put patients at risk.”

Import Alert 66-78
Import Alert 66-78 is new—it was added in July.  This import alert is for detention without physical examination of drugs based upon analytic test results.  “Part of the impetus for the creation of this import alert is during the COVID pandemic FDA is increasing the focus on sample collections to assess drug quality for material entering interstate commerce, whether it be imported or in the United States.”

Much like Import Alert 55-05 uses microbiological test results, Import Alert 66-78 uses analytical test results as the basis for the alert.  Depending on the nature of the test result that shows a violative situation, there are various charges that can be applied under 66-78— violations of various provisions of FD&C Act Section 501, including for:

  • Insanitary conditions
  • Failure to conform with CGMP
  • Strength, quality, or purity differing from the official compendium
  • Misrepresentation of strength, etc., where drug is unrecognized in compendium
  • Mixture with or substitution of another substance

Looking specifically at 2020, these data are for October 1 through July 31, “and I know there have been more import alerts since then,” Godwin commented.  “You will notice at the end of July there were about 15 import alerts for category 66-78 – analytical import alerts. By the time you see this presentation in September, I estimate that that number will be more than 30 based on what we have been seeing so far in August.”

The reason for the massive increase in warning letters is a result of FDA inspecting the uninspected

The analytical test result import alerts are all associated with hand sanitizers.  Hand sanitizers are over-the-counter drugs and regulated by FDA.

Analytical testing of hand sanitizers has shown a sharp increase in products that are labeled to contain ethanol (also known as ethyl alcohol) but that have tested positive for methanol contamination. Methanol, or wood alcohol, is a substance that can be toxic when absorbed through the skin or ingested and can be life-threatening when ingested.

The agency is aware of adults and children ingesting hand sanitizer products contaminated with methanol that has led to recent adverse events including blindness, hospitalizations, and death.

[Editor’s note: Author Jerry Chapman also covered FDA OPQ Director Ashley Boam’s presentation on FDA’s proposed Quality Maturity Model at the virtual 2020 PDA/FDA Joint Regulatory Conference.]


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