FDA officials review GMP compliance issues, enforcement misconceptions

Hand sanitizer manufacturers drove down the rate of good manufacturing practice (GMP) compliance among US companies as new entrants emerged to meet demand during the COVID-19 pandemic, according to Francis Godwin, director of the US Food and Drug Administration’s (FDA) Office of Manufacturing Quality.

Godwin also asserted that compliance metrics improved in other parts of the world, as the agency relied more on import alerts and less on inspections and warning letters for product enforcement during the pandemic. Godwin made these remarks during a 6 September webinar sponsored by FDA’s Small Business and Industry Assistance (SBIA) program on inspections.

During the webinar, Godwin and his colleagues addressed what the agency looks for in inspections and sought to dispel some misperceptions about warning letters and Form 483 reports.

In May 2020, 93% of drug manufacturing facilities in the US had “acceptable” final outcomes following an inspection, meaning the inspection resulted in a “no action indicated” (NAI) or “voluntary action indicated” (VAI). In Europe, the acceptable compliance rate was 98%, 91% for China and 86% for India.

Yet by May 2023, the number of firms found compliant with GMPs dropped slightly to 92% while remaining steady or improving in the rest of the world. In Europe the percentage of firms with acceptable GMP compliance remained at 98%, in China the rate of acceptable outcomes rose to 95% and in India the rate rose to 97%.

Godwin attributed the higher noncompliance rate in the US to problems found in hand sanitizers. He said that this shift in compliance rate was not seen in the foreign arena as the agency depended more on alternate tools such as import alerts to keep adulterated products out of the country instead of conducting inspections.

FDA has issued a plethora of warning letters and public health advisories over the past two years to firms making adulterated hand sanitizers contaminated with either methanol or benzene. In some cases, these firms have refused FDA’s request for records. (RELATED: FDA issues blitz of warning letters over testing violations and refusing records requests, Regulatory Focus 9 August 2023)

Godwin added that “things are headed back to pre-COVID inventory levels” when it comes to manufacturers in the FDA’s inspection inventory.

Enforcement misconceptions

FDA officials also sought to dispel some common misperceptions about warning letters and Form 483 reports. First, these regulatory actions are not meant to signify that a drug or a facility is failing.

“Warning letters do not mean that products are failing after distribution, and it does not mean that a drug is failing specifications.” Rather, said Godwin, these actions are meant to serve as a pre-emptive strike to signal a GMP problem before it gets worse.

Godwin added that the GMP regulatory framework was “designed to have multiple layers around the manufacturing process,” and if there are problems with one layer, such as raw material testing, finished product testing, process validation, stability and company investigations, the other areas will catch it before the drug is distributed.

Another misperception can arise from the technical language used in the warning letters. For example, if FDA notes that a firm’s water system has “dead legs” this term is an engineering term used to describe water that is stagnant or not circulating. “People were assuming that what we were talking about were body parts,” Godwin said.

Simone Pitts, a pharmaceutical expert in the Office of Regulatory Affairs, similarly noted some misperceptions concerning Form 483 reports. One is that these reports are “an all-inclusive list of violations,” which she said is not the case. There are instances where observations are not listed on the Form 483 and instead these observations are discussed with management at the close of the inspection.

The issuance of the FDA 483 is also not the agency’s “final communication” but should be viewed as an “opportunity to open a dialogue between FDA and the firm.”

Investigators focus on six systems when evaluating a firm’s compliance with GMPs, said Pitts. These systems include quality, facilities and equipment, materials, production, packaging and labeling and laboratory controls.

FDA routinely looks at investigation reports, equipment qualification reports, validation reports of the manufacturing process, whether there is documentation showing that incoming raw materials and finished products have been tested, and analytical methods.

Preparing for an inspection

Pitts said she was asked “the million-dollar question” at the end of her presentation: how should firms prepare for an inspection?

First, she said it is important to ensure that equipment is qualified before use, and that vendors and suppliers are also qualified and test raw materials. Companies should also ensure that analytical methods have been validated and are suitable for their intended use. Lastly, ensure that the right people are at the inspection.

Pitts said that in many cases, management addresses questions when FDA would rather hear from the operator or the analyst. She added that firms should “make sure you have the right people in place to answer those questions.”

SBIA webinar

FDA officials review GMP compliance issues, enforcement misconceptions

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