Expert: Companies should embrace ‘sustainable compliance’ to avoid 483s, warning letters

Drugmakers should establish “sustainable compliance practices” based on a strong quality culture, rather than simply doing the minimum required to pass inspections to avoid receiving a Form 483 or warning letter, said Donald Ashley, principal for regulatory compliance at Eliquent Life Sciences, during a webinar sponsored by the Food and Drug Law Institute (FDLI) on Wednesday.

During the webinar, Ashley, who previously led the Office of Compliance within FDA’s drug center, presented alongside attorney Kalie Richardson from Hyman, Phelps & McNamara, and others on best practices for avoiding enforcement actions and effectively responding to observations and warning letters.

Avoiding a warning

Ashley emphasized the importance of striving for sustainable compliance, which he said should be based on a strong quality culture.

The key elements of a robust quality culture include a commitment from executive leadership to quality, the presence of an independent quality unit that reports directly to senior management, and a proactive approach to investigating market signals as well as thoroughly examining deviations, he said.

Ashley emphasized that companies should adopt a comprehensive approach to compliance and establish high standards for themselves.

“When I was at CDER compliance, I’d see far too often many firms that were only focused on what they have to do to pass an inspection to resolve a warning letter. This can be a bit of a trap. They are aiming too low. Rather than aiming for a robust quality culture, they just want to do the bare minimum of what it takes to pass the next inspection.” These are the companies that fluctuate with being in and out of compliance.

Ashley stated that while at the agency, over 50% of drug manufacturing companies fail their first reinspection following a warning letter, emphasizing the importance of having a sustainable compliance program.

Ashley advised companies to always prepare for inspections, as the FDA is no longer preannouncing many foreign inspections or is only providing short notice.

To ensure preparedness, he recommended that companies perform mock inspections to identify any weaknesses in their quality systems and operations. Additionally, he suggested creating a standing inspection plan so that everyone is clear about their roles and responsibilities when inspectors arrive on site.

Responding to 483s and warning letters

Ashley said that companies that receive a Form 483 should distribute copies of the observation to senior leadership and establish a cross-functional team to help craft an appropriate response. Additionally, the company must quickly evaluate the need for product containment measures, which may include implementing a product hold, initiating a recall, or halting operations.

Companies should consider hiring external support to aid in preparing their response. Additionally, while drafting the response, firms should reflect on past, present, and future considerations for each observation and issue.

Richardson stated that if companies receive a Form 483, they should take the entire 15 days to respond, as there is no benefit to submitting their response early. There is no “extra credit” for an early submission, she said.

Richardson noted that while FDA does allow exceptions to this 15-day timeline, such instances are rare. Exceptions can occur in situations like natural disasters or if the response deadline falls on a major holiday in the country where the facility is located.

She suggested that companies reply to the Form 483 by requesting a secure link from the FDA to upload their response attachments, rather than sending multiple emails.

She also advised companies to double-check the FDA contact information for the response as email addresses for FDA staff may have changed.

Additionally, she said companies should include a cover page outlining their major commitments in response, which may not pertain to a specific observation. The response should address whether the company is initiating a recall, whether they are retaining third-party experts, and whether the leadership has changed.

If the company disagrees with FDA’s characterization of any of the observations, the initial response is the best time to push back, Richardson said. Companies should also not rush to complete commitments such as updating SOPs or training simply for the purpose of saying they’re done in an initial response. She also said that companies should make sure that their commitments are realistic, avoiding situations where they overpromise and underdeliver.

Expert: Companies should embrace ‘sustainable compliance’ to avoid 483s, warning letters

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