After a pharma company or its supplier receives a routine inspection from an FDA inspector, they will receive an FDA Form-483, usually referred to as a 483.
Depending on how many observations are made by the inspector — and the severity of those observations — this report could have serious consequences for the pharma companies or medical device manufacturers inspected. Loss of revenue, time spent on improving compliance processes and reputational damage are some of the potentially dire effects of a negative 483.
In this post, we explore what a 483 entails and how pharma and medical device companies can ensure they operate within a culture of compliance.
According to the FDA, the 483 is not a conclusive report of violations. It contains only what the inspector observed during the inspection. But the agency advises businesses to correct observed violations as well as any other trouble areas before regulatory action becomes mandatory.
Remedial action should begin upon receipt of the 483, writes business consultant Samantha Lim. That remedial action can be voluntary — violations were found but do not warrant regulatory action, or mandatory — corrective action is required by the FDA. The company may face regulatory and/or administrative sanctions if these violations are not corrected.
Responding to the 483 isn’t legally required, but pharma companies or their suppliers should inform the FDA as to how they plan to improve in order to avoid further action.
A bad 483 can cost an organization a lot of money. So pharma and medical device organizations should be quick to respond to them, says Michael De La Torre, CEO of Govzilla, a data source for regulatory and compliance professionals.
Reacting to a negative 483 requires internal teams to divert their energies and work hours to rectify the issues. External consultants with specific expertise are often required, further driving up the bill. De La Torre quotes an unnamed source citing costs of $250,000 from a moderately bad 483. Another said a bad 483 cost his company $5 million.
The costs are so high because the 483 often identifies significant issues that, when occurring across multiple sites, quickly add up to fix. There are other costs too, especially when a warning letter is issued, which will explore in more detail later.
De La Torre says these FDA warning letters are public so there’s risk of damage to a company’s reputation, especially if the media gets involved. The FDA might also choose to halt new drug applications from a site under observation, costing the pharma company time and money and even lost market opportunities as competitors pounce.
First, review the findings with the inspector. This provides an opportunity to understand why the observations were noted, debate any disagreements, ask questions and determine whether legal counsel is required, explains John Lehmann, director of business development at IMARC Research. Speaking with the inspector will also help direct efforts to rectify the violations.
As Lim noted above, a written response to a 483 is not required; however, Lehmann says it’s considered good practice to do so. “You should respond within 15 days, or the agency does not have to consider your response in their decisions for subsequent actions,” he writes.
The response should demonstrate that the company is aware of the observations and state its intention to make improvements, says the team at the regulatory and compliance services company Weinberg Group. This includes detailed timeframes for changes to be made so when the FDA returns for the follow-up inspection, the response letter matches the actions taken by the company during the intervening period.
“Not responding to a Form 483, or submitting an inadequate response, can lead to escalating enforcement actions. These actions include giving the opportunity to voluntarily correct and prevent violations, enforcing involuntary corrective action, removing violative products from the market, and punishing offenders,” explains the team.
They say there are steps your company can take to prepare for an FDA inspection, so you’re not facing administrative and judicial actions in the first place. For example, staff must be properly trained in order to be compliant with your own quality system and with FDA regulations.
Internal audits can test the performance of staff. Auditing should be continuous — monthly or quarterly — and based on consistent processes.
Researchers reviewed 85 FDA warning letters between 2014 and 2016 to determine how organizations could avoid non-compliance in the future. In their article published in the Research Journal of Pharmacy and Technology, Rajesh Kumar Jain, Ph.D. and Sanjay Kumar Jain categorized the observations into four major groups, under which most of the warnings fall:
Their findings suggest that the pharma industry improve quality with a specific focus on investigation and corrective action/preventive action (CAPA) systems as well as stability programs.
The FDA actually doesn’t send as many warning letters as it used to. Instead, it’s been holding regulatory meetings. So if the meeting comes before the warning letter, the FDA is essentially providing the company with opportunities to correct the inspector's observations using a more incremental approach, according to US FDA Compliance Branch directors Gina Brackett and Melissa Michurski.
A letter inviting the manufacturer to a regulatory meeting will be signed by the director of the compliance branch (DCB) from one of three divisions. These divisions have been structured to make audits more consistent for investigators and device-makers. Manufacturers should pay attention to the observations the agency wants to discuss. So while the 483 might show eight observations, the regulatory meeting letter might list just three topics to discuss.
Medical device manufacturers want to be able to respond to 483s with actions to correct observations but not be bound by the FDA to those proposed actions. So the FDA has created draft guidance to standardize this, writes Ann Mulero, news editor at Regulatory Affairs Professionals Society.
Issued by the Center for Devices and Radiological Health at the FDA, the guidance has five parts: submitting a timely request, statutory eligibility criteria, the manufacturer’s justification of the submitted request, the proposed actions and the nonbinding feedback.
The guidance also wants FDA staff to reply to a request for nonbinding feedback within 45 days. That response would determine whether the manufacturer’s proposed actions are adequate, partially adequate or inadequate — with reasons why should the actions be deemed inadequate.
A necessary condition of being compliant is proving compliance. This requires proper documentation of processes and procedures, explains mechanical engineer Matthew M. Lowe, executive vice president at software solutions provider MasterControl. Not being able to prove compliance is a major reason for companies receiving warning letters from the FDA.
The best way for companies to achieve this proof of compliance is through scrupulous record-keeping, showing have properly documented procedures. Lowe advises using an automated quality management system to address FDA and ISO document control demands.
He notes that compliance is not the same as quality. Passing an audit is possible without producing high-quality products. “The real burden of quality entails asking the tough question: Is this the best product you can make? Or are you simply marking the proverbial checklist to pass an inspection? In your compliance efforts, be sure your focus remains on achieving quality as the foundation of compliance and not the other way around,” writes Lowe.
Creating a compliance culture relies on senior leadership support and proper understanding of the consequences of noncompliance. Like Lehmann earlier, Peter Hargittay at SaaS enterprise software company Intellect, advises not to let the inspector offsite until you’ve had a chance to correct observations and note, with a timeline, how remaining issues are being rectified. This must be done before or during a close-out meeting and before the FDA inspection report is completed.
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