February 12, 2020
This article is the second installment of a four-part series which leverages available FDA enforcement data from 2016 to present, with an emphasis on the pharmaceutical and medical device industries, to provide companies with insight on how to best comply with FDA regulations and avoid common pitfalls in 2020. The first installment in this series focused on trends in FDA inspections. This article will focus on the most common FDA enforcement action that may follow from an inspection, Form 483 Inspectional Observations – most commonly referred to in the industry as simply “483s.”
As discussed in the first installment of this series, the FDA has a variety of enforcement tools designed to encourage and compel compliance with regulations, including Form 483s, warning letters, seizures, injunctions, criminal prosecution and fines.
As shown in the graphic above, Form 483s are the least severe FDA enforcement mechanism – and they are also the most common. However, there is no such thing as a “minor” Form 483 observation. By definition, FDA considers any observation it chooses to document in a Form 483 to be a serious violation of FDA regulations, one that could result in escalated regulatory action if not promptly addressed. Thus, companies should take all Form 483 Observations seriously.
Form 483s are issued and discussed at the close of an inspection and list conditions observed by the FDA investigator(s) that, in their judgment, constitute significant violations of the Food, Drug, and Cosmetic Act (FDCA). While 483s note only significant violations of the FDCA, they are not final agency determinations. In addition, companies are not required to respond – but they absolutely should. The response should be in writing and include the company’s corrective action plan. Importantly, the corrective action plan should be promptly implemented.
Form 483s can also have negative litigation implications for all FDA-regulated companies. Although Form 483s are not a final agency determination, Plaintiff’s lawyers may nonetheless seek to use the findings against a company in products liability lawsuits to support their claims that a company was not manufacturing products in compliance with FDA regulations.
In our first installment, we noted that the number of FDA inspections is on the decline. While inspection numbers are dropping, the number of Form 483 Observations has remained relatively consistent, according to available FDA data.1
Table 1. Total Number of Form 483 Observations for Fiscal Years 2016-2019
The percentage of Form 483 Observations attributable to drug and medical device manufacturing also remained consistent from 2016 to 2019 – with drug-related observations ranging between 14-16% of all observations, and medical device-related observations ranging between 17-21% of all observations. FDA has also focused on the same types of FDCA violations by drug and medical device manufacturers year after year – which provides insight into how companies can best prepare for upcoming inspections.
The following three observations topped the list of drug-related observations for FY 2016-2019:
5,045 (+11.4% from 2016)
4,910 (-2.7% from) 2017)
4,770 (-2.9% from 2018)
It is not enough to simply make a quality product. When FDA inspectors visit your facility, it’s imperative that you are able to demonstrate compliance with CGMPs through readily accessible, clearly written, and consistently maintained and modified Standard Operating Procedures (SOPs).
FDA is a science-based agency and, thus, will expect that your facility is relying on and applying good scientific principles and practices.
Laboratories should have a scientifically validated investigation strategy. For example, the laboratory should not simply re-test or test products into compliance. All out-of-spec (OOS) test results should be investigated to identify the root cause – whether or not the subject product or material is actually distributed.
The following two observations have topped the list of medical device-related observations for FY 2016-2019:
During an FDA inspection of a medical-device facility, the CAPA (corrective action and preventive action) processes will be scrutinized. Companies should take proactive steps to ensure that its approach to initiating CAPAs is effective and followed.
Medical device facilities should promptly investigate complaints and document the entire complaint handling process. The complaint handling process is imperative as it provides the data necessary for a company to determine if its medical device(s) present potential risks to patients. During an inspection, FDA investigators will take a close look at the facility’s complaint procedures to ensure that it maintains records of complaints received and has procedures in place for receiving, reviewing and evaluating complaints.
Given the consistency of available data, it is likely that the same Form 483 Observations will remain a high priority for the agency in 2020 and beyond. While Form 483s are the least severe FDA enforcement mechanism, it is crucial that companies appropriately respond to any Form 483 Observations and remedy all practices found to violate the FDCA. Repeat violations risk more damaging action by the agency.
Below are a few tips for responding to 483s to reduce the likelihood of receiving a warning letter in 2020:
FDA has consistently returned to the same Form 483 Observations for drugs and medical device manufacturers over the past four years – and this trend is likely to continue, giving companies insight into how to be best prepared for their next inspection.
In the event your company receives a Form 483, it is crucial to respond appropriately, as repeat violations can lead to more severe enforcement actions by FDA – including the issuance of a Warning Letter or worse. Warning Letters will be the subject of the third installment in this four-part series.
For more information, please contact the professional(s) listed below, or your regular Crowell & Moring contact.
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