The U.S. Food and Drug Administration has just finished an inspection and the results were not as stellar as your organization expected. In fact, the investigator has decided to leave your organization with a little gem, a Form 483 with multiple inspectional observations. The good news is you do not have to respond to the 483. The bad news is that if you fail to respond, FDA will send your organization another little gift, a warning letter. So what is the Chief Jailable Officer (CJO) to do?

Frankly, the CJO can start by asking the investigator about the observations noted and ensure the basis for the observations is understood. The CJO can disagree with an observation; however, vehemently arguing with the investigator, sheading real tears, holding one’s breath, screaming, or dropping to the floor and throwing a temper tantrum is not going to work. Frankly, if the 483 is for one or two minor issues, even if you disagree, just bite the bullet and fix the perceived issue. In any event, if the CJO agrees with the observations, ensure the “promise to correct” annotation is noted on the Form 483. Remember, the agency is not trying to “thimblerig” (look-it-up) device manufacturers into signing the 483. That being said, Dr. D hopes you enjoy this week’s guidance.

Just respond baby!

As the doctor stated, begin by understanding the basis for the Form 483 observations. Not wanting to state the obvious but obliged to do so, Dr. D believes that the offending organization just might have a compliance issue, if multiple observations are noted. If the organization is blessed with several 483 observations, the agency just might say the heck with it, and move to warning letter. Don’t laugh, it happens and happens more frequently than most CJOs care to admit.

From an agency perspective, they issue 483s when an inspector determines an organization has failed to comply with a specific part of the code delineated under the Act, typically, 21 CFR, Part 820 (the Quality System Regulation). FDA employs the 483 as a vehicle to ensure organizations quickly and promptly correct noted observations. In wrestling terms, it is what is called a choke hold. As Dr. D has already alluded to, a response is not mandated by law; however, the agency has the ability to unleash a whole lot of pain for organizations that choose not to comply with the request for correction. Trust the doctor when I say, “If the agency is not happy with your organization’s response to the 483, your organization is not going to be happy when they receive the warning letter.” Remember, “Warning letters equate to pain!” Fail to respond to the warning letter, and the Department of Justice and the federal courts will be in the offending device manufacturer’s future. CJOs do not have to be clairvoyant to be able to see how FDA will escalate the regulatory pain.

Crafting a response 

The next steps taken by the CJO is to ensure a response is drafted and returned to the Agency within 15 days, not 15 weeks, 15 months, or 15 years. From FDA’s perspective, a prompt and well-positioned response equates to an organization taking the Form 483 seriously. Dr. D recommends loading all 483 observations into the Corrective and Preventive Action (CAPA) system, regardless of how innocuous the observations might be. This way progress toward correcting each of the observations can be tracked individually. Additionally, it makes the review of actions pursued easier to review by the agency. Keeping it easy for FDA to understand is a good thing. 

Furthermore, the response to the Form 483 should contain sufficient granularity so the agency understands the steps being pursued to correct the non-compliances. For example, in responding to the Form 483, the doctor recommends the following information be considered in the response:

• A restatement of the Form 483 Observation(s);
• A well-articulated corrective action plan (ensure past, current, and future states influenced by the observation are assessed);
• Reference to the CAPA number opened;
• Identification of root cause;
• Impact to product that has been shipped to customers;
• Impact to product currently being manufactured;
• Potential impact to future products;
• Impact to the quality management system;
• The targeted date for completion; and
• Other information deemed relevant to addressing the Form 483.

Finally, do not forget to add a cover letter to the response. Remember, a thorough and well-thought out response to a Form 483 is an organization’s best preemptive defense in preventing the issuance of a warning letter. One final thought, make sure all of the corrections are implemented and effective. Why? Because during the agency’s next friendly visit to your facility, they will revisit previous observations and verify they are closed.

Disagreeing with an observation

It’s okay to disagree with a Form 483 observation; however, it is up to the offending organization to draft a salient response that delineates the points of disagreement. If an organization disagrees, it is incumbent upon the organization to provide supporting evidence as to why they believe the observation has been incorrectly made. The FDA’s expectation is that these types of disputes can be resolved as part of the inspection debrief; however, that is not always the case. 

One final thought: never ever, ever, ever, ever inform the agency that the reason your organization cannot achieve compliance is because of resources constraints. As Dr. D has stated on multiple occasions, “Compliance to regulations is just part of the price of admission to play in the medical device industry.” If an organization does not have or will not invest in adequate resources, they are playing in the wrong sandbox, consider making pet rocks as an alternative. 

In closing, Dr. D hopes you enjoyed this week’s guidance as much as the mad doctor enjoyed writing it. Please tune in next week when the subject matter will be, another surprise. Best wishes for continued professional success, Dr. D!