FDA Form 483s are very important to FDA regulated companies, regardless of how many, if any, each company has received.
A single 483 tells you exactly which areas to improve or correct to remain compliant (and therefore operational). Downplaying the 483 content and, more importantly, not responding seriously and completely to the observations can have unfortunate costly consequences.
Several 483s can tell you much, much more such as:
- FDA enforcement trends in your peer group
- Inspector tendencies (quick list of areas to focus on first)
- Reliability of your supply chain
However, before we get to the power of an FDA 483 database, the first thing to do is to understand exactly what a Form FDA 483 is, what to look for in a 483, how to respond to 483s, and what the price of failing to respond correctly can be.
To help you understand all of these things and more, we put together the ultimate guide that will give you an industry primer for everything you need to know about Form FDA 483s. Read through below or choose where to begin:
WHAT IS A FORM FDA 483?
The FDA has the authority to inspect factories that manufacture products regulated by the FDA. FDA inspectors can come in and inspect any given facility at any time, and they write down their observations on forms called Form FDA 483s (483s for short).
What is in a Form FDA 483?
The best way to tell you is to show you. Visit the FDA’s ORA FOIA reading room for a sample of 483s that the FDA makes available publicly. You’ll see these fields in a 483:
- Issuing FDA field office and address.
- Dates of inspections – can be as short as one day or as long as multiple weeks.
- FEI number – stands for the Firm Establishment Identifier, a number created by the corresponding district office.
- Manufacturer’s contact info
- List of observations – typically, there’s somewhere between 5 and 10, though we’ve seen some with 58+.
- Names and titles of the investigators – usually 1 or 2. One unfortunate pharma manufacturer got to host 11 of them!
What’s the difference between a Form FDA 483 and a warning letter?
Inspections, where investigators note observations that may be violations of regulations, lead to a 483. After a 483 is issued, FDA officials may conclude that a serious violation could exist and a warning letter is then issued. Warning letters usually result from:
- Failure to adequately address the observations of previously issued 483s
- Unsatisfactory or incomplete corrective actions proposed by the sponsor
- Other issues that are much more serious and require quick attention/escalation
Essentially, by listing deficiencies in a warning letter, FDA has determined that the practice violates a regulation to which the firm must comply. Issuance of 483s tends not to make headlines, whereas warning letters posted on the FDA website usually make the industry news section.
There’s one more report type to be aware of: the EIR (Establishment Inspection Report). This is a more detailed play-by-play description of the inspection, written by the inspector.
“Issuance of 483s tends not to make headlines, whereas warning letters posted on the FDA website usually make the industry news section.”
Think of the 483 as an executive summary of observations the inspector(s) made during the inspection (i.e. here’s the 10 key items) and the EIR as the inspector journal (i.e. “and then I talked to Peggy Smith, Associate Director of Regulatory Affairs, and she was responsive to our information requests”).
(NOTE: Are you interested in learning more about observations with specific industry keywords? Get your FREE 483 Observation Report and you can quickly determine who has been hit with the same observations. Learn more here!)
When should I respond to a Form FDA 483s?
Companies that receive a 483 should respond within 15 days to have their responses considered before FDA takes additional enforcement action. If companies do not respond within that 15-day window, FDA will not consider their response in the decision on whether to escalate to a warning letter.
WHO CAN SEE FORM FDA 483s, AND WHERE DO I GET THEM?
Form FDA 483s are central to anyone’s FDA inspection preparation program.
As the keeper of the world’s largest database of 483s, we often get asked, “How do you get a hold of actual 483s and who else can see them?”
This is where things get a little tricky.
Theoretically, 483s are public information and, thus, are available through the FDA’s Freedom of Information Act Office. Any 483 can be requested by anyone.
That said, requesting a 483 can be costly and may take a lot of time. The FDA must scrub/redact any potentially confidential information from the report before it is released to the public, and the FDA charges $46 per hour for FOIA requests. So, if the 483 has not been previously requested, you may end up paying hundreds of dollars and potentially waiting hundreds of days before getting it.
We’ve heard some people say they got their requested 483 two years after their initial request. Everyone seems to know someone that has experienced this (or maybe it’s the same person who keeps talking about it!).
“They got their requested 483 two years after their initial request.”
483s that have already been requested by someone else and subsequently processed can be turned around quickly—within days or weeks, depending on the backlog at the FDA FOIA office. You’ll likely be charged the minimum of 1 hour of work, or $46, for processing the request.
(NOTE: You can avoid the wait and know the cost of a 483 upfront by getting your 483s from FDAzilla.)
Keep in mind that if you request a 483 from the FDA, that request itself is also public information. We recently asked the FDA who has been asking for 483s, and you’ll find an interesting list of companies asking for their competitors’ 483s:
- Investment companies
- Major news media companies
- Worker’ unions
- Potpourri of others
All of this said, we’ve always found the Freedom of Information Office to be professional, courteous, and hard-working, though we suspect they are bound by outdated technology. It’s a world of PDFs and manual searching and such, so it’s not like you can strategically search for specific themes or trends.
6 FEATURES TO LOOK FOR IN FDA 483S
What Leads to a 483?
As you now know, a 483 is the document that the FDA issues at the close of an inspection where they identify potentially problematic observations made during the inspection. If none such observations are made, no 483 is issued.
Based on the response submitted by the firm, the FDA classifies the inspection as:
- No Action Indicated (NAI) when no 483 is issued
- Voluntary Action Indicated (VAI)
- Official Action Indicated (OAI)
Generally, when the FDA issues a 483 with observations and the firm’s response is satisfactory, the inspection is classified VAI.
FDA is now informing drug/API manufacturing facilities of their inspection status within 90 days after the end of the inspection. This change came with FDA’s commitments as part of GDUFA II and applies to all firms, not just the generic drug industry. The agency will confirm implementation of corrective and preventive actions at the next inspection.
In the absence of acceptable responses, the FDA can:
- Determine that these observations represent a failure to comply with GMP regulations
- Classify the inspection as OAI
- Issue a warning letter
- And/or take additional enforcement action (i.e. an import alert or product seizure)
How to Interpret a 483?
A challenge with interpreting 483s that are issued to firms other than your own is that 483s don’t provide the context for what occurred during the inspection and how the issues were identified.
[NOTE: You can see 483s in context with the FDAzilla 483 Observation Report. You can request a free report here.]
“A 483 issued to a firm in China identified 6 ½ pages of examples of how the firm manipulated electronic records.”
To evaluate the seriousness of a 483 and the potential for additional enforcement action, ask the following questions:
- Is the 483 longer than 8-10 pages? Longer is not better. That doesn’t mean that a short 483 may not lead to serious enforcement actions, but a long 483 suggests problems may exist in many quality systems. The FDA also concludes that if one quality system is out of control, they are all out of control.
- Do any of the observations have an extensive description of examples? At the end of 2015, a 483 issued to a firm in China identified 6 ½ pages of examples of how the firm manipulated electronic records. This is a situation where the FDA may be attempting to drive home a point to the firm and to others who read the 483. As a rule of thumb, consider any observation supported by more than 3 examples is one where the agency is trying to send a message about the breadth of the problem within the organization, and may be an indication that additional enforcement actions are in store.
- Do any of the observations state that they are repeat observations from previous inspections? This statement indicates that while the firm’s response to the previous inspection may have been acceptable, they did not implement effective/corrective/preventive actions to ensure a permanent ‘fix’ for the problem. This type of statement suggests that additional enforcement actions may be forthcoming.
- Is the 483 issued to an executive? Is the 483 addressed to the CEO of the company rather than the head of the site at which the inspection was conducted? If so, it is yet another suggestion that the FDA is sending a message to the corporation regarding the seriousness of the inspection observations.
- Do the areas addressed include lack of data integrity and poor aseptic practices with potential for contamination or cross-contamination? This combination of problems, particularly in the past few years, has frequently resulted in a warning letter or additional enforcement action.
- How many investigators performed the inspection and who were they? If any are national experts, that is important because observations in their areas of recognized expertise often reflect an agency-wide focus and interpretation of requirements.
HOW TO RESPOND TO FDA 483S
What does it mean to officially respond to a 483 and, better yet, how can a 483 be avoided altogether? The answer can essentially be split into three parts:
- The Pre-Response
- The Response Itself
- The Post-Response
1. The Pre-Response
You can talk directly with the inspectors during and after the inspection to clarify points and understand their reasoning better. Inspectors are, in fact, directed to discuss all observations with management as they are observed (or at least on a daily basis) in order to minimize any surprises down the line.
You don’t have to agree with every observation. Or, even if you agree with the observation itself and the facts used to get there, you might disagree that the observation represents an “objectionable condition or practice”; this is where you must know the law/code – the Federal Food, Drug, and Cosmetic Act Section 704(b) is all about factory inspections. Remember, the FDA can issue 483s under this authority:
“The observations of objectionable conditions and practices listed on the front of this form are reported:
- Pursuant to Section 704(b) of the FD&C Act
- To assist firms inspected in complying with the Acts and regulations enforced by the FDA”
“You don’t have to agree with every observation.”
Of course, don’t make excuses (i.e. “Come on, we’re just a struggling company trying to survive. Cut us a break?”). If you disagree with the facts of the observations or that the observations are objectionable, back up your claims with:
- Literature references
- Code references
- Other scientifically sound justifications
If you do feel that there is an error in the 483, it is worth trying to correct it. After all, the 483 is a legal document and part of your company’s official history.
2. The Official Response
In short, the response must:
- Take a systemic and global approach. Don’t simply address the one or two examples in the observation that the FDA found problematic. Look broadly. Also, look across all company sites. FDA does not want to find the same problem at each of the company sites they inspect. That alone may be cause for additional actions.
- Be well-reasoned. Identify root causes, consider systemic issues, and look at specific issues. Explain things carefully and back it up by submitting data/documentation including revised SOPs, protocols, or other documented evidence. Many warning letters identify the failure to submit documentation and evidence as part of the 483 response.
- Be timely. Submit the response within 15 business days after the close of inspection if you want your responses to be considered by FDA when they decide whether to take additional enforcement action such as a warning letter. If you respond later than 15 business days, FDA is not required to consider your response as they decide on additional enforcement action.
- Be complete. Address every single observation (not just all of them in general), articulate a plan of action for each (including timelines, metrics, and monitoring systems). This should include short-term as well as long-term corrective actions to prevent a recurrence.
- Include a commitment/statement from senior leadership.
Also keep in mind that your response will be read by multiple people at the FDA, some of whom are not as technically familiar with your company or your technologies. At the very least, the following personnel will review your response:
- The investigator
- His/her supervisor
- A compliance officer at the district office
- Maybe other FDA headquarters
3. The Post-Response
This likely goes without saying, but once you submit the response, be diligent in executing the plan. At the end of the day, the 483 and your response to it is just one aspect of a broader relationship that your firm has with the FDA. It represents your commitment to the FDA, and rest assured that the FDA takes those commitments seriously. Tell them what you’re going to do and do it. If an unanticipated delay occurs in remediation, it is reasonable to communicate that delay to the FDA.
A BAD 483 COULD COST A COMPANY MILLIONS
We heard this from a reputable Head of Manufacturing of one of the largest biopharma companies in the world. While most pharma and medical device companies seem to learn quickly from everyone else’s mistakes, companies still occasionally get a “moderately bad” 483. And then what happens after that?
Internal teams are put together to address the issues. External (and expensive) consultants are brought in for specific expertise. Hundreds, if not thousands, of hours of remediation, training, process redesign, process implementation, and meetings occur. It’s not hard to imagine the bill running up.
“Forget about actual warning letters. The cost of us receiving a moderately bad 483 is roughly $250,000.”
One of our co-founders spoke to a former VP of Quality at a PDA/FDA Joint Regulatory Conference in 2016. He said one of his bad 483s probably cost him $5,000,000. The 483 was simply the symptom of a deeper problem that he decided to proactively fix across all 40 sites.
That’s just a 483. What about a warning letter? There is an even greater magnitude of:
- Reputation Damage. FDA warning letters are public information, and the business media love to draw attention to these. Even if the warning letter can be easily fixed, companies inevitably take a hit from being in the negative news cycle. This has a ripple effect on shareholder and stakeholder confidence.
- Impact on New Drug Approvals. In many cases, the FDA can put on hold any New Drug Application that may be impacted by the site in question. For instance, one Wall Street Journal article discussed an instance in which Boston Scientific was forced to delay the launch of a new product by two years due to a quality issue at one of their sites. This event cost the company the majority of their market opportunity.
- Competitive Response. In some instances, competitors will leverage the opportunity provided by the warning letter’s effects by implementing a short-term marketing or promotional push to grab additional market share. This can further damage the company’s prospects.
- Loss of Business. Depending on the severity of the warning letters, state and federal governments, insurance companies, and other business entities may cancel, postpone, or delay business contracts with the company. Tied to reputational damage, consumers may simply opt for the competitor product. A McKinsey Case Study on the medical device industry provides three examples of this kind of sales loss ranging from $270,000,000 to $600,000,000.
- Management Attention. Once a 483 or warning letter is received, companies must dedicate management time and resources to solving the urgent matter at hand. In the most ideal case, management will also dedicate resources to solve any systemic problems through a deeper root cause analysis. The WSJ article cited above notes a case in which Stryker spent $200,000,000 in an attempt to fix compliance/quality issues.
Another pricey item from the FDA worth mentioning here is the Complete Response Letter (CRL).
No matter how you look at it, receiving a CRL after the FDA reviews your new or generic drug application will always cost you money. Just how much money depends on the situation. Here’s what you should look out for:
- List of Deficiencies: FDA uses CRLs to cite issues that must be addressed before it will review the application again. If the issues cited require more clinical trials, get ready for a gush of funds flowing out the door. On the other hand, if the disclosed issues are limited to your new manufacturing facility instead of with the drug itself, the comparative amount feels more like a slap on the wrist.
- Shareholder Reaction: Failure to inform shareholders about receiving a CRL will most likely result in litigation; however, full disclosure of the specific details of the letter are not required. If you receive a CRL for your new drug application and don’t provide the details of the specific issues cited, stakeholders might read between the lines and begin to bail on you. If you are a large company like Amgen, you’ll probably be able to weather the storm pretty easily. But if you are a smaller biotech company, it might mean the beginning of the end for you.
A colleague once walked through the parking lot of a large biopharma company and saw a mid-tier Porsche with license plate “Zero483s.” Now we know – that’s an achievement worth at least a $100,000 car.
(NOTE: Stay one step ahead of the FDA and avoid getting a 483 by knowing what observations your peers are getting. The best way to do this is with a 483 Observation Report. You can get one here.)
HOW THE FDA AND THE 483 HAVE CHANGED
We asked our GMP Editor in Chief three important questions and got three insightful answers. Using decades’ worth of professional experience, she shares both the strengths and weaknesses of the 483.
What are one or two key ways you’ve seen the FDA change over the last ten years?
I think the most important change over the past ten years has been the FDA’s shift to become globally active in GMP enforcement as the drug supply chain changes. Some of the countries to which manufacturing is outsourced have differing interpretations of US GMPs and have regulatory authorities that may not be as mature as, for example, the FDA or EMA.
The FDA is not the only regulatory authority impacted by this change. As a result, we see the FDA collaborating with other regulatory agencies, such as the EMA, so that both may make the most effective use of their resources. This also requires the FDA to develop new ways to assess the risks posed by the sites they regulate and focus inspections on those who pose the most significant risk to patient safety.
How do you use 483s in your role?
483s provide an early warning of what investigators are evaluating during inspections. The challenge is that they are only “observations”, rather than confirmed deficiencies in GMP operations.
The information in a 483 is also provided without context and that needs to be considered. Sometimes an investigator has a particular area of focus where they are trying to make a point.
Now, with all of those caveats, 483s are very useful in identifying the specific instances that were troubling to investigators. My focus is not on finding the specific statement that identifies the regulation in question. I’m interested in the actual activity that the FDA found problematic.
And when they include page after page of examples for a single finding statement, I conclude that this is a significant problem area within the company and not just a one-off event.
Simply counting the number of 483 items doesn’t give an accurate perspective on the firm’s GMP status. The FDA might identify a single item that could be expensive and time-consuming to remediate, or they could identify four or five that could be addressed fairly quickly.
A 21-page 483, however, strongly suggests that the firm may have a broad range of activities that need remediation. Also, if the 483 was issued to a company who received multiple warning letters within the past few years, it suggests a global problem that the firm has likely not addressed in an effective manner. In this case, I will generally re-read the warning letters and other 483s issued to the company, even if issued to different sites.
Bottom line, 483s are important pieces of the puzzle when trying to understand the GMP enforcement environment. But they should be considered within the incomplete context of the examples, scope, and other actions that may have been taken against the firm in question. Avoid over interpreting, but don’t ignore them either. They are a key piece of the puzzle.
Do you think FDA 483s have become more or less important over time, and why?
I think 483s remain important and how the firm addresses them has become more important. Years ago, companies and the FDA would have multiple rounds of communication about responses to a 483 before the FDA agreed to the firm’s corrective actions or the FDA progressed to a warning letter.
“A firm now has one chance to convince the FDA that they have the issue(s) in hand and are taking appropriate action.”
An announcement in the Federal Register on August 11th, 2009 changed that time frame. Now a firm has 15 business days to respond, and that response will be considered when deciding whether or not to take additional compliance action.
So, a firm now has one chance to convince the FDA that they have the issue(s) in hand and are taking appropriate action. Similarly, an unsatisfactory response may lead to a warning letter and/or additional compliance actions like a seizure.
For products manufactured outside the US, imposition of an import alert can have financial consequences for the company. Consent decree agreements and fines can also have financial consequences including the “lost opportunities” category while the firm is focusing on meeting the requirements of the agreement.
Downplaying the 483 content and, more importantly, not responding seriously and completely to the observations can have unfortunate costly consequences.
Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483s, InspectorProfiles, Enforcement Analytics, and GMP Regulatory Intelligence. Contact us if you ever have questions at [email protected].
About the Author
Michael de la Torre is the CEO of FDAzilla.