When you are working for a drug manufacturing unit, clinical trials facilities, or a medical device company, you can expect random and routine inspections by FDA. The FDA regulates food, medicines, vaccines, medical devices, cosmetics, and tobacco products. The riskiest stake a pharmaceutical company can make is to be questionable for its quality practices by the Food and Drug Administration (FDA). When the FDA inspects such facilities, they can either alert the company ahead of time or show up unannounced. Once the inspection is over, FDA prepares a list of discrepancies and will send what is called an FDA form 483, and later a warning letter based on the observation of inspection.

All you need to know about FDA Form 483 and Warning Letter

Depending on the number and severity of the observations made by the inspector, this report could have serious consequences for pharma companies or medical device manufacturers inspected. Loss of revenue, time spent on improving compliance processes, and reputational damage are some of the potentially calamitous effects of a Form 483 and a Warning Letter. Get ahead of Form 483’s by getting a Part 11 compliant and validated learning management system.

In this blog, we will explore what a Form 483 and a Warning Letter is, and how pharma and medical device companies can ensure they operate within a culture of compliance. Before we proceed further, it is necessary to understand that receiving a Warning Letter or FDA 483 does not signal the end of the product, or the company. There are clear procedures to follow to overcome this hurdle.

What is FDA form 483 observation?

An FDA Form 483 Observation, also referred to as “inspectional observation” or “Form 483” is sent by the FDA to highlight any potential regulatory violations found during a routine inspection. The FDA Form 483 Observation can relate to the company’s facility, equipment, processes, controls, products, employee practices, or records.

An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific, and significant. Observations are made when the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device, or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.

What is the purpose of an FDA Form 483?

The purpose of the FDA Form 483 is to notify the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Before leaving the facility, the inspector will submit any FDA Form 483 Observations. Upon receipt of the FDA Form 483 Observations, the company has 15 days to respond. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.

An FDA Form 483 is not a final interpretation on regulation violations, they are reasons for concern and need to be addressed with urgency. The financial impact of an FDA Form 483 Observation can cost companies several million dollars. The FDA Form 483 Observation can trigger training, redesign, process implementation, and other measures.

What are the implications of the FDA Form 483 for agency enforcement and what happens next?

The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company. The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.

Let’s have a look on how the FDA enforcement series flows:

Know about FDA Form 483 and Warning Letter

Most common causes of a 483 observation:

  • Procedures not fully followed: The Pharmaceutical industries must have established standard operating procedures (SOPs) and modify them in a timely manner in order to provide evidence of compliance, quality and commitment to safety. SOP records must be centrally located and readily available to investigators. When employees aren’t given accurate or current written instructions for their tasks, or if they do not clearly follow written instructions, mistakes and quality problems certainly occur.
  • Poor investigations of discrepancies or failures: The deviations from written procedures are required to be thoroughly investigated and document the results of those investigations. If the company is unable to identify root causes and document them sufficiently, the FDA regards their internal investigations as incomplete. Failure to investigate quality events can result in consequences for a pharmaceutical or life sciences company.
  • Absence of written procedures: As per the FDA observations, written procedures are missing in different pharmaceutical facilities. Companies are not following the rule of thumb rule regarding regulatory industries, i.e., write what you do and do what is written. Many companies struggle to manage and control written procedures, as it can be time consuming and requires additional efforts, especially if the organization is dependent on paper-based processes, or if the documentation is scattered between multiple systems in different locales. When deviations or other similar events are not adequately documented or tracked in Pharma manufacturing environments, it’s impossible to pinpoint root causes and take the appropriate corrective and/or preventive actions.
  • Data integrity issues: Data integrity has become a common issue in the life science industry. FDA and WHO recently published their data integrity guidelines. This is a frequent issue but very easy to eliminate and doesn’t require working too hard. See how eLeaP can help. FDA found data integrity issues more than 125 times during inspection in the last one year, where the data was not secure in the computer system. Digital or physical records must be protected with documented procedures by the companies.
  • Cleaning, sanitizing, and maintenance: Cleaning issues in manufacturing facilities are frequently observed during investigation. Proper cleaning and sanitization of equipment is essential in order to achieve a quality product. FDA can raise an observation if the schedules for the adjustment, cleaning, and other maintenance of equipment have not been established and followed.
  • Environmental monitoring: Many companies don’t take environmental monitoring seriously, especially manufacturing facilities. But the FDA takes it seriously and expects environmental monitoring to be followed especially for sterile facilities. A proper environmental monitoring program must be prepared and implemented in all classified areas of the facility. Environmental monitoring must be performed with schedule intervals and should be monitored.

How to prepare for an FDA inspection:

Life science organizations should always be inspection ready. Although, there’s no way of controlling what happens during an FDA inspection, but there are things a company can do to prepare for it as best they can:

  1. Close out all CAPAs and ensure that root analysis is performed
  2. Ensure Data Integrity regulations are followed
  3. Ensure to document all procedures, activities, protocols etc.
  4. Maintain simplified SOPs and update them regularly
  5. Ensure staff are well trained on company procedures and have sound understanding of the procedures followed
  6. Ensure the compliance and quality is followed
  7. Perform mock inspections regularly to ensure staff know what to expect and everything is kept up to date.
  8. Ensure the data is readily available on request.

What to Do After Receiving an FDA Form 483 Observation

If you have received an FDA Form 483 Observation, it needs to be handled with care. First and foremost, the document must be reviewed with the inspector before he/she leaves the facility. One should have full understanding of the observations and what needs to be done to correct the issues.

Before the inspector leaves, be sure to:

  • Gain an understanding of observations noted and assure their accuracy
  • Understand the broader message the FDA is sending
  • Identify and discuss any errors in the observations
  • Ask questions
  • Demonstrate awareness of applicable regulations
  • Consult with legal counsel as necessary

Companies should send the response within 15 days, or the FDA will not be required to consider your response in their decisions for subsequent actions. Once your response is submitted, the FDA will review the Form 483 Observations along with an Establishment Inspection Report and your response. The agency will use this information to determine what further actions to take.

FDA Form 483 Trends 

Let’s have a look at the 483 trends from fiscal year 2020-2021. The below data describes the product and program areas along with the number of the 483 issued:

Form 483 Trends

What is a Warning Letter?

After a Form 483 is issued and the inspector has completed an Establishment Inspection Report, the regulatory agency may issue a Warning Letter. When a serious violation is found regarding the quality of the product, a Warning Letter is issued by the higher officials after reviewing the observation. The letter makes clear that the company must take action to correct the problem and provides directions and a timeframe for the organization to inform the FDA of its plans for correction.

What is the difference between the FDA Form 483 and the Warning Letter?

After going through the above details, it’s clear that the Form 483 is a notice to inform the company about the potential regulatory violation, while a Warning Letter is a serious escalation of this notice. The company must respond to the FDA in writing within 15 days of receiving a Form 483 and a Warning Letter.

Form 483 is not a final determination on regulation violations, they are concerns which need to be addressed with urgency while a warning letter is an official deficiency letter issued when the quality and compliance are considered as unacceptable. Not all 483 observations result in a Warning Letter, but the companies must respond and must be willing to comply with the FDA regulations.

What to Do After Receiving an FDA Warning Letter

When the FDA determines that a company has significant deficiencies with their regulatory policies and issues a Warning Letter, here’s how to respond to the issues raised. The following 4 steps should be taken:

  1. Create Corrective and Preventive action plan
  2. Immediate acknowledgement of the receipt of letter
  3. Develop an action plan to mitigate the issues if one has not been developed. If a plan has been in place, modify it accordingly
  4. Determine most experienced person in the quality group to prepare a written response to the Warning Letter

Be proactive and prevent compliance issues 

Companies must always be ready for random FDA inspections. They should keep having the mock-up inspection in order to be ready for the actual one. They should know the most efficient way to avoid Form 483 and know how to respond. If a company has a strong internal audit procedure, this will significantly improve its chances of avoiding a 483 observation. Adhering strictly to quality control regulations and following internal procedures at all times will help staff operate at a consistently high level. Check out a sandbox of eLeaP to allow you to comply with FDA’s 21 CFR Part 11 regulations.