The FDA uses various inspections Forms to support their inspection and surveillance activities. The following blog describes each of FDA forms and when and how they are used

FDA 482 Notice of Inspection

An FDA 482 may conduct an inspection of your operation for a variety of reasons, such as a routinely scheduled investigation, a survey, or a response to a reported problem. The investigator will present credentials and “Notice of Inspection” (FDA Form 482) upon arriving at your facility.

FDA may conduct an inspection of your operation for a variety of reasons, such as a routinely scheduled investigation, a survey, or a response to a reported problem. The investigator will present credentials and “Notice of Inspection” (FDA Form 482) upon arriving at your plant. A knowledgeable person in your firm, such as the head of quality or plant manager, preferably designated ahead of time, should always accompany the investigator. It is in your best interest to fully understand FDA’s inspection procedures. When you are unsure of certain actions taken by the investigator, don’t hesitate to ask questions.

Arrival of the FDA Inspector and Initial Meeting

Companies should have written procedures that detail the process of how to manage an FDA inspection.
Before an inspection ask the inspector to provide the Form 482 – Notice of Inspection if they do not present it or if the inspector declines to provide the notice in writing, the inspection may be part of a criminal investigation and require a search warrant. Contact your company’s General Counsel immediately. The following is an example of the process steps:

Greet the FDA inspector at a previously specified location and take them to the reserved inspection room for the initial meeting.
The inspection coordinator should greet the inspector, or otherwise make sure front desk staff know what to do when the inspector arrives.
At the beginning of the initial meeting, the inspector must present their badge/credentials to the company representative (QA or Plant Manager or other designee) to verify that they are in order.
Document all information from the inspector’s identification (however, making copies of identification badges is prohibited).
Ask the inspector to see their credentials if they do not present them. The inspection should not commence if the inspector does not present their credentials.
The inspector will then present a Notice of Inspection (Form 482) to the company representative. This notice authorizes the inspection, and its presentation officially begins the inspection. Retain a copy of the Form 482.
The inspector will explain the intended purpose and scope of the inspection. Make sure to clarify whether the inspection is routine or for-cause.
The inspector may ask the company representative to give an overview of the area and manufacturing processes of the facility. The company may consider utilize a PowerPoint presentation for this overview.
The inspector may ask for a tour of the facilities. The inspection coordinator or assistant should always stay with the inspector during any tour. Inform other staff when the inspector will be on a tour of the facility.
Inform the inspector of who to contact and how if they need anything. If there are multiple people, providing a list of contacts may be useful.
Request that the inspector provide a summary of observations at the end of each day.

483 Observation

An FDA 483 observation, or “inspectional observation,” is a notice sent by the FDA to document regulatory violations found during a routine inspection. This can relate to the company’s facilities, equipment, processes, controls, products, employee practices, or records, etc.
An FDA 483 observation can be very expensive if not properly addressed, resulting in thousands or even millions of dollars in costs for some companies. If the issues are systemic, the Form 483 observation can produce many extensive compliance efforts such as retraining, facility and equipment redesign, process implementation, and other measures.

Usually, the investigator will examine your production process, look at certain records and collect samples. At the conclusion of the inspection, the investigator will discuss with your firm’s management any significant findings and concerns; and leave with your management a written report of any conditions or practices, which, in the investigator’s judgment, indicate objectionable conditions, or practices.

This list of “Inspectional Observations,” also called an FDA Form 483, can be used by your firm’s management as a guide for corrective action, since the FDA representative will not usually recommend specific corrective measures. Your firm can and should respond to the FDA-483 during the discussion with the investigator. In fact, corrective actions or procedural changes that were accomplished immediately in the presence of the investigator are regarded as positive indications of your concern and desire to voluntarily correct discrepancies.
If you do not agree with the actions being taken by the FDA or if you have a question about the jurisdiction of the agency in a particular matter, you can contact the FDA’s Office of the Ombudsman to seek a resolution.
Handling these problems all at the same time is expensive and disruptive to your company. It’s is important to be proactive to manage issues that might result in a Form 483 and build your processes to avoid that scenario.
The most common causes of a 483 observation are:

Procedures not fully followed.
Poor investigations of discrepancies or failures (CAPA process not used).
Absence of written procedures.
Lack of proper training
Critical system not properly validated or not validated at all.
Poor equipment design and maintenance, lack of hygiene and aseptic practices that can cause a potential adulteration of product.
Data integrity issues

Taking the time to be diligent with your written procedures and properly training staff on procedures can help prevent you from receiving a 483. SOPs (standard operating procedures) are required for document control, risk management, design controls, and many other aspects of GMP manufacturing.
Regulators want evidence that your company has outlined a way to handle these fundamental processes, otherwise they may issue a Form 483 observation. If you do receive a Form 483, there are a few rules around responding you should consider.

How To Properly Respond to An FDA Form 483 Observation

The FDA Form 483 does not constitute a final agency determination and firms are encouraged to respond to the FDA Form 483 in writing with their corrective action plan with supporting documentation within 15 business days from the issuance of the FDA Form 483 and implement the corrective action plan expeditiously.

Once you’ve received a Form 483 observation, you should request to review the document with the FDA inspector. This will give you a better understanding of their concerns. You can streamline the inspection process by addressing questions during the inspection process, coming to terms with the observations made, and identifying any potential errors in their observations. “Never be argumentative, always maintain professional demeanor”. I have seen incidents where inspections have gone poorly because one of company’s representative argued the merits of observation based on emotions instead of presenting supportive objective events.

You are obligated to respond to an FDA 483 observation in writing within 15 days. Before an inspector leaves your facility, you’ll receive a draft of their inspection report (known as an Establishment Inspection Report, or EIR) as well as drafts of any 483 observations. They’ll ask you whether you plan to address those observations, too.

Failure to demonstrate that the observed problems have been handled can result in an FDA warning letter. In our experience, companies who choose not to take action to resolve issues raised in a Form 483 observation tend to end up with a warning letter later.

484 Receipt for Sample

During the inspection, if FDA inspectors want to take any sample, they must issue a receipt of those samples on Form 484. It has the quantity of samples with the lot number of the product sampled.

463 Affidavit

An affidavit is produced by the production authorities declaring the receipt and use of the raw material used in product manufacturing after the completion of the FDA audit.

Closing Notes

Remember, after an FDA inspection this is an opportunity to address all internal company GMP issues; typically, a risk-based GAP analysis can help in finding internal system GAPs within a company’s processes. If you receive a 483 observation, consider it to be fair warning that your company’s processes have potential problems, and the FDA observation may have only touched the surface of the issues. It may be worth your time to investigate those and other issues further. If not, the alternative is getting a warning letter or worse a consent decree.
Next Blog will discuss what to do during inspections and once you received Forms, 482 “Notice of Inspection”, 483 “Observation”, 484 “Receipt for Sample” and 463 “Affidavit how to manage it.