What is a Form 483?
Form 483 is an observation document used by the US Food and Drug Administration (FDA) to record and communicate objectionable conditions discovered during inspections of facilities related to the manufacturing, processing, packing, or holding of food, drugs, medical devices, or biological products in the United States. The FDA is authorized to perform such inspections under the Federal Food, Drug, and Cosmetic Act, Sec. 704. The form is also known as "Inspectional Observations" or "483."
The 483 contains information on observations made by the FDA representatives during the inspection of the facility. It includes the FDA district issuing office that performed the inspection, the date(s) of inspection, the name and address of the facility that was inspected, the name and title of the individual to whom the 483 is issued to, a brief description of the type of facility, and the facility's FDA Establishment Identification (FEI) number. The observations are the opinion of the FDA investigator and may be subject to review by other FDA personnel. They are not the final determination regarding the company's compliance.
Observations
The observations listed in the form are not an exhaustive listing of objectionable conditions. The FDA typically includes only significant observations that can be directly linked to a violation of regulations. Observations of questionable significance should not be on the 483 but should have been discussed with the firm's management so that they understand how uncorrected problems could become a violation. The form also contains a section for annotation, where the FDA investigator(s) offer to annotate the 483 with information on whether the problem has been corrected or is under consideration.
The FDA also inspects facilities that produce cellular and tissue-based products, which it refers to as "human cells, tissue (biology), and cellular or tissue-based products" (HCT/Ps), under 21 CFR 1271 Subpart F. Observations for these facilities are captured on a 483 to protect the health of consumers.
Although the FDA has jurisdiction only within the United States, the agency has an interest in assuring that foreign operations part of the U.S. supply chain are in an appropriate state of control, even though they have no legal authority to do so. Therefore, the agency performs foreign inspections, and observations for these are also captured on a 483. Regardless of the local language, the 483 are written in English.
Causes of an Observation
An FDA 483 observation can be very expensive, resulting in thousands or even millions of dollars in costs for some companies. If the issues are systemic, the Form 483 observation can trigger training, redesign, process implementation, and other measures.
Handling these problems all at the same time can be expensive and disruptive to a company. It’s far better to anticipate issues that might result in a Form 483 and build 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.
- Inadequate training.
- Inadequate controls.
Taking the time to be diligent with written procedures can help prevent a company from receiving a 483. SOPs (standard operating procedures) are required for document control, risk management, design controls, and many other aspects of device manufacturing.
Regulators want evidence that a company has outlined a way to handle these fundamental processes, otherwise they may issue a Form 483 observation. If a company does receive a Form 483, there are a few rules around responding that should be considered.
How to Respond to FDA Form 483
The recipient of a 483 should respond to the FDA with a corrective action plan within 15 business days, regardless of the number of observations. The response should address each item proactively, indicating agreement and either providing a timeline for correction or requesting clarification of what the FDA requires.
While a response is not compulsory, a good response can usually help a company avoid receiving a Warning Letter from the FDA, withholding of product approval, or plant shut-down. Most experts recommend that responses be comprehensive, well-reasoned, well-documented, and timely, and that each observation should be addressed individually.
The FDA encourages resolution of issues through informal mechanisms before issuing a 483. After issuance, manufacturers can use a formal two-tiered dispute resolution process described in the FDA document Guidance for Industry - Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP, and they have 30 calendar days to do so.
Summary
Form 483 is a crucial document used by the FDA to document and communicate concerns discovered during inspections of facilities related to the manufacturing, processing, packing, or holding of food, drugs, medical devices, or biological products in the United States. It provides important information for the recipient to address the concerns and improve compliance. The recipient should respond to the FDA within 15 business days, and the response should be comprehensive, well-reasoned, well-documented, and timely, addressing each observation individually.
