United State Food and Drug Administration (USFDA) and Form 483 and Warning Letters at a Glance

Who is USFDA :

The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services. The FDA was empowered by the United States Congress to enforce the Federal Food, Drug, and Cosmetic Act, which serves as the primary focus for the Agency.

The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate. The Commissioner reports to the Secretary of Health and Human Services. The FDA has its headquarters in unincorporated White Oak, Maryland.

FDA’s organization consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency.

Responsibility of FDA :

  • Protecting the public health by assuring that foods are safe, wholesome, sanitary and properly labeled; ensuring that human and veterinary drugs, and vaccines and other biological products and medical devices intended for human use are safe and effective.
  • Protecting the public from electronic product radiation
  • Assuring cosmetics and dietary supplements are safe and properly labeled
  • Regulating tobacco products Advancing the public health by helping to speed product innovations
  • FDA’s responsibilities extend to the 50 United States, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions.
  • To provide Approval of new drugs & to Perform routine inspection of a regulated facility
  • Inspect the foreign manufacturing and processing sites for FDA-regulated products that are sold in the United States
  • To perform pre-approval inspection after a company submits an application to FDA to market a new product.
  • “for-cause” inspection to investigate a specific problem that has come to FDA’s attention

What is Form 483 :

The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act. Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. It is also referred to as “Form 483” or merely “483”.

A recipient of a 483 should respond to the FDA, addressing each item, indicating agreement and either providing a timeline for correction or requesting clarification of what the FDA requires.

This response must be submitted within 15 business days.

When is an FDA Form 483 issued :

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 in 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 may injurious to health.

What is the purpose of an FDA Form 483 :

The FDA Form 483 notifies 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. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan.

How is the FDA Form 483 shared with the company :

FDA Form 483s are discussed with a company’s management at the conclusion of the inspection. Each observation is read and discussed so that there is a full understanding of what the observations are and what they mean.

What are the implications of the Form 483 for agency enforcement :

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, (EIR) 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.
The FDA calls for a response to the Form 483 observations within 15 working days.

What is FDA Warning Letter :

An FDA warning letter is an official message from the United States Food and Drug Administration (FDA) to a manufacturer or other organization that has violated some rule in a federally regulated activity which is identified by Inspectors or agency during  inspections or investigations .

A Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act .

When FDA Issues Warning Letter :

  • The FDA calls for a response to the Form 483 observations within 15 working days. Though a written response is not mandatory, it is preferred so that a warning letter can be avoided.
  • The company has to respond to the observations in detail with reasons for the shortcomings and corrective action plans and each observation should be addressed individually.
  • If the management does not convincingly address the Form 483 observations within the specified time period, the FDA issues a warning letter.
  • Sometimes, if the observations are of a severe nature, the FDA may issue a warning letter even without issuing Form 483.
  • The firm’s compliance history, e.g., a history of serious violations, or failure to prevent the recurrence or repeat of violations .
  • The nature of the violation, e.g., a violation that the firm was aware of (was evident or discovered) but failed to correct.
  • The risk associated with the product and the impact of the violations on such risk.

Conclusion :

Unsatisfactory response to the warning letter could lead to further action including import alert for products or the facility, withholding of product approval, and suspension or cancellation of manufacturing license.

Many pharma stocks have taken a beating in the recent past due to adverse Form 483 observations and their escalations into warning letters and import alerts.


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