Form FDA 483
Encyclopedia
The U.S. Food and Drug Administration
(FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act
, SEC. 704 (21 USC
§374) "Factory Inspection". Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. Also referred to as "Form 483" or merely "483"
, it states thereon that it
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 regardless of the number of observations, as of September 2009. 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 warn that responses should 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 prior to the issuance of 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.
The FDA refers to cellular and tissue-based products as “human cells, tissue (biology)
, and cellular or tissue-based products” (HCT/Ps). To protect the health of consumers, the agency also inspects these facilities and documents observations on a 483. The authority to do so is granted by 21 CFR 1271 Subpart F.
The US FDA has jurisdiction only within the United States
. However, the supply chain
for pharmaceuticals often extends far beyond the boundaries of the US, so the agency has an interest in assuring that foreign operations part of the US supply chain are in an appropriate state of control, even though they have no legal authority to do so -- although they can restrict importation into the US. The agency therefore performs foreign inspections, and observations for these are also captured on a 483. Regardless of the local language, the 483 will be written in English.
Inspections began in 2011 in various countries to ensure compliance with the FDA's regulations concerning food. These inspections are directed to selected food processors in the fields of diary, fish, processed products, and are expected to expand to other commodities. This marks the beginning of Form FDA 483 being issued to foreign food processors.
The 483 then has a large area for recording the observations, which may be continued on several pages. The observations should be ranked in order of significance. If an observation made during a prior inspection has not been corrected or is a recurring observation, that may be noted on the 483.
The FDA will typically include only significant observations that can be directly linked to a violation of regulations — not suggestions, guidance, or other comments. ("Significant" is somewhat arbitrary and may be subject to the bias
of a particular inspector.) 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 483 will not normally include actual regulatory references.
The actual annotation of the 483 occurs during the final discussion with the firm's management; if the firm prefers no annotation, then annotation will not be performed. The annotations may be after each observation, at the end of each page, or at the bottom of the last page prior to the investigator's signature(s).
Addenda/amendments are not normally used for adding observations to a 483 after the inspection has been closed out and the investigator(s) have left the premises.
but may be redacted
to remove non-public information.
The FDA publishes select 483s on their website at this location:
Some third parties query the FDA and publish a listing of Form FDA 483s issued since 2000.
As of 21-Nov-2009, the FDA is seeking input from the public "on whether inspection reports should be re-designed to separate out a summary or key findings page that could be made available to the public quickly." Responses from the public can be submitted on the FDA's web site.
programs. Investigations accounted for 27% of the observations in 2009. The next most problematic areas were Equipment/Facilities/Operations
at 11% (2009) and Validation
at 10% (2009).
The FDA issued 9,910 483s in 2010, which is at least a 10-year high based on available data. Among these, the top three issues were quality unit deficiencies, inadequate batch failure investigations, and lack of follow-up procedures. For international inspections, the top three were deficient laboratory controls, quality unit deficiencies, and deficient procedures.
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act
Federal Food, Drug, and Cosmetic Act
The United States Federal Food, Drug, and Cosmetic Act , is a set of laws passed by Congress in 1938 giving authority to the U.S. Food and Drug Administration to oversee the safety of food, drugs, and cosmetics. A principal author of this law was Royal S. Copeland, a three-term U.S. Senator from...
, SEC. 704 (21 USC
United States Code
The Code of Laws of the United States of America is a compilation and codification of the general and permanent federal laws of the United States...
§374) "Factory Inspection". Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. Also referred to as "Form 483" or merely "483"
, it states thereon that it
“...lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance”
A recipient of a 483 should respond to the FDA, addressing each item, indicating agreement and either providing a timeline
Timeline
A timeline is a way of displaying a list of events in chronological order, sometimes described as a project artifact . It is typically a graphic design showing a long bar labeled with dates alongside itself and events labeled on points where they would have happened.-Uses of timelines:Timelines...
for correction
Correction
Correction may refer to:* An euphemism for punishment* Correction , the posting of a notice of a mistake in a past issue of a newspaper* Correction , in financial markets, a short-term price decline...
or requesting clarification of what the FDA requires.
This response must be submitted within 15 business days regardless of the number of observations, as of September 2009. While a response is not compulsory, a good response can usually help a company avoid receiving a Warning Letter
FDA Warning Letter
The United States Food and Drug Adminstration defines a Warning Letter as "...a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations...
from the FDA, withholding of product approval, or plant shut-down. Most experts warn that responses should 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 prior to the issuance of a 483. After issuance, manufacturers can use a formal two-tiered dispute resolution
Dispute resolution
Dispute resolution is the process of resolving disputes between parties.-Methods:Methods of dispute resolution include:* lawsuits * arbitration* collaborative law* mediation* conciliation* many types of negotiation* facilitation...
process
Business process
A business process or business method is a collection of related, structured activities or tasks that produce a specific service or product for a particular customer or customers...
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.
The FDA refers to cellular and tissue-based products as “human cells, tissue (biology)
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
, and cellular or tissue-based products” (HCT/Ps). To protect the health of consumers, the agency also inspects these facilities and documents observations on a 483. The authority to do so is granted by 21 CFR 1271 Subpart F.
The US FDA has jurisdiction only within the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. However, the supply chain
Supply chain
A supply chain is a system of organizations, people, technology, activities, information and resources involved in moving a product or service from supplier to customer. Supply chain activities transform natural resources, raw materials and components into a finished product that is delivered to...
for pharmaceuticals often extends far beyond the boundaries of the US, so the agency has an interest in assuring that foreign operations part of the US supply chain are in an appropriate state of control, even though they have no legal authority to do so -- although they can restrict importation into the US. The agency therefore performs foreign inspections, and observations for these are also captured on a 483. Regardless of the local language, the 483 will be written in English.
Inspections began in 2011 in various countries to ensure compliance with the FDA's regulations concerning food. These inspections are directed to selected food processors in the fields of diary, fish, processed products, and are expected to expand to other commodities. This marks the beginning of Form FDA 483 being issued to foreign food processors.
Form FDA 483 content
The content of a 483 may be handwritten, typed, completed in a PDF file and printed, or completed via the FDA's computer system called Turbo EIR.Header information
The header identifies the FDA district office that performed the inspection, the date(s) of inspection, name and address of the facility that was inspected, the name and title of the individual to whom the 483 is issued to (usually the most responsible individual physically present in the facility), a brief description of the type of facility, and the facility's FEI (FDA Establishment Identification) number.Observations
This section starts with a "disclaimer" that the form contains the observations of the inspector and does not necessarily "represent a final Agency determination regarding your compliance." Observations placed on a 483 are the opinion of the FDA investigator and may be subject to review by other FDA personnel. The full text is as follows:"This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone number and address above.
"The observations noted in this Form FDA-483 [sic] are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self-audits to identify and correct any and all violations of the quality system requirements."
The 483 then has a large area for recording the observations, which may be continued on several pages. The observations should be ranked in order of significance. If an observation made during a prior inspection has not been corrected or is a recurring observation, that may be noted on the 483.
The FDA will typically include only significant observations that can be directly linked to a violation of regulations — not suggestions, guidance, or other comments. ("Significant" is somewhat arbitrary and may be subject to the bias
Bias
Bias is an inclination to present or hold a partial perspective at the expense of alternatives. Bias can come in many forms.-In judgement and decision making:...
of a particular inspector.) 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 483 will not normally include actual regulatory references.
Annotation
As of 1997, the FDA established an annotation policy for medical device inspections. The investigator(s) should offer to annotate the 483 with one or more of the following:- Reported corrected, not verified.
- Corrected and verified.
- Promised to correct (may be appended with "by xxx date" or "within xxxx days or months").
- Under consideration.
The actual annotation of the 483 occurs during the final discussion with the firm's management; if the firm prefers no annotation, then annotation will not be performed. The annotations may be after each observation, at the end of each page, or at the bottom of the last page prior to the investigator's signature(s).
Signatures
The investigators' names are printed and signed, and the date of issue is recorded in this section. Titles for the investigators may also be included. If the 483 is multiple pages, the first and last pages have full signatures while the intervening pages are only initialed.Converse side
The converse side of the form has this text:"The observations of objectional conditions and practices listed on the front of this form are reported:
- 1. Pursuant to Section 704(b) of the Federal Food, Drug and Cosmetic Act, or
- 2. To assist firms inspected in complying with the Acts and regulations enforced by the Food and Drug Administration.
"Section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 USC374(b)) provides:
'Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him which, in his judgement, indicate that any food, drug, device, cosmetic in such establishment (1) consists in whole or in part of any filthy, putrid, or decomposed substance or (2) has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. A copy of such report shall be sent promptly to the Secretary.' "
Addenda/amendments
It is possible that an error is discovered by the inspector(s) after issuing the 483. If the 483 was generated via Turbo EIR, then an amendment is created within that system. Else, an addendum is created. If possible, the investigator(s) will personally deliver the addendum/amendment to the firm.Addenda/amendments are not normally used for adding observations to a 483 after the inspection has been closed out and the investigator(s) have left the premises.
Public access to Form FDA 483s
Form 483s are available under the Electronic Freedom of Information Act Amendments of 1996,but may be redacted
Sanitization (classified information)
Sanitization is the process of removing sensitive information from a document or other medium, so that it may be distributed to a broader audience. When dealing with classified information, sanitization attempts to reduce the document's classification level, possibly yielding an unclassified...
to remove non-public information.
The FDA publishes select 483s on their website at this location:
Some third parties query the FDA and publish a listing of Form FDA 483s issued since 2000.
As of 21-Nov-2009, the FDA is seeking input from the public "on whether inspection reports should be re-designed to separate out a summary or key findings page that could be made available to the public quickly." Responses from the public can be submitted on the FDA's web site.
Recent trends in Form FDA 483 observations
From 2002 to 2009, the dominant problem area documented on Form FDA 483 was Investigations, which are integral to good CAPACorrective and preventive action
Corrective action and preventive action are improvements to an organization's processes taken to eliminate causes of non-conformities or other undesirable situations. CAPA is a concept within good manufacturing practice...
programs. Investigations accounted for 27% of the observations in 2009. The next most problematic areas were Equipment/Facilities/Operations
Manufacturing operations
Manufacturing operations concern the operation of a facility, as opposed to maintenance, supply and distribution, health, and safety, emergency response, human resources, security, information technology and other infrastructural support organizations....
at 11% (2009) and Validation
Validation (drug manufacture)
Validation in the pharmaceutical, medical device, food, blood establishments, tissue establishments, and clinical trials industries is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the...
at 10% (2009).
The FDA issued 9,910 483s in 2010, which is at least a 10-year high based on available data. Among these, the top three issues were quality unit deficiencies, inadequate batch failure investigations, and lack of follow-up procedures. For international inspections, the top three were deficient laboratory controls, quality unit deficiencies, and deficient procedures.