We receive a lot of questions, especially from our international colleagues, about how FDA 483s are actually written – the whole “lifecycle”, if you will. Based on manuals and other FDA resources that are publicly available, we answer your 10 most frequently asked questions in this area. Especially if you are new to FDA 483s, this is for you. For the seasoned among you, this is a good review.

1. Can you give us an overview of the internal processes around the FDA Form 483?

FDA ORA Investigations Operations Manual 5.2.3 – REPORTS OF OBSERVATIONS

The FORM FDA 483 INSPECTIONAL OBSERVATIONS (see Exhibit 5-5³¹) is intended for use in notifying the inspected establishment’s top management in writing of significant objectionable conditions, relating to products and/or processes, or other violations of the FD&C Act and related Acts (see IOM 5.2.3.2) which were observed during the inspection. These observations are made when in the investigator’s “judgment”, conditions or practices observed, indicate that any food, drug, device, or cosmetic have been adulterated or are being prepared, packed, or held under conditions whereby they may become adulterated or rendered injurious to health. The issuance of written inspectional observations is mandated by law and ORA policy.

Be alert for specific guidance in assignments or Compliance Programs which may supplement the following general instructions.

All FDA-483s should adhere to the following general principles:

Observations which are listed should be significant and correlate to regulated products or processes being inspected.
Observations of questionable significance should not be listed on the FDA-483, but will be discussed with the firm’s management so that they understand how uncorrected problems could become a violation. This discussion will be detailed in the EIR.

All FDA-483s should have the following characteristics to be useful and credible documents:

Each observation should be clear and specific.
Each should be significant. Length is not necessarily synonymous with significance.
Observations should not be repetitious.
The observations should be ranked in order of significance.
All copies of the FDA-483 should be legible.

If an observation made during a prior inspection has not been corrected or is a recurring observation, it is appropriate to note this on the FDA 483.

As of 1997, ORA established a FDA 483 annotation policy for medical device inspections. See IOM 5.2.3.4. Regardless of whether an establishment’s FDA 483 is annotated, investigators and analysts should make every reasonable effort to discuss all observations with the management of the establishment as they are observed, or on a daily basis, to minimize surprises, errors, and misunderstandings when the FDA 483 is issued. This discussion should include those observations, which may be written on the FDA 483 and those that will only be discussed with management during the closeout meeting. Industry may use this opportunity to ask questions about the observations, request clarification, and inform the inspection team what corrections have been or will be made during the inspection process. Investigators are encouraged to verify the establishment’s completed corrective actions as long as the verification does not unreasonably extend the duration of the inspection.

As of April 2010, ORA established a policy of reporting positive environmental samples on the FDA 483 prior to closeout for food inspections. This policy is applicable only if the results are known before conclusion of the inspection; the investigator should not prolong the inspection to include the results.

There may be instances where same day discussion of observations may not be possible due to the volume of documents collected and document review reveals observations on a different day than the documents were collected or in other circumstances. When these instances occur immediately prior to the conclusion of the inspection the lack of a daily discussion of observations does not preclude listing of significant observations which were not previously discussed on the FDA 483.

Turbo EIR

Turbo EIR is an automated FDA 483 and EIR reporting system. Use Turbo EIR to generate the FDA 483 where applicable cite modules exist. Turbo EIR should not be used to create a FDA 483 during an inspection of a firm involving multiple commodity areas when FDA 483 cites do not exist for ALL of the commodity areas for which observations need to be included on the FDA 483. You should be able to write the entire FDA 483 using Turbo EIR.

Use Turbo EIR for all EIRs whether or not your FDA 483 was generated using Turbo and when no FDA 483 was issued. See IOM 5.10.4³².

5.2.3.1 – Preparation of Form FDA 483

It is not necessary to complete all headings of the FDA 483, when multiple page 483s are issued. Complete all headings on the first page and, on subsequent pages, only those necessary to identify the firm and dates inspected. FDA 483s should be issued at the conclusion of the inspection and prior to leaving the premises. However, in preparing some complex FDA 483s, it may be necessary to leave the premises and return at a later time to issue and discuss your inspectional observations. In this case, you should advise the firm’s management your inspection has not been completed and you will return to issue the FDA 483 and discuss inspectional findings. There should be no unreasonable or unwarranted delays in issuing and discussing the FDA 483. During the inspection, do not show the firm’s management a draft, unsigned copy of the FDA 483 or an electronic copy of the FDA 483 on your computer screen. You should issue only a signed FDA 483 at the closeout discussion with management.

5.2.3.1.2 – SIGNATURE POLICY

Everyone present at issuance signs the first and last pages of the FDA 483 and initials each intervening page in the signature block. Note: if you are not using the official multi-part FDA 483 form and a copier is not available, insert carbon paper to reproduce a signed copy of the FDA 483. (See IOM 5.2.3.6 – Distribution of the FDA 483.)

5.2.3.1.3 – DATE ISSUED

Enter the date the form is actually issued to the firm’s management.

5.2.3.1.4 – OBSERVATIONS

“During an inspection of your firm (I) (We) observed” – Where applicable, when formulating each FDA 483 observation, answer Who (using titles or initials when necessary), What, When, Where, How, and challenge each observation by asking So What? (regarding its significance)

Enter your reportable observations succinctly and clearly. Conditions listed should be significant and relate to an observed or potential problem with the facility, equipment, processes, controls, products, employee practices, or records. “Potential problems” should have a reasonable likelihood of occurring based upon observed conditions or events. Do not cite deviations from policy or guidance documents on your FDA 483.

As appropriate, FDA 483 observations should include relationship of observations to a given population, for example, “Two out of 50 records examined were * * *” or “4 out of 12 bags examined were ***.” When appropriate, a FDA 483 observation may refer to inadequate situations as long as you provide supporting facts (examples) or explanation as to why the condition, practice or procedure observed is inadequate.

It is preferred not to identify individuals or firms by name i.e., suppliers and consignees within the FDA 483. Where appropriate to support the FDA 483 observation, identify the individual(s) or firm(s) by substituting other non-specific identifying information as below. Document your evidence in your EIR, fully explaining the relationship(s).

The lot number for a component received from or shipped to firm “A”.
The invoice number for a shipment from or to firm “A”.
A patient #, record #. See IOM 5.2.3.3 item 7.
The study number for a particular Clinical Investigator site.
Other necessary but non-specific identifying information to show the observation’s relationship to a particular firm and/or individual.

Presently there are three ways to issue a FDA 483.

Turbo EIR Field Agent
Traditional hard copy FDA 483
Electronic (non-turbo EIR) version of the FDA 483.

When using a traditional hard copy FDA 483 or electronic (non-turbo) version of the FDA 483, the current version of the 483 must be used. As of the printing of the 2012 IOM, the current version of the FDA 483 is dated 9/08.

5.2.3.1.5 – MEDICAL DEVICE INSPECTIONS

The following language should be inserted on the FDA 483 in addition to the above statement: “The observations noted in this form FDA 483 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.”

5.2.3.1.6 – CORRECTION OF FDA 483 ERRORS

These procedures do not pertain to adverse conditions noted and then corrected during the inspection. Observations of this type stand and should remain on the FDA 483.

The Inspectional Observations (FDA 483) is of critical importance to both the Agency and regulated industry. Individual FDA 483s may become public through publishing in industry trade press, FOI inquiries, Headquarters postings and other means. Therefore, complete and accurate documentation of corrections to this official document is critical.

5.2.3.1.6.1 – Errors Discovered Prior to Leaving the Establishment

Non-Turbo, FDA 483s:

Make handwritten changes to correct the error/s on the original FDA 483 and initial the changes. Correct errors by striking through the erroneous text and entering the correct information (if any). When possible retrieve and destroy all uncorrected copies of the FDA 483 either provided to or produced by the establishment.
If the establishment has photocopying equipment available and will provide you with a copy of the corrected original FDA 483 then obtain a copy of the corrected original document from the establishment. If the establishment has no such equipment or refuses to provide you with you a copy of the original corrected FDA 483 then make the corrections and initial the changes using carbon paper and retain the carbon copy of the corrected FDA 483 for your District’s official establishment file.

Turbo FDA 483s – All corrections/deletions should be made in Turbo.

Changes made to correct errors in the text of the observation will show on the face of the final printed FDA 483. Changed Text deletions will remain visible as strike through and correction made. For example, “lot 1234 5678” – (select text, right click, select font and select strike-through) or from “lot 1234” to “lots 1234 and 5678” and bold the changes “lots 1234 and 5678”
If an entire observation is removed, incidental text will be used to add the statement “An observation concerning *** was removed based on discussion with management.”
Addition of a new item

5.2.3.1.6.2 – Errors Discovered after Leaving the Establishment

Normally, you should not use addenda/amendments to issue additional FDA 483 items after the inspection has been closed out and you have left the premises.

Non-Turbo, FDA 483s: Discuss any errors with your supervisor. If necessary a revised FDA 483 will be prepared.
Turbo FDA 483s: Discuss any errors with your supervisor. Make all corrections/deletions in Turbo. Changes made to correct errors in the text of the observation will show on the face of the final printed FDA 483. Changed Text deletions will remain visible as strike through and additions added.
Issuing FDA 483s: Personally deliver the revised and/or corrected FDA 483 addendum/amendment to the firm for discussion. If personal delivery is not practical, mail the addendum/amendment to the firm with a full explanation cover letter. Include a copy of the original FDA 483, and a copy of the letter in the EIR. In addition, you should call the person to whom the original FDA 483 was issued, to discuss the change(s). Document your discussion in your EIR.

5.2.3.2 – Reportable Observations

You should cite factual observations of significant deviations from the FD&C Act³⁵ [21 U.S.C. 301], PHS Act³⁶, 21 CFR³⁷, and other acts where FDA has enforcement authority unless these cites require concurrence or are specifically prohibited – see IOM 5.2.3.3 Non-Reportable Observations. Examples of these observations generally fall into two categories.

5.2.3.2.1 – ADULTERATION OBSERVATIONS

Review Sections 402³⁸, 501³⁹, 505(k)⁴⁰, 601⁴¹, and 704⁴² of the FD&C Act [21 U.S.C. 342, 351, 355(k), 361, and 374]. Include specific factual observations of:

Foods, drugs, devices, or cosmetics consisting in whole or in part of filthy, putrid, or decomposed substances.
Undesirable conditions or practices, bearing on filth or decomposition, which may reasonably result in the food, drug, device, or cosmetic becoming contaminated with filth.
Insanitary conditions or practices which may reasonably render the food, drug, device, or cosmetic injurious to health.
Careless handling of rodenticides or pesticides.
Results of field tests (organoleptic examination of fish, crackout of nuts, etc.) if the results revealed adulteration.
Observations of faulty manufacturing, processing, packaging, or holding, of food, drug, or device products as related to current good manufacturing practice regulations including inadequate or faulty record keeping.
Observations of faulty can closures and/or deviations from recommended processing times and temperatures.
Deviations from the animal proteins prohibited in ruminant feeds requirements (21 CFR 589.2000⁴³).
Results of analytical laboratory findings which reveal adulteration.

5.2.3.2.2 – OTHER OBSERVATIONS

You may include other factual observations of significant deviations from the FD&C Act⁴⁴ [21 U.S.C. 301], 21 CFR⁴⁵, Government Wide Quality Assurance Program (GWQAP) requirements, and other Acts as directed by CPs and other agency directives. In some cases, you may cite labeling deviations as directed below. This list is not all inclusive.

Observations indicating non-conformity with commitments made in a New Drug Application, New Animal Drug Application, or in an antibiotic certification or certification exemption form.
Observations, forming the basis for product non-acceptance under the Government Wide Quality Assurance Program (GWQAP). See IOM 5.2.3.5.
Deviations from blood and blood products labeling requirements as specified in 21 CFR 606.121⁴⁷ and 21 CFR 640⁴⁸.
Animal protein products, and feeds containing such products, that are not in compliance with the labeling requirements of paragraphs (c) through (f) of 21 CFR 589.2000⁴⁹. See Section 403(a)(1) or 403(f) of the FD&C Act⁵⁰ [21 U.S.C. 343(a)(1) or 343(f)].
Deviations from the applicable labeling regulations for human cells, tissue, and cellular and tissue-based products (HCT/Ps) as specified in 21 CFR 1271⁵¹ and CP 7341.002⁵².
Observations indicating drug misuse, failure to maintain proper drug use records, and/or poor animal husbandry practices during tissue residue investigations. See the applicable Compliance Program(s) for guidance.
Observations indicating non-conformity with the postmarketing adverse drug experience reporting requirements as specified in 21 CFR 310.305⁵³, 314.80⁵⁴, 314.98⁵⁵, 314.540⁵⁶, or 600.80⁵⁷ or other postmarketing requirements as specified in 21 CFR 314.81⁵⁸ or 600.14⁵⁹. See Sections 505⁶⁰ and 760 ⁶¹of the FD&C Act [21 U.S.C. 355(k)and 379aa].
Observations indicating non-conformity with the Medical Device Reporting requirements as specified in 21 CFR 803⁶² {See Section 519(a) of the FD&C Act⁶³ [21 U.S.C. 360i]}; the Medical Devices Reports of Corrections and Removals requirements as specified in 21 CFR 806⁶⁴ {See Section 519(f) of the FD&C Act [21 U.S.C. 360i(f)]}; and the Medical Device Tracking requirements as specified in 21 CFR 821⁶⁵ {See Section 519(e) of the FD&C Act [21 U.S.C. 360i(e)]}.
Observations indicating noncompliance with medical device pre-market notification requirements and pre-market approval requirement under FD&C Act sections 510(k)⁶⁶ and 515⁶⁷ [21 U.S.C. 360 (k) and 360e] respectively, should only be made with the prior confirmation of CDRH and/or CBER.
21 CFR PART 200.10⁶⁸ does allow reporting observations noted at a contract facility to the contracting facility. Before doing this, check with your supervisor to determine if this is appropriate.
Observations indicating non-compliance with LACF/Acidified food registration and failure to file scheduled processes. Before doing this, verify lack of such, as covered in CP 7303.803A⁶⁹.

5.2.3.3 – Non-Reportable Observations

Do not report opinions, conclusions, or characterize conditions as “violative.” The determination of whether any condition is violative is an agency decision made after considering all circumstances, facts and evidence. See IOM 5.2.7 involving discussions with management at which time opinions may be discussed. Do not quote Regulations (e.g., specific CFR sections) when listing items.

Do not report observations pertaining to:

Label and labeling content, except per IOM 5.2.3.2.2, items 2, 3, 4 and 5 above.
Promotional materials.
The classification of a cosmetic or device as a drug.
The classification of a drug as a new drug.
Non-conformance with the New Drug Regulations, 21 CFR 312.1⁷⁰ (New Drugs for Investigational Use in Human Beings: Exemptions from Section 505(a)) unless instructed by the particular program or assignment.
The lack of registration required by Section 415⁷¹ and 510 of the FD&C Act. ⁷²The lack of registration per 21 CFR 1271 Subpart B⁷³ Procedures for Registration and Listing, promulgated under Section 361 of the PHS Act.
Patient names, donor names, etc. If such identification is necessary, use initials, code numbers, record numbers, etc.
Corrective actions. Specific actions taken by the firm in response to observations noted on the FDA 483 or during the inspection are not listed on the FDA 483, but are reported in the EIR. Except as described in IOM 5.2.3.4.
The use of an unsafe food additive or color additive in a food product.

Use Turbo EIR to document in the “General Discussion with Management” section Non-Reportable Observations, which you discussed with management. These objectionable conditions fall into three basic categories:

Observations of significant deviations from specific Laws and/or regulations, non-reportable items 1-9 above.
Observations of deviations from specific Laws and/or regulations, which in your judgment, are of “questionable significance” and “deemed not to merit inclusion on the FDA 483,” but do warrant discussion with management.
Observations which in your judgment deviate from official published guidance, not regulations, but warrant discussion with management.

The reporting of observations in these 3 categories is as follows:

Category 1: You should select the appropriate Turbo cite, verify or set the “Print type” to “Do Not Print,” and save the observation in the Turbo database. This should be done even if there are no other reportable observations. For example, Lack of Food Registration as covered in IOM 5.4.1.5.3⁷⁴ is not reportable.

Category 2 or 3: You should always report these two categories of observations which were discussed with management under the “General Discussion with Management” heading in the EIR as specified by IOM 5.10.4.3.15⁷⁵. You have options in choosing how observations in category 2 are reported. You may select the appropriate cite in Turbo, enter the “specifically” text regarding the observation, and discussion with management, set it to “Do not print”, save, and it will be automatically entered into the Turbo EIR when it is generated.

The second option which is also true for category 3 (i.e., there are no Turbo cites for official guidance, only regulations) is the observation/s discussed with management may be entered directly into the Turbo EIR under the “General Discussion with Management.”

5.2.3.4 – Annotation of the FDA 483

Offer to annotate the FDA 483 for all medical device inspections. The district has discretion to annotate the FDA 483s in other program areas. BIMO inspections are generally excluded from annotations. Annotations of FDA 483s for inspections in other program areas may be done if both the establishment and the investigator/team believe annotation will facilitate the inspection process. When a FDA 483 is annotated it should be done in accordance with the guidance that follows.

Inform the establishment of the annotation program at some point prior to the final discussion with management. Determine from management whether they wish to have their FDA 483 observations annotated. It is voluntary on the part of the establishment. If the establishment does not want one or more observations annotated, you must honor the request.

The actual annotation of the FDA 483 should occur during the final discussion with management. The annotations are succinct comments about the status of the FDA 483 item. It is not permissible to pre-print or pre-format the annotations onto the FDA 483 form. The annotations can be made after each observation, at the end of each page of the FDA 483 or at the bottom of the last page of the FDA 483 prior to the investigator’s signature. The establishment should review the annotations on the issued FDA 483 to ensure there are no misunderstandings about promised corrective actions. See IOM 5.2.3 for discussions of FDA 483 observations with management.

If the establishment has promised and/or completed a corrective action to an FDA 483 observation prior to the completion of the inspection, the FDA 483 should be annotated with one or more of the following comments, as appropriate:

Reported corrected, not verified.
Corrected and verified.
Promised to correct.
Under consideration.

The term “verified” means “to confirm; to establish the truth or accuracy”. In this case, you must do the verification. In some situations, you will not be able to verify the corrective action unless there is further district or Center review or until there is another inspection of the establishment.

The establishment’s stated objections to any given observation or to the FDA 483, as a whole should not be annotated on the FDA 483. If they would prefer no annotation, do not annotate it. The EIR should include the establishment’s objections to the observation and the fact the establishment declined to have the observation annotated.

When an establishment has promised corrections and furnishes a date or timeframe (without a specific date) for completion, then you may add “by xxx date” or “within xxxx days or months” in the annotation. Where the investigator and the establishment have “agreed to disagree” about the validity of an observation, you may annotate this observation with “Under consideration” or with no annotation based on the establishment’s desire.

All corrective actions taken by the establishment and verified by FDA should be discussed in detail in the Establishment Inspection Report (EIR) and reported using the Compliance Achievement Reporting Systems (CARS).

5.2.3.5 – Government Wide Quality Assurance Program (GWQAP)

When performing product acceptance examinations under the GWQAP, you must discuss all deficiencies with management and report these deficiencies in writing on the FDA 483. This includes all deficiencies related to the FD&C Act as well as deficiencies in complying with contract requirements, which result in non-acceptance. There must be a clear differentiation on the FDA 483 between these two types of deficiencies.

Enter the FD&C type deficiencies (GMP deviations, etc.) first on the FDA 483. If there are deficiencies in contract provisions, draw a line across the sheet and add a heading “The Following Additional Contract Non-Conformances Were Observed.” Enter each deficiency, which forms a basis for non-acceptance, followed by the reference to the applicable contract requirement or specification.

5.2.3.6 – Distribution of the FDA 483

Be sure all copies of the original FDA 483 are legible and distribute as follows.

5.2.3.6.1 – ORIGINAL

The FDA 483 issued to the firm signed in pen and ink.

Before leaving the premises at the end of the EI present the original to the individual who received the FDA 482, Notice of Inspection, if the person is present and qualifies as “most responsible.” If the person is not available or is outranked by someone else, present it to the individual who meets the definition of owner, operator, or agent in charge.

5.2.3.6.2 – COPIES

Replicas of the “original”.

Attach one copy of all FDA 483s issued to the firm to the EIR. This includes turbo or non-turbo copies of any signed, modified, and/or amended FDA 483, or 483 addenda. See IOM 5.2.3.1.6 (Correction of FDA 483 Errors). A copy may be sent to the top management of the firm including foreign management, unless the individual to whom you gave the original is the top official of the firm.

If the inspection covered vehicles as described in IOM 5.2.2.2, leave an exact copy of the list of observations with the firm being inspected. The original will be sent by your district to the firm owning or leasing the vehicle. You must make every effort to obtain the name and address of the vehicle owner. Usually the firm name is on the vehicle; however, it may require a trace of the vehicle license number. Discuss with your supervisor before taking this step. See IOM 4.4.7.2⁷⁶.

2. Which of the FDA inspectors actually write the FDA 483?

Please see Investigations Operations Manual 5.2.3.1 Preparation of Form FDA 483

Employee(s) signature and Employee(s) name and title – The names of everyone who participated in the inspection with the issuance of a FDA 482 should be listed on the FDA 483 even if they are not available to sign the FDA 483. Each member of an inspection team should sign the FDA 483. However, absence of a team member at the conclusion of an inspection need not prevent issuance of the FDA 483. See IOM 5.1.2.5.1. If you use an electronically generated FDA 483, assure you have a copy for the District files — an unsigned photocopy or printed duplicate is unacceptable. See IOM 5.2.3.6.2.

5.2.3.1.2 – SIGNATURE POLICY

3. Who must approve it before it goes out?

Investigations Operations Manual 5.2.3 – REPORTS OF OBSERVATIONS

The FORM FDA 483 INSPECTIONAL OBSERVATIONS

(see Exhibit 5-5) is intended for use in notifying the inspected establishment’s top management in writing of significant objectionable conditions, relating to products and/or processes, or other violations of the FD&C Act and related Acts (see IOM 5.2.3.2) which were observed during the inspection. These observations are made when in the investigator’s “judgment”, conditions or practices observed, indicate that any food, drug, device, or cosmetic have been adulterated or are being prepared, packed, or held under conditions whereby they may become adulterated or rendered injurious to health. The issuance of written inspectional observations is mandated by law and ORA policy.

4. How is it stored/ logged?

Investigations Operations Manual 5.2.3.6.2 – Attach one copy of all FDA 483s issued to the firm to the EIR. This includes turbo or non-turbo copies of any signed, modified, and/or amended FDA 483, or 483 addenda.

5. Who redacts the information, etc.?

An FDA Freedom of Information Officer/employee redacts FDA documents. For more information you may contact the following FDA FOIA points-of-contact.

6. What criteria is used to determine which 483s are written with Turbo 483?

Investigations Operations Manual Turbo EIR 5.2.3 – REPORTS OF OBSERVATIONS

See: Inspectional Observations and Citations

As laws and regulations are frequently complex, identifying multiple areas for concern, the short description identifies the specific element which is objectionable for an observation. The long description and reference number provide context for a short description that is cited in an observation.

Citations are maintained in a database and are reviewed, edited and updated on a periodic basis. Citations relate to a Code of Federal Regulations (CFR) reference, and there may be many citations for a single CFR reference. To create an FDA Form 483, citations are selected from the pre-established system or database. The Long Description is entered into the FDA Form 483, ensuring uniformity of presentation, then specific information related to the observation may be entered, and the citations may be ranked by significance on the 483. At the present time, the citation database does not contain cites for all areas of the Food Drug and Cosmetic Act or the regulations enforced by FDA, so FDA Form 483’s that reference these are written manually and the citations are not be available for reporting from this database.

7. What internal processes happen prior to issuing a closeout letter?

Regulatory Procedures Manual 4-1-8 Warning Letter Follow-Up

The issuing district or center will evaluate the response to the Warning Letter. If the response is inadequate, or if no response is received, the district or center will begin follow-up action as necessary to achieve correction. If the Warning Letter contains violations that by their nature are not correctable, then no close-out letter will issue.

If the response appears adequate, the district or center will verify that commitments have been fulfilled and that correction has been achieved, and will notify other appropriate agency units. Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection. Follow-up inspections should be conducted promptly after the agreed upon date of completion of the promised corrections.

1. Acknowledgment Of Response To A Warning Letter

The district or center that issued the Warning Letter should acknowledge, in writing, receipt of Warning Letter responses. The district or center should save a PDF copy of the issued correspondence under the Final Outcome tab in CMS, identified as doc type = “courtesy acknowledgment correspondence”.

Warning Letter responses regarding CTP Retailer Compliance Check Inspections are acknowledged with “Reply to Warning Letter Response” letters. CTP should save a PDF copy of the issued Reply letter under the “POST Action Mgt” tab in CMS, identified as doc type = “Letter of FDA’s review of firm’s response.”

2. Warning Letter Close-out Letter

A Warning Letter close-out letter (“close-out letter”) will not be issued based on representations that some action will or has been taken. The corrective actions must actually have been made and verified by FDA.

The district or center that issued the Warning Letter should issue a close-out letter for Warning Letters issued on or after September 1, 2009, if the violations in the Warning Letter have been adequately addressed, and the following conditions have been met:

a. The firm replied to the Warning Letter with sufficient information to demonstrate that any listed violations have been adequately corrected; or

b. A follow-up inspection shows that implementation of the corrective actions was adequate, or, based on other verified, appropriate and reliable information, FDA determines that the follow-up inspection is not needed; and

c. The follow-up inspection (or other appropriate and reliable information) does not reveal other significant violations.

The issuing office will evaluate the firm’s response to the Warning Letter.

Where the district is the issuing office, the following procedure should be followed prior to issuance of a close-out letter. If the district performs an inspection to verify correction, the district may, but need not, ask the center whether it has a comment or objection prior to issuing a close-out letter. If the district decides not to inspect to verify correction, and the Warning Letter required center concurrence, the district will ask the center, via CMS, whether it has a comment or objection prior to issuing a close-out letter. The center will enter any comments or objections to the issuance of a close-out letter (i.e., FDA’s conclusion that the firm’s corrective actions are adequate to address the violations contained in the Warning Letter), via the center documents tab in CMS within 30 working days. If the center requests more time, an additional 30 working days should be granted. At the end of the 30 (or 60) working day period, the district will review the center’s comments or objections, if any, providing deference to the center in areas of the center’s expertise, and, where the center has provided comments or objections, will issue the close-out letter only if consensus is reached with the center.

Districts or centers should issue close-out letters within a total of 65 working days of having the necessary information upon which to make a decision. Use the model “close-out letter” in Exhibit 4-2. The issuing district or center is responsible for ensuring that a PDF copy of the final, signed close-out letter is added into CMS.

A close-out letter does not relieve the recipient from their responsibility for taking all necessary steps to assure sustained compliance with the Act, and all other applicable requirements. If a subsequent inspection reveals problems with the adequacy or sustainability of the corrections that were taken in response to the Warning Letter, such violations would be considered serious. If FDA observes violations during subsequent inspections or through other means, we may take enforcement action without further notice.

The issuing district or center will ensure that FDA posts a notice on http://www.fda.gov/foi/warning.htm when a close-out letter is issued.

Requests to Post Response on Internet The agency policy on posting Warning Letter responses on the internet is found at: http://www.fda.gov/foi/warning.htm In accordance with this policy, when a recipient of a Warning Letter requests that their response to that Warning Letter be posted on FDA’s internet site and provides the response electronically in a word processing format, the agency will post that response. The agency has reserved the right not to post certain responses, such as when posting likely would mislead the public about the safety or efficacy of a regulated product. Note: CTP is not required to post Tobacco Retailer Warning Letter responses on the internet. The issuing district or center must redact the response to the extent permitted by the Freedom of Information Act, and send a redacted copy of the response to FDA’s Division of Freedom of Information, OMP, and the FOI office will then post the response to the above-referenced website. Submissions should be sent to the attention of Brenda Dorsey.

3. Follow-Up Enforcement If a firm has been issued a Warning Letter and has been unable or unwilling to correct the violations, districts and centers should consider further administrative and/or regulatory actions. When considering further action, one factor to evaluate is prior notice (see RPM Chapter 10). This evaluation is particularly relevant for firms operating multiple facilities and producing a variety of products when administrative and/or regulatory action involving more than one location is being considered. Although a second Warning Letter to the same firm should not be issued for the same or similar violations, ensuring prior notice through issuance of a second Warning Letter in some situations may best support the agency’s objectives. In determining whether to issue a second Warning Letter, district directors and center issuing officials should consider whether:

a. The products, processes, and/or significant violations are different, taking into account that systems-based inspectional observations may transcend individual products and processes and may, thereby, provide prior notice without an additional Warning Letter;

b. The responsible individual(s) is (are) different; or,

c. The Warning Letter will support the agency’s objectives (e.g., letters sent to different facilities within a corporation to achieve correction of corporate-wide problems).

Whether or not a second Warning Letter is issued, any proposed administrative or regulatory action must be supported by adequate evidence (inspectional or other). The Office of Enforcement (Division of Compliance Management and Operations) and center office of compliance contacts can assist districts in evaluating the evidence, the prior notice, and in developing a regulatory approach when multiple facilities are involved. (Also, see section on Ad hoc Committees in Chapter 10.) Districts and centers also have the option of conducting a meeting with firm’s management prior to pursuing an administrative or regulatory action. Such meetings also serve as further prior notice. (See sections on Prior Notice and Regulatory Meetings in Chapter 10.)

4. Inspection Classification A Warning Letter constitutes official but not final, agency action. Inspections will be classified Official Action Indicated, OAI, whenever a Warning Letter is issued. This procedure provides greater consistency and uniformity in the classification system and regulatory policy.

If an OAI classification is based on tissue residue violations, it is not necessary to conduct a follow-up inspection unless additional violations have been reported to the agency by the Department of Agriculture’s Food Safety and Inspection Service, or a follow-up inspection is appropriate for other reasons (e.g., to update evidence prior to initiating an enforcement action). For further information on classification of inspections see Field Management Directive No. 86, found on the web at http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061430.htm.

If a facility has received a Warning Letter and then has another inspection with a lengthy 483, what happens next? Another Warning Letter or something else?

Please see the answer to the question below, What criteria does FDA use to decide that a Warning Letter should be issued?

FDA Form 483 FAQ

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

A: 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.

FDA Regulatory Procedures Manual – Chapter 4 – Advisory Actions 4-1 Warning Letters

When it is consistent with the public protection responsibilities of the agency and depending on the nature of the violation, it is the Food and Drug Administration’s (FDA’s) practice to give individuals and firms an opportunity to take voluntary and prompt corrective action before it initiates an enforcement action. Warning Letters are issued to achieve voluntary compliance and to establish prior notice. (Prior notice is discussed in Chapter 10.) The use of Warning Letters and the prior notice policy are based on the expectation that most individuals and firms will voluntarily comply with the law.

The agency position is that Warning Letters are issued only for violations of regulatory significance. Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency’s principal means of achieving prompt voluntary compliance with the Federal Food, Drug, and Cosmetic Act (the Act).

The Warning Letter was developed to correct violations of the statutes or regulations. Also available to the agency are enforcement strategies which are based on the particular set of circumstances at hand and may include sequential or concurrent FDA enforcement actions such as recall, seizure, injunction, administrative detention, civil money penalties and/or prosecution to achieve correction. Despite the significance of the violations, there are some circumstances that may preclude the agency from taking any further enforcement action following the issuance of a Warning Letter. For example, the violation may be serious enough to warrant a Warning Letter and subsequent seizure; however, if the seizable quantity fails to meet the agency’s threshold value for seizures, the agency may choose not to pursue a seizure. In this instance, the Warning Letter would document prior warning if adequate corrections are not made and enforcement action is warranted at a later time.

Responsible officials in positions of authority in regulated firms have a legal duty to implement whatever measures are necessary to ensure that their products, practices, processes, or other activities comply with the law. Under the law such individuals are presumed to be fully aware of their responsibilities. Consequently, responsible individuals should not assume that they would receive a Warning Letter, or other prior notice, before FDA initiates enforcement action.

FDA is under no legal obligation to warn individuals or firms that they or their products are in violation of the law before taking enforcement action, except in a few specifically defined areas. When acting under the authority of Subchapter C – Electronic Product Radiation Control (formerly the Radiation Control for Health and Safety Act of 1968) of Chapter V of the Act, FDA is required by law to provide a written notification to manufacturers when the agency discovers products that fail to comply with a performance standard or that contain a radiation safety defect. Because of the legal requirements of Subchapter C, minor variations in the procedures may occur.

A Warning Letter is informal and advisory. It communicates the agency’s position on a matter, but it does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action on which it can be sued.

There are instances when issuing a Warning Letter is not appropriate, and, as previously stated, a Warning Letter is not a prerequisite to taking enforcement action. Examples of situations where the agency will take enforcement action without necessarily issuing a Warning Letter include:

1. The violation reflects a history of repeated or continual conduct of a similar or substantially similar nature during which time the individual and/or firm has been notified of a similar or substantially similar violation;

2. The violation is intentional or flagrant;

3. The violation presents a reasonable possibility of injury or death;

4. The violations, under Title 18 U.S.C. 1001, are intentional and willful acts that once having occurred cannot be retracted. Also, such a felony violation does not require prior notice. Therefore, Title 18 U.S.C. 1001 violations are not suitable for inclusion in Warning Letters; and,

5. When adequate notice has been given by other means and the violations have not been corrected, or are continuing. See Chapter 10, Prior Notice, for other methods of establishing prior notice.

In certain situations, the agency may also take other actions as an alternative to, or concurrently with, the issuance of a Warning Letter. For example:

1. The product is adulterated under Section 402(a)(3) or 402(a)(4) of the Act;

2. There is a violation of CGMP;

3. The product contains illegal pesticide residues; or

4. The product shows short contents, subpotency, or superpotency.

Additional instructions for Warning Letters in specific product areas are found in compliance program guidance and in compliance policy guides.

Also, reference Exhibit 4-1, the agency’s “Procedures for Clearing FDA Warning Letters and Untitled Letters.”

Regulatory Procedures Manual 4-1-8 Warning Letter Follow-Up

b. The responsible individual(s) is (are) different; or,

c. The Warning Letter will support the agency’s objectives (e.g., letters sent to different facilities within a corporation to achieve correction of corporate-wide problems).

8. Does the FDA have a certain time period or deadline for submitting warning letters and EIRs after a 483 has been issued?

FDA Field Management Directive 145 – Procedure for Release of Establishment Inspection Report to the Inspected Establishment

You may reference the FDA Regulatory Procedures Manual Exhibit 4-1, 6.1 Timeframes in Procedures for Clearing FDA Warning Letters and Untitled Letters.

You may also reference the FDA Regulatory Procedures Manual 4-1-7 Timeframes:

Within fifteen (15) working days after completion of the inspection, or, if applicable, sample analysis, the district should submit a Warning Letter recommendation to the appropriate reviewing office for concurrence.

Within fifteen (15) working days after receipt of the Warning Letter recommendation, the center should review the Warning Letter and notify the district office of its decision. If the Warning Letter is disapproved, the center will notify the district office of its decision within 15 days of receipt, and will issue a memorandum stating its reasons for disapproval within 30 days. The Center will provide notification by e-mail or similar means to the District, the Office of Enforcement (Division of Compliance Policy and the Division of Compliance Management and Operations (DCMO) that the memorandum is available in CMS. If the Warning Letter is approved, the center will forward its approval memo and the proposed Warning Letter, as appropriate, for further review and concurrence. See Exhibit 4-1, the agency’s “Procedures for Clearing FDA Warning Letters and Untitled Letters.” All agency components responsible for issuing Warning Letters and Untitled Letters must follow these procedures.

The district compliance officer (or, the center CSO/scientist, if the Warning Letter was center-initiated) assigned to the Warning Letter should diligently pursue and actively monitor the progress of the case through the agency review process to its conclusion (i.e., voluntary compliance or enforcement action). The Office of Enforcement (Division of Compliance Management and Operations) can assist in situations where significant delays are experienced or assistance is needed to resolve technical, scientific, or policy issues. (Also, see section on Ad hoc Committees in Chapter 10.)

9. What criteria do you use to determine who is sent on any particular inspection?

Please see FDA Field Management Directive No. 17 Field Assignment Issuances Guidelines for Headquarters Offices for information on headquarters assignment inspection assignments to field staff.

For additional information on individual district procedures on assigning personnel to inspections you may submit a FOIA request.

10. Why do some inspections involve 1 or 2 inspectors vs. 5 or 6?

Please see above answer and link.

Everything you’ve ever wanted to know about how FDA 483s are written

1. Can you give us an overview of the internal processes around the FDA Form 483?

Turbo EIR

5.2.3.1 – Preparation of Form FDA 483

5.2.3.1.2 – SIGNATURE POLICY

5.2.3.1.3 – DATE ISSUED

5.2.3.1.4 – OBSERVATIONS

5.2.3.1.5 – MEDICAL DEVICE INSPECTIONS

5.2.3.1.6 – CORRECTION OF FDA 483 ERRORS

5.2.3.1.6.1 – Errors Discovered Prior to Leaving the Establishment

5.2.3.1.6.2 – Errors Discovered after Leaving the Establishment

5.2.3.2 – Reportable Observations

5.2.3.2.1 – ADULTERATION OBSERVATIONS

5.2.3.2.2 – OTHER OBSERVATIONS

5.2.3.3 – Non-Reportable Observations

5.2.3.4 – Annotation of the FDA 483

5.2.3.5 – Government Wide Quality Assurance Program (GWQAP)

5.2.3.6 – Distribution of the FDA 483

5.2.3.6.1 – ORIGINAL

5.2.3.6.2 – COPIES

2. Which of the FDA inspectors actually write the FDA 483?

5.2.3.1.2 – SIGNATURE POLICY

3. Who must approve it before it goes out?

4. How is it stored/ logged?

5. Who redacts the information, etc.?

6. What criteria is used to determine which 483s are written with Turbo 483?

7. What internal processes happen prior to issuing a closeout letter?

1. Acknowledgment Of Response To A Warning Letter

2. Warning Letter Close-out Letter

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

8. Does the FDA have a certain time period or deadline for submitting warning letters and EIRs after a 483 has been issued?

9. What criteria do you use to determine who is sent on any particular inspection?

10. Why do some inspections involve 1 or 2 inspectors vs. 5 or 6?