Regulatory Procedures Manual

Chapter 4: ADVISORY ACTIONS

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This chapter defines and establishes uniform guidance and procedures for Warning 

Letters and Untitled Letters.

This chapter includes the following sections:

Section Topic Page

4-1 WARNING LETTERS....................................................................................3

4-1-1. Warning Letter Procedures .....................................................................3

4-1-2. Warning Letters to Government Agencies ..............................................5

4-1-3. Issuing Warning Letters - Factors to Consider........................................5

1. General Considerations ..........................................................................6

2. Ongoing or Promised Corrective Actions ................................................6

3. Completed Corrective Actions.................................................................7

4. Response Letter......................................................................................7

5. Verification of Corrective Actions ............................................................8

4-1-4. Center Concurrence and Letters Issued by Centers ...............................8

1. All Centers ..............................................................................................8

2. Center for Drug Evaluation and Research (CDER).................................8

3. Center for Biologics Evaluation and Research (CBER) ..........................9

4. Center for Devices and Radiological Health (CDRH)............................10

5. Center for Veterinary Medicine (CVM)..................................................11

6. Center for Food Safety and Applied Nutrition (CFSAN)........................12

7. Center for Tobacco Products ................................................................12

4-1-5. Letters for Illegal Promotional Activities ................................................13

4-1-6. Multiple Center Review .........................................................................13

4-1-7. Time Frames.........................................................................................14
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4-1-8. Warning Letter Follow-Up .....................................................................15

1. Acknowledgment of Response to a Warning Letter ..............................15

2. Warning Letter Close-Out Letter ...........................................................16

3. Requests to Post Response on Internet ...............................................17

4. Follow-Up Enforcement.........................................................................18

5. Inspection Classification........................................................................18

4-1-9. Firm Profile Updates in eNSpect...........................................................19

4-1-10. Warning Letter Format.......................................................................19

4-1-11. Warning Letter Distribution ................................................................21

4-1-12. Warning and Untitled Letters Addressed to Importers, Customs 

Brokers, and Foreign Firms ...............................................................................22

4-1-13. Freedom of Information (FOI) ............................................................24

4-1-14. Center for Biologics Evaluation and Research (CBER) .....................25

4-1-15. Center for Drug Evaluation and Research (CDER)............................27

4-1-16. Center for Devices and Radiological Health (CDRH).........................32

4-1-17. Center for Food Safety and Applied Nutrition (CFSAN) and Center for 

Veterinary Medicine (CVM)................................................................................35

4-1-18. Center for Tobacco Products (CTP) Retailer Compliance Check 

Inspection Program............................................................................................35

4-1-19. Tracking.............................................................................................36

4-2 UNTITLED LETTERS..................................................................................37

4-2-1. Format and Content ..............................................................................37

4-2-2. Center Concurrence and Letters Issued By Centers.............................37

4-2-3. Tracking ................................................................................................37

4-3 USE OF STATE EVIDENCE FOR FDA WARNING LETTERS AND 

UNTITLED LETTERS............................................................................................38

4-4 EXHIBITS ....................................................................................................39

Exhibit 4-1 Procedures for Clearing FDA Warning Letters and Untitled Letters

.......................................................................................................................40

Exhibit 4-2 Warning Letter Close-Out Letter...................................................63

 
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4-1 WARNING LETTERS

4-1-1. Warning Letter Procedures

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 - Other Procedures.) The use of Warning Letters 

and prior notice 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 if 

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 
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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 - Other Procedures, 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 current good manufacturing practices (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, 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. Developed to facilitate 

review of all Warning Letters and Untitled Letters by the Office of Chief Counsel 
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(OCC), the procedures provide instructions for submitting such letters to OCC, and 

include timeframes and routing information.

4-1-2. Warning Letters to Government Agencies

Government establishments should be held to the same standards as 

nongovernment establishments. The public health standards are identical; 

however, the method used to ensure compliance with these standards may vary. 

FDA believes that government establishments will achieve and maintain a higher 

rate of voluntary compliance with FDA regulations compared with nongovernment 

establishments. Efforts to obtain voluntary compliance should be made and 

documented before recommending the issuance of a Warning Letter. These efforts 

may include discussing the violations with the responsible government officials by 

phone or in a meeting, recommending an Untitled Letter, or requesting a written 

corrective action plan and periodic progress reports. The government 

establishment’s progress should be monitored and a follow-up inspection should 

be scheduled within a reasonable time consistent with the noted violations to 

confirm correction of the violations.

Whenever significant violations are observed at a government establishment, or if 

attempts to achieve compliance have been ineffective, the office (or center) should 

arrange a meeting with OEIO, OCC, and the relevant center to determine a 

strategy to achieve timely and effective compliance. The meeting should include 

the Office of Partnerships (OP) if the government establishment is a state or local 

agency.

Also, 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.

4-1-3. Issuing Warning Letters - Factors to Consider

The Warning Letter is the agency's principal means of notifying regulated industry 

of violations and achieving prompt voluntary correction. Warning Letters can be 

issued at the discretion of the program office director without center concurrence, 

except in specific program areas that require prior center concurrence. Warning 

Letters may also be generated through work done at agency headquarters (ORA 

or centers), processed under appropriate procedures and issued under the 

authority of a division or office director. (See Center Concurrence and Letters 

Issued by centers. Also, 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.)
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1. General Considerations

In determining whether to issue a Warning Letter, program office directors 

and center or other officials with authority to issue should consider whether:

a. Evidence shows that a firm, product, and/or individual is in violation 

of the law or regulations and that failure to achieve adequate and 

prompt correction may result in agency consideration of an 

enforcement action;

b. The violation(s) are determined to be of regulatory significance, and 

the issuance of a Warning Letter is appropriate and consistent with 

agency policy, as described in Compliance Policy Guides or 

elsewhere; and

c. There is a reasonable expectation that the responsible firm and 

persons will take prompt corrective action.

2. Ongoing or Promised Corrective Actions

Corrective action may be undertaken or promised during an establishment 

inspection or addressed in correspondence to the agency after an 

inspection. Ongoing or promised corrective actions generally do not 

preclude the issuance of a Warning Letter. In addition to being the agency’s 

primary means to achieve prompt, voluntary compliance, Warning Letters 

remain a primary means to establish prior notice (see Chapter 10 - Other 

Procedures) and serve to ensure that the seriousness and scope of the 

observed violations are understood by top management and that the 

appropriate resources are allocated to fully correct the violations and to 

prevent recurrence.

When a firm is in the process of correcting the violations or has made a 

written promise to take prompt corrective action, a program office or center 

should consider the following factors when determining whether or not to 

issue a Warning Letter:

a. The firm’s compliance history, e.g., a history of serious violations, or 

failure to prevent the recurrence of violations;

b. The nature of the violation, e.g., a violation that the firm was aware of 

(was evident or discovered) but failed to correct;

c. The risk associated with the product and the impact of the violations 

on such risk;

d. The overall adequacy of the firm’s corrective action and whether the 

corrective action addresses the specific violations, related violations, 

related products or facilities, and contains provisions for monitoring 

and review to ensure effectiveness and prevent recurrence;
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e. Whether documentation of the corrective action was provided to 

enable the agency to undertake an informed evaluation;

f. Whether the timeframe for the corrective action is appropriate and 

whether actual progress has been made in accordance with the 

timeframe; and,

g. Whether the corrective action taken ensures sustained compliance 

with the law or regulations. In the case of Warning Letters being 

considered for products offered for sale through internet web sites, 

corrective action to remove claims from or inactivate the website is 

easily reversible, and should be carefully considered, along with the 

other factors above, in determining whether or not to issue a Warning 

Letter. Warning Letters for, or involving, internet web sites should be 

issued in as close proximity as possible to the time when the claims 

were last observed, and reference to the date on which the claims 

were observed should be included in the letter.

If a decision is made not to issue a Warning Letter, see “Response Letter” 

below. Relying on a firm’s promised corrective actions does not preclude 

consideration of regulatory action should we later observe that the same or 

similar violations have not been corrected.

3. Completed Corrective Actions

As a general rule, a Warning Letter should not be issued if the agency 

concludes that a firm’s corrective actions are adequate and that the 

violations that would have supported the letter have been corrected. If you 

believe that an exception is necessary due to the facts or circumstances of 

the case (e.g., the firm’s compliance history, the nature of the violation, or 

the risk associated with the product) discuss this background in the Warning 

Letter referral package and be sure to adapt the language in the proposed 

letter to fit the circumstances (e.g., recite the history and the consequences 

if there is a recurrence).

If a decision is made not to issue a Warning Letter, see “Response Letter” 

below. Relying on a firm’s completed corrective actions does not preclude 

consideration of regulatory action should we later observe that the same or 

similar violations have not been corrected.

4. Response Letter

If a decision is made to not issue a Warning Letter because adequate 

corrective action has been taken, or because corrective action is being 

taken or has been promised, it is recommended that an alternative form of 

communication (e.g., a response letter to the firm’s letter promising 

corrective action) be issued to the responsible individuals at the firm to 

supplement the record of the violation(s) and reflect the agency’s decision to 
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rely on the firm’s actions and/or promises. The response letter should 

indicate that the agency is relying on the firm’s corrections or commitment

regarding corrective actions. Further, the letter may include a statement that 

should we later observe that these or similar violations have not been 

corrected; regulatory action (e.g., seizure, injunction and, if appropriate, civil 

penalties) may be taken without further notice.

5. Verification of Corrective Actions

Verification of the overall completeness and effectiveness of the corrective 

action should be undertaken during the next inspection, the timing of which 

may be expedited or routine as determined by the issuing office.

4-1-4. Center Concurrence and Letters Issued by Centers

Center concurrence is required prior to issuing Warning Letters in the areas listed 

below, or Warning Letters are issued directly by the center.

Also, 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.

1. All Centers

a. All labeling violations - except where specific guidance has been 

provided, e.g., Compliance Programs, Compliance Policy Guides, 

and Drug Health Fraud Bulletins;

b. Computer application and software violations;

c. Bioresearch Monitoring Program violations; and

d. Product advertising violations.

Note: Only centers issue Warning Letters for violations associated with 

product advertising, OTC drug monographs, and the Bioresearch Monitoring 

Program.

2. Center for Drug Evaluation and Research (CDER)

a. New drug charges - including unapproved changes in processes or 

formulations and recommendations to withhold approvals of 

applications or supplements;

b. Adverse drug experience reporting violations;

c. Novel and unusual tamper-evident packaging violations;

d. Prescription Drug Marketing Act violations;

e. Investigational drug use violations;
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f. CGMP charges involving active pharmaceutical ingredients and other 

drug component manufacturing deficiencies;

g. CGMP charges involving all dosage forms, including medical gases;

h. CGMP charges involving inspections of facilities for therapeutic 

biologic products regulated by CDER;

i. CGMP charges involving combination products where CDER is the 

lead center;

j. Pharmacy compounding issues; or

k. Violations related to required postmarketing studies and clinical trials. 

The MARCS-Compliance Management System (MARCS-CMS or CMS) is 

now being used for electronic submission of Warning Letter 

recommendations from program offices. All recommendations by the 

program offices must use CMS for submitting the proposed Warning Letter, 

the FDA 483 supporting alleged violations, the EIR, and any written 

response by the firm. For any questions, or if you need to submit a document 

as a hardcopy, the CDER Office of Compliance contact is: CDER-OC-OMQCommunications.

Also, 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.

3. Center for Biologics Evaluation and Research (CBER) 

a. Donor re-entry violations (e.g., HBsAg, anti-HIV-1); 

b. Violations relating to drug CGMP* (see below);

c. CGMP violations involving combination products where CBER is the 

lead center;

d. Violative inspections of federal government agencies;

e. Violative inspections related to licensed biologic drug and device 

products regulated by CBER;

f. Viral marker test run deficiencies** (see below);

g. Violations in areas where specific guidance has not been provided*** 

(see below);

h. Violations relating to HIV and HCV lookback; or

i. Violative inspections of manufacturers of human cell, tissue, and 

cellular and tissue-based products (HCT/Ps).

*CGMP regulations in Part 211 and blood establishments: CBER 

concurrence is required for Warning Letters involving deviations from Part 
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211 that are not associated with provisions in Part 606, such as 21 CFR 

211.68(b) or 211.113.

**Viral marker testing violations: ORA does not need center concurrence 

regarding viral marker testing violations. However, center concurrence is 

required for Warning Letters based on invalidation of viral marker test run 

deficiencies since center guidance on this issue is relatively recent.

***Violations in areas where specific guidance has not been provided: In 

these situations, we encourage the programs to contact the Division of Case 

Management (DCM) in CBER's Office of Compliance and Biologics Quality 

(OCBQ) before recommending a Warning Letter to the center.

Also, 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.

4. Center for Devices and Radiological Health (CDRH)

a. All 21 U.S.C. 352(j) “dangerous to health” violations;

b. Medical device reporting violations which cite failure to report 

malfunctions as defined in 21 CFR 803.3(n). Center medical and 

technical expertise is necessary for these evaluations;

c. Restricted device violations;

d. Radiation Control for Health and Safety Act violations - except for 

sunlamp products and x-ray assemblers;

e. Violation of requirements for post market surveillance studies;

f. Any violation of device tracking regulations other than failure of the 

firm to implement any form of a tracking system;

g. All suspected violations of the user reporting regulations;

h. Failure to submit a premarket notification (510(k)) or premarket 

approval application (PMA);

i. Failure to submit a 510(k) or a PMA supplement for a significant 

modification(s) and/or the addition of a new intended use(s) to a 

previously cleared or approved device;

j. All violations arising from pre-approval PMA inspections including 

supplements to a previously approved PMA application; and,

k. Mammography Quality Standards Act (MQSA) violations in the 

following situations, unless superseded by a relevant Compliance 

Program or other directive:
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l. Where numerous Level 2 or 3 inspection findings were observed, but 

no single noncompliance constitutes a Level 1 or repeat Level 2 

inspection finding; or

m. Any situations not specifically identified as a Level 1 noncompliance 

or repeat Level 2 noncompliance; or

n. CGMP (e.g., 21 CFR Part 211 or Part 820) charges involving 

combination products where CDRH is the lead center.

Note: For direct reference situations regarding MQSA violations, reference 

the instructions contained in Part V of the Compliance Program or other 

directive.

Also, 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.

5. Center for Veterinary Medicine (CVM)

a. Product approval violations;

b. All drug residue violations involving meat, poultry, aquacultured 

seafood, and other animal-derived products;

c. Feed contaminant violations where no tolerance has been 

established;

d. Adverse drug reaction reporting violations;

e. Low acid canned pet food violations requiring technical review; and, 

f. CGMP violations for medicated feed [21 CFR Part 225], Type A 

Medicated Articles [21 CFR Part 226], and dosage form drugs [21

CFR Part 211]. 

Submit complete recommendation package (recommendation, EIR, CRs, all 

exhibits, and other supporting documents).

Recommendations, coupled with their supporting evidence, should only be 

submitted using CMS using CMS, an electronic case submission system. 

This system is available from the IT Applications page on FDA's intranet site.

Also, 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.
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6. Center for Food Safety and Applied Nutrition (CFSAN)

All violations not covered by direct reference authority, including those issues 

addressed in a compliance policy guide or in a compliance program. These 

letters requiring Center concurrence or Center issuance include, but are not 

limited to, the following examples:

a. Any Warning or Untitled Letter involving a novel, controversial, or 

sensitive legal issue;

b. Pesticide and chemical contamination violations not covered by direct 

reference authority;

c. Dietary supplements, medical foods, and infant formulas, including 

dietary supplements CGMPs;

d. Food and color additive violations;

e. Actions involving environmental microbial contamination;

f. All situations involving violations of section 402(a)(4) of the Act, 

including deviations from regulations for bottled water and any other 

CGMP regulation concerning CFSAN issues; except districts have 

direct reference for seafood HACCP violations and 21 CFR Part 110 

violations that do not include environmental sampling or allergen 

issues;

g. Mycotoxins;

h. Animal drugs in foods (aquaculture chemotherapeutic agents);

i. Food standards;

j. Cosmetics; and

k. Egg rule (21 CFR 118) violations.

Recommendations, coupled with their supporting evidence, should only be 

submitted using CMS to CFSAN via CMS, an electronic case submission 

system. This system is available from the IT Applications page on FDA's 

intranet site.

Also, 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.

7. Center for Tobacco Products

a. CTP directly issues Warning Letters for tobacco retailer compliance 

check violations. Tobacco Retailer Warning Letters are not subject to 

the time frames established in section 4-1-7 or to the Warning Letter 

close-out procedures described in section 4-1-8 due to their nature 

and volume. CTP has developed internal procedures to address time 
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frames and close-out corresponding WL and close out CTP 

procedures.

b. CTP directly issues Warning Letters to regulated industry for all other 

violations of the Federal Food, Drug, and Cosmetic Act, as amended 

by the Family Smoking Prevention and Tobacco Act, and 

implementing regulations.

4-1-5. Letters for Illegal Promotional Activities

Warning Letters, not Untitled Letters, should be issued for promotional activities if 

the nature of the activity is such that the center would support further regulatory or 

administrative action. The warning letters are generally initiated by the Centers and 

may be issued by the Centers or by the Program Offices. 

NOTE: For web-based promotion, appropriate further action may involve, e.g., 

FDA notification of any Internet Service Providers (ISPs) or other related service 

providers with whom the offending website has a contractual relationship, or FDA 

notification of the public through consumer or import alerts, rather than the physical 

(re) inspection of regulated establishments.

The center should alert the program office of the violation and ask that they bring 

the promotional activity to the attention of the firm on the next scheduled visit. If the 

inspection reveals additional problems, this violation may be included as part of 

their regulatory action plan. If the problem is urgent, the district could request a 

meeting with the firm to discuss the violations.

4-1-6. Multiple Center Review

For issues in a Warning Letter that require review by more than one center, a 

designation of “lead center” 1 should be made at the earliest possible opportunity. 

This is necessary to ensure a timely and appropriately coordinated review process. 

The lead center is responsible for communication with the other involved center(s), 

the program office, and OCC. The lead center is responsible for shepherding the 

1 Note that a combination product is assigned to a medical product “lead center” (i.e., CBER, 

CDER, or CDRH) that has primary jurisdiction for the regulation of that specific combination 

product. The lead center will consult with other centers, as needed, to evaluate inspectional 

observations for combination products. See SMG 4101 Inter-Center Consult Request Process. 

Questions on which center is lead for a combination product should be directed to 

combination@fda.hhs.gov. In most cases, the lead center will coordinate issuance of warning 

letters for combination products assigned to it. However, there may be cases where a different 

center issues is responsible for coordination of development and issuance of a warning letter 

concerning a combination product. For example, if a warning letter is for a facility that manufactures 

both drug products and device-led combination products and the drug product-related issues are 

more significant, CDER may be the center that coordinates the warning letter process, though the 

lead center for the implicated device-led combination products would be CDRH.
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Warning Letter through the review process, including the review and incorporation 

of comments as appropriate from the other involved entities.

For issues in a Warning Letter that require review by more than one center, the 

program should, prior to submission of the recommendation, communicate with 

each center and identify which center will serve as the lead. The recommendation 

should identify the lead center and the other involved center(s). The 

recommendation should be sent electronically via CMS to the lead center, and the 

lead center will create a consult task to the other reviewing center(s). The centers 

should conduct concurrent (not sequential) reviews.

If the program did not identify the need for multiple reviews prior to submission of 

the recommendation, the center receiving the recommendation should 

communicate with the program and the other involved center(s) to appropriately 

designate the lead center. The program should then promptly send a copy of the 

recommendation to the other involved center(s).

4-1-7. Time Frames

Within fifteen (15) working days after completion of the inspection, sample 

analysis, or collection of evidence, the program 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 

program of its decision. If the Warning Letter is disapproved, the center will notify 

the program 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 appropriate ORA program 

office, and to the Office of Strategic Planning and Operational Policy (OSPOP)

Division of Enforcement (DE) 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. If a Program or Office enters a 

formal agreement with another Center, such as a Concept of Operations 

(CONOPS), the agreement's timelines supercede the procedures in Exhibit 4-1. 

Recommendations to the Center and Warning Letter time frames for Human Drug 

Inspections (Surveillance and For-Cause Inspections) which fall under the review 

of CDER, can be found in FDA’s INTEGRATION OF FDA FACILITY EVALUATION 

AND INSPECTION PROGRAM FOR HUMAN DRUGS: A CONCEPT OF 

OPERATIONS.
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The program 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). OSPOP DE 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 - Other Procedures.)

4-1-8. Warning Letter Follow-Up

The issuing program office or center will evaluate the response to the Warning 

Letter. If the response is inadequate, or if no response is received, the program 

office 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 recipient of the Warning Letter is verified to be out 

of business, then no close-out letter will issue. If the recipient of the Warning 

Letter ceases operation with respect to the issues presented in the Warning Letter

but otherwise continues business, FDA may decide not to issue a close-out letter 

based solely on the recipient’s representation that they have ceased the operations 

related to the issues presented in the Warning Letter.

In the case of Warning Letters issued for products marketed through internet 

websites, corrective actions such as claim removal or website inactivation are 

reversible. FDA also may not be able to conduct follow-up inspections of firms or 

individuals who sell products online without a physical location. FDA will consider 

whether the information provided or is otherwise available to the agency 

demonstrates sustained compliance, and may decide not to issue a close-out letter 

based solely on website corrections.

If the response appears adequate, the program office 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 program office or center that issued the Warning Letter should 

acknowledge, in writing or via electronic mail, receipt of Warning Letter 

responses. The program office 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” 
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letters when necessary, in accordance with internal procedures. 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 program office 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

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

b. 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 program office is the issuing office, the following procedure 

should be followed prior to issuance of a close-out letter:

If the program office performs an inspection to verify correction, the program 

office may, but need not, ask the center whether it has a comment or 

objection prior to issuing a close-out letter. If the program office decides not 

to inspect to verify correction, and the Warning Letter required center 

concurrence, the program office 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 program office will review the center’s comments or 

objections, if any, providing deference to the center in areas of the center’s 
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expertise, and, where the center has provided comments or objections, will 

issue the close-out letter only if consensus is reached with the center.

The Program office may also ask other program offices whether they have 

any comments or objections prior to issuing a close-out letter if the other 

program office has a potential or open case for the same individual or firm.

Program offices 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 program 

office 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 recipients from their responsibility to take

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 program office or center will ensure that FDA posts a notice on 

FDA Warning and Close-Out Letters webpage when a close-out letter is 

issued.

3. Requests to Post Response on Internet

Warning Letters are posted publicly on fda.gov. FDA does not remove 

Warning Letters from its Internet site unless the Agency rescinds or amends 

the letter. A recipient, however, may submit a request to post and make 

available to the public their response to the Warning Letter.

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 or legible pdf 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.

ORA DIDP 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 (DFOI), Office of the Executive 

Secretariat, and DFOI will then post the response to the above-referenced 

website. Submissions should be sent to the attention of the appropriate 

“privacy contacts” available on FDA’s intranet site. See 4-1-13 for more 

information.
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4. Follow-Up Enforcement

If a firm has been issued a Warning Letter and has been unable or unwilling 

to correct the violations, program offices 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 - Other 

Procedures). 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, program 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). OSPOP DE and center office of compliance contacts 

can assist program offices 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 - Other Procedures.)

Program offices 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 - Other Procedures.)

5. 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.
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For further information on classification of inspections see Field Management 

Directive No. 86, Establishment Inspection Report Conclusions and 

Decisions.

4-1-9. Firm Profile Updates in eNSpect

When a profilable firm (i.e., domestic or foreign drug, biologics, medical device, or 

combination product facility) undergoes a CGMP or Quality System (QS) 

inspection, the inspected profile classes should be updated by the action office at 

each stage in the review process. When an inspection is final classified OAI, the 

date and type of letter should be entered in the Remarks field for the relevant 

profile classes, and these profile classes should be changed to unacceptable.

When a Warning Letter close-out letter is issued, the final profile for the relevant 

profile classes should be changed to acceptable. For profile procedures, see IOM 

Exhibit 5-14.

4-1-10. Warning Letter Format

Warning Letters can vary in form, style, and content to provide the flexibility 

needed to accurately and effectively state the nature of the violation(s) found and 

the response expected. However, the elements listed below are common to 

Warning Letters:

1. Title: "WARNING LETTER."

2. Delivery: Sent to ensure overnight delivery, and receipt of delivery (e.g., 

return receipt requested, FedEx) documented.

3. Addressed to the highest known official in the corporation that includes the 

facility that was inspected, and a copy sent to the highest known official at 

the facility that was inspected. If you are requesting a separate response 

from other officials, they would be included as addressees. A suitable 

notation (e.g., cc, or copy sent to) in the letter would be included, and each 

person would be identified by name, title, and, if appropriate, address. The 

letter to each addressee and each person who is identified as having 

received a copy of the letter would be issued separately and in accordance 

with the delivery instructions above.

Tobacco Retailer Warning Letters are addressed to the legal entity or to the 

sole owner at the retail establishment that was inspected. The legal entity or 

sole owner is copied if the entity’s business address is different than the 

inspected retail establishment.

4. The dates of the inspection and a description of the violative condition, 

practice, or product in brief but sufficient detail to provide the respondent the 

opportunity to take corrective action. The citation of the section of the law 

and, where applicable, the regulation violated would be included, and the

violations of the law using the appropriate section(s) of both the FD&C Act 
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and the U.S. Code, e.g., Section 501(a)(2)(B) of the Act , 21 U.S.C. 

351(a)(2)(B) would be cited. Violations of other laws (e.g., the Public Health 

Service Act) would be cited in the same manner.

5. Citations to the appropriate application number, post marketing 

requirements (PMR) reference number (if appropriate) and the date that the 

applicant was notified of the PMR for Warning Letters not based on 

inspections and citing violations of statutory requirements for studies such 

as PMRs and clinical trials.

6. Appropriate acknowledgement of corrections promised during the 

inspection, annotated on the 483, or provided to the FDA in a written 

response. It would reply as to the apparent adequacy of the firm’s corrective 

actions set forth in the response.

7. A request for correction and a written response within a specific period of 

time after the date of receipt of the letter, usually fifteen (15) working days. 

At the program office's discretion, the recipient may be offered an 

opportunity to discuss the letter with program office officials or, when 

appropriate, with center officials.

8. A warning statement indicating that failure to adequately address the issues 

that are the subject of the letter may result in regulatory or legal action. 

Examples of such actions may be cited. 

9. In most cases, language to the effect that, if the recipient believes that it or 

its product is not in violation of the FD&C Act or other laws (e.g. the Public 

Health Service Act) or FDA regulations, it should provide FDA with its 

reasoning and any supporting evidence or information for FDA’s 

consideration within a specified period of time.

10.Where appropriate, language to the effect that the recipient should 

investigate and determine the causes of any violations and take prompt 

actions to correct any violations and bring products into compliance.

11.Where appropriate, language to the effect that other federal agencies may 

take the recipient’s compliance history into account when considering the 

award of federal contracts.

12.CTP Retailer Warning Letters (except those issued to online tobacco 

product retailers) would include language to the effect that, if the recipient 

believes that the Warning Letter was issued in error, they should preserve 

any relevant evidence or information in the event FDA initiates regulatory 

action at a later date.

13.Drug Warning Letters (except those issued to IRBs, clinical investigators, 

sponsors, and monitors involved in clinical trials) that cite CGMP violations 

would include a statement to the effect that violations may be the cause for 

FDA to withhold issuance of Export Certificates. Where appropriate, these 

letters would also include language indicating that any violations may be 
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cause for FDA to withhold approval of new applications or supplements 

listing the recipient as a manufacturer.

14.Device Warning Letters (except those issued to IRBs, clinical investigators, 

sponsors, and monitors involved in clinical trials) would include language to 

the effect that, should FDA determine that devices, or other articles as 

appropriate, or facilities do not meet the requirements of the FD&C Act, 

requests for Certificates to Foreign Governments (CFG) may not be 

granted. Device Warning Letters concerning PMAs would include language 

to the effect that if FDA determines that there has been a specific violation 

and those violations are not addressed, the PMA may be subject to 

withdrawal.

Device Warning Letters that include CGMP violations would include 

language to the effect that if FDA determines that there are Quality System 

regulation violations that are reasonably related to premarket approval 

applications for Class III devices, such devices would not be approved until 

the violations have been corrected. Where appropriate, these letters may 

also include language to the effect that failure to address violations of a 

statutory or regulatory citation may result in the withdrawal of a PMA.

15.A statement in letters that pertain to imported products to the effect that 

products that appear to be adulterated or misbranded or that appear to be 

violation of section 505 or another specified violation listed in 801 may be 

detained or refused admission.

16.Warning Letters may request the recipient cease any violative conduct.

17.Instructions, as appropriate, that the response include:

a. each step that has been or will be taken to completely correct the 

current violations and to prevent similar violations;

b. the time within which correction will be completed;

c. any reason the corrective action has not been completed within the 

response time; and,

d. any documentation necessary to show that correction has been 

achieved.

18.A designated program or center official to whom the response should be 

addressed.

19.“Issued by” the program office director, division director, or higher agency 

official.

Some program areas will require center concurrence before issuance.

4-1-11. Warning Letter Distribution

Warning Letter distribution is as follows:
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1. Original – Addressee(s)

2. Copy to each person identified in the Warning Letter

3. Blind copy (bcc) to the following:

a. MARCS-CMS case file. The final, unredacted signed letter should be 

added to the MARCS-CMS case file under the Final Outcome tab 

with the file type identified as PDF VERSION Non-Redacted Issued 

Violation Letter. Once added, this copy becomes available to the full 

text DOC search within MARCS-CMS. It also serves as an internal 

copy for FDA that is available through the system to anyone who may 

need a copy of the issued letter.

b. Division of Freedom of Information (DFOI) – For more information, 

see Section 4-1-13 – Freedom of Information (FOI) and the operating 

instructions within the FOI User’s Guide hyperlink in MARCS-CMS 

located under the User’s Guides/Training hyperlink.

4. If the Warning Letter is to a foreign food facility, contact the U.S. agent for 

the foreign facility by email, phone, facsimile, or regular mail within 5 

business days and inform the agent that a redacted letter is available on the 

Warning Letter page.

5. Also provide copies to Local Distribution, factory file, WL file, the appropriate 

program office, and appropriate federal and state agencies.

6. Provide one redacted copy of Warning Letters regarding Dietary 

Supplements to:

Associate Director

Division of Advertising Practices (link)

Federal Trade Commission

600 Pennsylvania Avenue, N.W. Washington, D.C. 20580

(Or, send a redacted e-copy to: mengle@ftc.gov).

4-1-12. Warning and Untitled Letters Addressed to Importers, 

Customs Brokers, and Foreign Firms

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.

Warning Letters should be addressed to the party responsible for the violation. 

Therefore, before issuing either a Warning Letter or an Untitled Letter, the issuing 

office must determine the identity and role of the “responsible party.” OEIO may 

make this determination by examining the entry documents or the electronic entry 

data submitted to FDA’s OASIS via the Automated Commercial System (ACS) of 

Customs of Customs and Border Protection (CBP). The ACS is used by CBP to 

track, control, and process all goods imported into the United States. A key 
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component of ACS is the Automated Broker Interface ABI/ACS, which allows 

qualified participants to electronically file required import data with CPB. OEIO may 

also examine other supporting records. 

It is particularly important to determine whether the firm identified as the importerof-record is the actual importer, that is, importing for its own account, or whether 

the importer-of-record is a customs broker acting as the agent for the actual 

importer. Generally, customs brokers are merely agents for actual importers and 

therefore are not the responsible parties to whom Warning Letters should be 

addressed. For more information, see “Customs Brokers” below. Contact OEIO, 

Division of Import Operations Management (DIOM) and Division of Import Program 

Development (DIPD)for assistance in issuing a Warning or Untitled Letter to an 

importer, consignee, owner, or broker of imported goods. Use the OEIO contact 

information on the OEIO intranet page.

1. Importers

FDA may issue Warning Letters and Untitled Letters to importers, owners, or 

consignees of FDA-regulated imports when they engage in practices that 

violate the Act.

2. Customs Brokers

Generally, it is not appropriate to issue a Warning Letter or Untitled Letter to a 

customs broker unless that broker also is the owner, consignee, or importer 

responsible for the imported goods. In cases where a customs broker also is 

the owner, consignee, or importer, that is, the party initiating the importation, or 

if the broker has authority over the product through prior arrangement with the 

importer, it may be appropriate to issue a Warning Letter or Untitled Letter to 

that broker.

In all cases, authorized FDA officials should ensure that Warning Letters and 

Untitled Letters are addressed to the party responsible for the violation.

3. Foreign Firms

A Warning Letter or Untitled Letter may be appropriate if FDA has regulatory 

authority over the company and is prepared to exercise that authority. Firms 

may be placed on detention without physical examination (DWPE) because of 

repeatedly offering violative products for import. Unless the foreign firm is under 

the regulatory purview of FDA, issuing Warning Letters and Untitled Letters 

should be discussed with OCC. Authorized FDA officials may issue Warning 

Letters to foreign producers of FDA- regulated products based on 

establishment inspections or other information. For CBER regulated products, 

administrative actions may also be considered for licensed foreign 

establishments.
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4-1-13. Freedom of Information (FOI)

1. When submitting redaction requests to ORA DIDP for posting firm Warning 

Letter responses, ORA-issued Untitled Letters and Pharmacy Compounding 

(483's, 483 responses, State Hand-Off Letters, and State Referral Letters) 

create a linked CMS Work Activity, “DIDP Redaction Request.” Select “ORA 

DIDP FOIA” and do not assign to a specific individual. For Warning Letters 

see below.

2. Internet Posting of Warning Letters

DFOI will obtain the Redacted Warning Letters for posting using - CMS. 

When the Action Taken Date (i.e., date on the letter) is entered into CMS, 

an FOI section in the electronic case file for the Warning Letter opens.

a. Before selecting redaction office and FOIA officer, upload the 

warning letter confirmation of delivery receipt to the firm under the 

“Final Outcome” tab in Documents with the “Confirmation of Delivery” 

document type. 

b. Select the redaction office and the FOIA officer that will be redacting 

the letter. 

c. For ORA-issued warning letters only:

1) When submitting redaction requests to ORA DIDP follow the 

Warning Letter FOI process in CMS. Select “ORA DIDP FOIA” as 

the redaction office and leave the redaction officer “blank” as the 

FOIA officer will be assigned by Division of Information Disclosure 

Policy management. The FOIA officer will confirm there is a 

“Confirmation of Delivery Receipt” included before proceeding 

with redactions. 

2) For expedited redaction related to high profile posting, concurrent 

with a press release, send an e-mail to ORA’s DIDP 

management at oraospopfoiainfodiscpolicydivmgmt@fda.hhs.gov

with the subject line “Expeditited Redaction” include the name of 

firm, FEI # and CMS case number in the body of the e-mail. to 

process.

d. The FOI Officer redacts the letter and uploads a redacted Adobe 

PDF version of the letter into CMS under the “Final Outcome” tab and 

sets the status to “FOI Office Review” to notify DFOI it is ready for 

their review prior to posting.

NOTE: Do not include “bcc” information, or the “credit page” related to 

drafting sequence, etc., on the redacted copies.

For more information, see the operating instructions within the FOI User’s 

Guide hyperlink in MARCS-CMS under User Guides/Training. 
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3. FOI Requests for Warning Letters

All FDA-issued Warning Letters (redacted) should be posted on FDA’s 

Warning Letters internet page and thus the public can obtain a copy directly 

without the need to submit a formal FOIA request. If FDA has not yet posted 

the Warning Letter on the Warning Letter internet page, the requester 

should fax the request for a copy of the Warning Letter to DFOI to answer. 

By following this procedure, the agency will comply with its “first in, first out” 

policy. Do not disclose the existence of s Warning Letter or release a copy 

of a Warning Letter to the public unless your office receives the response to 

the FOIA request through DFOI.

DFOI will obtain the issued letter from within MARCS-CMS, or DFOI will 

notify OSPOP DE if the final letter is not contained in the MARCS-CMS 

case file per established regulatory procedures.

Refer the public to FDA's procedures in the agency's webpage for 

submitting a Freedom of Information Act (FOIA) request at: How to Make a 

FOIA Request. The webpage includes DFOI's mailing address and fax

number. Generally, do not accept electronic or telephone requests for 

records, including Warning Letters.

CTP Retailer Compliance Check Inspection Warning Letters are posted to 

the Tobaco Retailer Warning Letters webpage.

4-1-14. Center for Biologics Evaluation and Research (CBER)

The compliance programs for CBER regulated products are located at: 

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform

the page for Compliance Programs (CBER). Evaluate violations to decide if they 

are of regulatory significance. To help in this determination, refer to Part V of each 

Compliance Program, which provides information on deviations that may warrant 

action.

The organizational unit in the CBER Office of Compliance and Biologics Quality 

(OCBQ) that handles warning letter recommendations is the Division of Case 

Management (DCM). The office can be reached at the contact information on the 

CBER OCBQ intranet page, or at 240-402-9155.

1. CBER Program Warning Letters

a. All correspondence to licensed establishments should be addressed 

to the most responsible person. A copy of the correspondence should 

also be sent to the authorized official. For unlicensed establishments, 

correspondence should be addressed to the most responsible 

individual, e.g., blood bank director or hospital administrator.
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b. The lists of deviations (those that may lead to enforcement action if 

not promptly and adequately corrected) serve as guides for 

determining the recommended course of action. Any significant 

deviation, whether repetitive or an isolated occurrence, may warrant 

the issuance of a Warning Letter.

c. The specific areas that require CBER concurrence for program office 

directors to issue a Warning Letter are listed above in “Center 

Concurrence and Letters Issued by Centers.” In addition, program 

offices do not have direct reference authority to issue a Warning 

Letter to other federal agencies. Once the appropriate reviews are 

completed, Warning Letters are issued directly by the program office.

Also, 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.

d. Schedule a follow-up inspection approximately 30 days after the 

response to the Warning Letter is received to determine the 

adequacy of the reported corrective actions. When corrective action 

has not been made or the firm has failed to respond, the program 

office should consider suitable follow-up.

e. Send copies of all Warning Letters to OCBQ DCM.

f. Program offices should routinely provide copies of Warning Letters to 

the appropriate state agency or agencies. If the state regulatory office 

for these products is not known, contact ORA, OP using the contact 

information available on ORA OP’s intranet page. The letter should 

be redacted to protect confidential commercial information unless the 

state officials are commissioned or the sharing is authorized by law. 

See Chapter 3 for commissioning procedures.

2. Federal-State Relations For Blood Bank Inspections

Currently, the agency has no formal cooperative program with state or local 

jurisdictions for the inspection or regulation of blood banks. Cooperation with 

these authorities is encouraged especially if a state or local jurisdiction has a 

regulatory program for blood banks. Exchange of information should occur 

with all levels of state government whenever possible.

3. Advertising and Promotional Labeling Branch Procedural Guide

The Advertising and Promotional Labeling Branch (APLB) in DCM, OCBQ 

may initiate regulatory action if the advertising and promotional labeling are 

not consistent with the approved labeling (package insert), clinical data used 

to approve the product, or applicable sections of the Act and regulations for 

labeling and advertising by notifying the manufacturer in writing of the 

violations.
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Also, 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.

4. Warning Letter Recommendations

Send Warning Letter recommendations to CBER’s Office of Compliance and 

Biologics Quality

1. For Blood, Plasma and HCT/Ps:

Chief, Blood and Tissue Compliance Branch

Division of Case Management

2. For Biological Drugs and Devices:

Chief, Biological Drug and Device Compliance Branch

Division of Case Management, (except for therapeutic biological 

drugs, which are submitted to CDER for concurrence.)

Direct CBER Warning Letter questions to the Division of Case Management, 

240-402-9155.

Also, 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.

4-1-15. Center for Drug Evaluation and Research (CDER)

1. Preapproval Inspections/Pending Applications - Withhold Approval

Warning Letters are not to be recommended by the program offices as a 

follow-up to a preapproval inspection for pending drug or device applications 

(ANDAs, NDAs, BLAs) if no other FDA regulated products are marketed by 

the firm.

Warning Letters may be recommended by the program offices for 

preapproval inspections of drug and device firms if other FDA regulated 

products are marketed by the firm and the issue(s) affect marketed products 

or the inspection has extended to marketed products which are included on 

the FDA 483. These letters should include the following statement: "Due to 

the deficiencies listed on the attached FDA-483 we are recommending to the 

center that approval of the "..." application be withheld."

2. Surveillance Inspections For Assessing Conformance With Adulteration 

Provisions of the Act, Including CGMP

Warning Letters may be recommended by the program offices based on 

findings from surveillance inspections made to assess conformance of a 
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manufacturing site with the adulteration provisions of the Act, including 

CGMP. See Standard Charge i, in Section 3, below. The lists of deviations 

(those that may lead to enforcement action if not promptly and adequately 

corrected) serve as guides for determining the recommended course of 

action. Any significant deviation, whether repetitive or an isolated 

occurrence, may warrant the issuance of a Warning Letter. In therapeutic 

biologic drugs, operations to assess their conformance to the adulteration 

provisions, including CGMP, will be conducted by appropriately trained 

investigators. Therapeutic biologic drugs will be subject to the same 

regulatory procedures and actions as other drugs regulated by CDER. If 

there is a question of which center presides over a therapeutic biologic drug, 

contact the Office of Compliance, CDER, via email using the following email 

link CDER-OC-OMQ-Communications.

3. Standard CDER Charges

a. Grandfather New Drug Charge: The charge for drugs that claim to 

have been on the market before 1938 or before 1962:

505(a), 21 U.S.C. 355(a) - The articles are new drugs within 

the meaning of Section 201(p) of the Act, 21 U.S.C. 321(p), 

and approval of an application filed under Section 505(b) of 

the Act, 21 U.S.C. 355(b), is not effective for such drugs and a 

Notice of Claimed Investigational Exemption under Section 

505(i) of the Act, 21 U.S.C. 355(j), and 21 CFR Part 312 is not 

on file for such drugs, and documentation in support of such 

drugs, and "grandfather" exemption has not been submitted 

per 21 CFR 314.200(e)(2) which constitutes a waiver of such 

claims.

b. Back Door New Drug Charge: When the new drug charge (505) 

cannot be used because of lack of interstate movement of the article 

to be seized but there is documentation of the interstate movement of 

a component as a 301(k) sample then the charge is that the product 

was misbranded while held for sale:

502(f)(1), 21 U.S.C. 352(f)(1) - The article of drug, (DRUG 

NAME), is misbranded in that its labeling fails to bear 

adequate directions for the use for which the article is 

represented or suggested (as described above), and it is not 

exempt from this requirement under regulation 21 CFR 

201.115, since the article is a new drug within the meaning of 

Section 201(p) of the Act, 21 U.S.C. 321(p), and no approval 

of an application filed pursuant to Sections 505(b) and 505(j) 

of the Act, 21 U.S.C. 355(b) and (j), is effective for this drug.

A 502(f)(1) charge is appropriate for OTC drugs for which the 

directions are “inadequate in fact.” These are drugs which: 
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a) have no directions; 

b) have directions that deviate from those required by a final 

monograph; or 

c) have directions, but those directions lack information which 

is necessary for the drug to be used safely, such as dosage or 

frequency of administration. 

(See 21 CFR 201.5.) However, a 502(f)(1) charge should not be used 

if “adequate directions for common uses thereof are known to the 

ordinary individual.” (See 21 CFR 201.116.)

A 502(f)(1) charge is appropriate for all prescription drugs that are 

unapproved new drugs. This includes a drug with an indication that is 

generally not amenable to lay diagnosis, even if the drug would not 

ordinarily be thought of as a prescription drug (e.g., shark fin cartilage 

for the treatment of cancer.)

c. When the product is not a new drug, the simple misbranding charge 

should read:

502(f)(1), 21 U.S.C. 352(f)(1) - The article of drug, (Drug 

Name) is misbranded in that its labeling fails to bear adequate 

directions for use for which the article is represented or 

suggested.

d. Prescription Drug Where There Is No Labeling Bearing Directions for 

Use The charge is as follows:

502(f)(1), 21 U.S.C. 352(f)(1) - The article(s), (DRUG NAME), 

is subject to the provisions of Section 503(b)(1) of the Act, 21 

U.S.C. 353(b)(1), and it is not exempt from Section 502(f)(1) of 

the Act, 21 U.S.C. 352(f)(1), in that its labeling fails to bear 

information required by regulation 21 CFR 201.100, providing 

adequate directions for use under which a practitioner licensed 

by law can use the drug safely and for the purposes for which 

it is intended, including indications; effects, dosages, routes, 

methods, frequency and duration of administration, relevant 

hazards; contraindications, side effects, and precautions.

e. Drug Registration and Listing

The charge is misbranding under section 502(o) of the Act but the 

violation is failure to register and list:

502(o), 21 U.S.C. 352(o) - The articles, (DRUG NAMES), are 

misbranded in that they were manufactured, prepared, 
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propagated, compounded, or processed in an establishment 

not duly registered under Section 510 of the Act, 21 U.S.C. 

360, and the articles have not been listed as required by 

Section 510(j) of the Act, 21 U.S.C. 360(j).

f. Prescription and OTC Drugs

Section 503(b)(1) provides criteria for determining if the article is a 

prescription drug. Section 503(b)(1) is not a violation charge:

503(b)(1) 21 U.S.C. 353(b)(1) - The article, (DRUG NAME), 

because of its toxicity or other potential for harmful effect, or 

the method of use, is not safe for use except under the 

supervision of a practitioner licensed by law to administer such 

drug, and is misbranded because it is not dispensed upon 

prescription by a licensed practitioner.

The charge is:

i. For a prescription drug:

503(b)(4)(A), 21 U.S.C. 353(b)(4)(A) - The article of drug, 

(DRUG NAME), is subject to Section 503(b)(1) of the Act, 21 

U.S.C. 353(b)(1), and is misbranded in that its label fails to 

bear the symbol, "Rx only."

ii. For an OTC drug that is not to bear the symbol, “Rx only”: 

503(b)(4)(B), 21 U.S.C. 353(b)(4)(B) - The article of drug, 

(Drug name), is not subject to Section 503(b)(1) of the Act, 21 

U.S.C. 353(b)(1), and is misbranded in that its label bears the 

symbol, "Rx only” and it is not entitled to bear such symbol.

g. The following straight UNAPPROVED NEW DRUG charge may be 

used when there is interstate movement of the finished, labeled drug 

product.

505(a), 21 U.S.C. 355(a) - The article of drug, (DRUG NAME), 

is a drug within the meaning of Section 201(g) of the Act, 21 

U.S.C. 321(g), which may not be introduced or delivered for 

introduction into interstate commerce under Section 505(a) of 

the Act, 21 U.S.C. 355(a), since it is a new drug within the 

meaning of Section 201(p) of the Act, 21 U.S.C. 321(p), and 

no approval of an application filed pursuant to Section 505(b) 

of the Act, 21 U.S.C. 355(b), is effective for such drug.

h. For information regarding health fraud issues, contact OSPOP, DE, 

Health Fraud Branch using the information on the DE Staff Contacts 

page.
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i. For information regarding pharmacy compounding issues, contact the 

Pharmacy Compounding Team at (301) 796-3409.

j. Combination product CGMP charges (violations of 21 CFR part 820 

and 21 CFR part 210 and 211):

i. The products you manufacture at this facility are combination 

products under section 503(g) of the Federal Food, Drug, and 

Cosmetic Act (FD&C Act), 21 U.S.C. 353(g) as your products 

include [drug, device, biological product] constituent parts.

ii. This warning letter summarizes significant violations of current 

good manufacturing practice (CGMP) requirements for 

combination products. See 21 CFR part 4, 21 CFR parts 210 

and 211 (drug CGMP), and 21 CFR part 820 (Quality System 

or QS Regulation).

iii. Because your methods, facilities, or controls for 

manufacturing, processing, packing, or holding do not conform 

to drug CGMP requirements, 21 CFR parts 210 and 211, your 

combination products are adulterated within the meaning of 

section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351 (a)(2)(B).

In addition, your combination products are adulterated within 

the meaning of section 501(h) of the FD&C Act, 21 U.S.C. 

351(h), in that the methods used in, or the facilities or controls 

used for, their manufacture, packing, storage, or installation 

are not in conformity with applicable CGMP provisions of the 

Quality System regulation (21 CFR part 820).

k. Adulteration Due To Inadequate Conformance with CGMP.

The charge is as follows:

501(a)(2)(B), 21 U.S.C. 351(a)(2)(B) - The article(s), (DRUG 

NAME), is (are) adulterated within the meaning of Section 

501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B), in that the 

methods used in, or the facilities or controls used for, its 

manufacture, processing, packing, or holding fails to conform 

to, or is not operated or administered in conformity with, 

CGMP regulations [21 CFR 210, 211].

l. Adverse Drug Experience Reporting Violations and NDA Field Alerts 

Reporting Violations

The charge is as follows:

505(k)(1), 21 U.S.C. 355(k)(1) – Your firm failed to establish 

and maintain records and report data relating to clinical 

experience, along with other data or information for drugs for 

which an approved application is in effect, as required by 
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Section 505(k)(1) of the Act, 21 U.S.C. 355(k)(1). Failure to 

comply with Section 505(k) is a prohibited act under Section 

301(e) of the Act, 21 U.S.C. 331(e).

If CDER would like to include a charge related to a violation of 

505(o)(3) in a Warning Letter, they should consult with OCC.

Also, 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.

4-1-16. Center for Devices and Radiological Health (CDRH)

1. Violations Under The Mammography Quality Standards Act (MQSA) 

For routine Level 1 or repeat Level 2 noncompliances found during MQSA 

inspections, programs will not need CDRH concurrence before sending 

Warning Letters. Also, programs may send a Warning Letter without CDRH 

concurrence when a facility has performed mammography without a 

certificate. Under other circumstances, where inspections show numerous 

Level 2 and 3 noncompliances but no Level 1 or repeat Level 2 

noncompliances, programs will need CDRH concurrence before sending a 

Warning Letter. For any of the situations mentioned above where CDRH 

concurrence is needed for an MQSA Warning Letter, the program should 

send the draft Warning Letter to the Division of Mammography Quality and 

Radiation Programs. (See Part V of the Compliance Program.)

Most Level 1 and repeat Level 2 inspection observations will not result in 

Warning Letters (see Part V of the Compliance Program).

Also, 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.

2. Sample Wording For Charges

a. Adulteration Charges

i. Section 501(f)(1)(B), 21 U.S.C. 351(f)(1)(B), in that it is a 

Class III device under Section 513(f), 21 U.S.C. 360c(f), and 

does not have an approved application for premarket approval 

in effect pursuant to Section 515(a), 21 U.S.C. 360e(a), or an 

approved application for an investigational device exemption 

under Section 520(g), 21 U.S.C. 360j(g).

ii. Section 501(c), 21 U.S.C. 351(c), in that its strength, purity, or 

quality falls below that which it purports or is represented to 

possess.
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iii. Section 501(h), 21 U.S.C. 351(h), in that the methods used in, 

or the facilities or controls used for, the manufacture, packing, 

storage, or installation are not in conformance with the CGMP 

requirements for medical devices which are set forth in the 

Quality System regulation, as specified in Title 21, Code of 

Federal

iv. Section 501(i), 21 U.S.C. 351(i), in that it is a device for which 

an exemption has been granted under section 520(g), 21 

U.S.C. 360j(g), for investigational use and the person who was 

granted such exemption or an investigator who has used the 

device under such exemption has failed to comply with a 

requirement imposed by or under such section.

b. Misbranding Charges

i. Section 502(a), 21 U.S.C. 352(a), in that the labeling for the 

device represents or suggests that the device is adequate and 

effective for (......), which representations or suggestions are 

false or misleading or otherwise contrary to fact because the 

device is not adequate or effective for such purposes.

ii. Section 502(b), 21 U.S.C. 352(b), in that the device is in 

package form and its label fails to contain: (1) the name and 

place of business of the manufacturer, packer, or distributor; 

and (2) an accurate statement of the quantity of the contents 

in terms of weight, measure, or numerical count.

iii. Section 502(f)(1), 21 U.S.C. 352(f)(1), in that the labeling for 

the device fails to bear adequate directions for the purposes 

for which it is intended, because adequate directions cannot 

be written for (e.g., such purposes, etc.)

iv. Section 502(f)(1), 21 U.S.C. 352(f)(1), in that the labeling for 

the device fails to bear adequate directions for use because 

the labeling does not contain an expiration date based upon 

the stated storage instructions, as required by 21 CFR 809.10.

v. Section 502(o), 21 U.S.C. 352(o), in that the device was 

manufactured, prepared, propagated, compounded, or 

processed in an establishment not duly registered under 

Section 510, 21 U.S.C. 360, was not included in a list required 

by Section 510(j), 21 U.S.C. 360(j),, and a notice or other 

information respecting the device was not provided to FDA as 

required by Section 510(k), 21 U.S.C. 360(k).

vi. Section 502(o), 21 U.S.C. 352(o), in that a notice or other 

information respecting the device was not provided to FDA as 

required by 21 CFR 807.81(a)(3)(i), when the device was 

significantly changed or modified by (describe change).
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For examples of model Quality System regulation/MDR Warning 

Letters, see Medical Device Compliance Program 7382.845 -

Inspection of Medical Device Manufacturers.

CDRH has established a separate mailbox for electronic submission 

of device Warning Letters from program offices. The address is 

CDRHOCWarningLetterResponses..

3. Letters To X-Ray Assemblers

Letters issued to assemblers of diagnostic x-ray systems as a result of 

routine compliance field testing which uncover Class B Violations (see CP 

7386.003, Field Compliance Testing of Diagnostic Medical X-Ray 

Equipment) will be issued as Untitled Letters. Letters issued for more 

serious radiation hazard violations (Class A Violations) which require 

immediate corrective action will be issued as Warning Letters. Warning 

Letters may also issue to x-ray assemblers for “pattern of violations” 

situations where the agency is prepared to take enforcement action if the 

violations continue and/or if failure to correct violations continues. 

Subchapter C - Electronic Product Radiation Control (formerly the Radiation 

Control for Health and Safety Act of 1968) of Chapter V of the Act requires 

the Secretary to notify the assembler/manufacturer concerning 

noncompliant or defective radiation emitting devices and solicit follow-up 

corrective action by the assembler/manufacturer whether or not the agency 

is prepared to take follow-up enforcement action. If there are specific cases 

to discuss or a need for further information on this subject, contact CDRH, 

Office of In Vitro Diagnostics and Radiological Health, Division of 

Radiological Health, Diagnostic X-Ray Devices Systems Branch at the 

contact information provided on the office’s Intranet page.

Also, 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.

4. Combination product CGMP charges (violations of 21 CFR part 820 and 21 

CFR part 210 and 211):

i. The products you manufacture at this facility are combination 

products under section 503(g) of the Federal Food, Drug, and 

Cosmetic Act (FD&C Act), 21 U.S.C. 353(g) as your products 

include [drug, device, biological product] constituent parts.

ii. This warning letter summarizes significant violations of current 

good manufacturing practice (CGMP) requirements for 

combination products. See 21 CFR part 4, 21 CFR parts 210 

and 211 (drug CGMP), and 21 CFR part 820 (Quality System 

or QS Regulation).
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iii. Because your methods, facilities, or controls for

manufacturing, processing, packing, or holding do not conform 

to drug CGMP requirements, 21 CFR parts 210 and 211, your 

combination products are adulterated within the meaning of 

section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351 (a)(2)(B).

In addition, your combination products are adulterated within 

the meaning of section 501(h) of the FD&C Act, 21 U.S.C. 

351(h), in that the methods used in, or the facilities or controls 

used for, their manufacture, packing, storage, or installation 

are not in conformity with applicable CGMP provisions of the 

Quality System regulation (21 CFR part 820).

4-1-17. Center for Food Safety and Applied Nutrition (CFSAN) 

and Center for Veterinary Medicine (CVM)

CFSAN and CVM will provide instructions for priority areas to be covered in 

Warning Letters in Compliance Programs.

Recommendations, coupled with their supporting evidence, should only be 

submitted using CMS, to CFSAN or CVM via CMS. This system is available from 

the IT Applications page on FDA's intranet site.

4-1-18. Center for Tobacco Products (CTP) Retailer 

Compliance Check Inspection Program

The Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) 

(Public Law 111-31; 123 Stat. 1776) was enacted on June 22, 2009, amending the 

Federal Food, Drug, and Cosmetic Act (the Act) and providing FDA with the 

authority to regulate tobacco products. As required by section 102 of the Tobacco 

Control Act, FDA published a final rule regarding sales and distribution of 

cigarettes and smokeless tobacco. This final rule was identical in its provisions to 

the regulation issued by FDA in 1996 (61 FR 44396, August 28, 1996), with certain 

specified exceptions. The rule at 21 CFR Part 1140, has two main sections:

1. Access provisions, which consist of restrictions on the sale of cigarettes, 

smokeless tobacco products, and cigarette tobacco; and

2. Restrictions on advertising, marketing, and promotion of cigarettes and 

smokeless tobacco products.

The Tobacco Control Act also amended the Act to require that the agency contract 

with States, where feasible, to carry out inspections of retailers within that State to 

enforce applicable provisions of the Act and its implementing regulations. 

Therefore, compliance check inspections of retailers are carried out in accordance 

with each contract and pursuant with agency authority.
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FDA’s State Tobacco Compliance Check Inspections of retailers are completed by 

FDA –commissioned state inspectors. Inspections that result in violations are 

reviewed by the State Programs Group within the Office of Compliance and 

Enforcement (OCE) of the Center for Tobacco Products. If it is determined that 

there has been a violation, OCE initiates appropriate action in the form of a 

Warning Letter or enforcement action. The program offices are not involved in 

retailer compliance check inspections or the issuance of related Warning Letters.

Standard tobacco retailer violation charges include:

1. Misbranded tobacco products within the meaning of section 903(a)(7)(B) of 

the FD&C Act, 21 U.S.C. § 387c(a)(7)(B), in that they are sold or distributed 

in violation of 21 C.F.R. Part 1140.

2. Adulterated cigarettes with certain characterizing flavors within the meaning 

of section 907(a)(1)(A) of the FD&C Act, 21 U.S.C. § 387g(a)(1)(A).

3. Violative modified risk tobacco products within the meaning of section

911(b)(2) of the FD&C Act, 21 U.S.C. § 387k(b)(2).

Tobacco Retailer Warning Letters are not subject to the time frames laid out in 

section 4-1-7 or the issuing of Warning Letter Close-Out Letters in 4-1-8 due to 

their nature and volume. Additionally, Tobacco Retailer Warning Letters are not 

routinely acknowledged as stated in 4-1-8. CTP internal procedures to address 

time frames, acknowledgment of responses, and close-out procedures.

4-1-19. Tracking

1. Identification Of Warning Letters

All Warning Letters must be entered into the Compliance Management 

System (CMS); whether they are generated by a program office or center, 

and whether they are approved and issued or not. Every Warning Letter that 

is issued should bear the CMS-assigned number or a sequential code 

number assigned by the issuing program office or center. If a program office 

or center assigned number is used, this number should be recorded in CMS 

to facilitate tracking.

2. Updating Firm Profile Status in eNSpect

When a violation letter is the result of a CGMP or QS inspection of a 

domestic or foreign drug, biologics, or medical device facility, the firm’s 

profile status information in eNSpect is to be appropriately updated at each 

stage in the review process. The action office (i.e., the program office or 

center initiating the recommendation) is responsible for entering the status 

of the violation letter into eNSpect. (See “Firm Profile Updates in eNSpect”

in this chapter and Exhibit 4-1 for more information.)”
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4-2 UNTITLED LETTERS

4-2-1. Format and Content

An Untitled Letter cites violations that do not meet the threshold for significance of 

regulatory significance for a Warning Letter. Therefore, the format and content of 

an Untitled Letter should clearly distinguish it from a Warning Letter. For example:

1. The letter is not titled.

2. The letter does not include a statement that FDA will advise other federal 

agencies of the issuance of the letter so that they may take this information 

into account when considering the awarding of contracts.

3. The letter does not include a warning statement that failure to take prompt 

correction may result in enforcement action.

4. The letter does not evoke a mandated follow-up.

5. The letter requests (rather than requires) a written response from the firm 

within a reasonable amount of time (e.g., “Please respond within 30 days”), 

unless more specific instructions are provided in a relevant Compliance 

Program.

Any appropriate agency compliance official may issue an Untitled Letter.

Also, 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.

4-2-2. Center Concurrence and Letters Issued By Centers

Center concurrence is required prior to issuing Untitled Letters unless direct 

reference has been granted.

Also, 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.

4-2-3. Tracking

1. Identification Of Untitled Letters

All Untitled Letters must be entered into CMS; whether they are generated 

by a program office or center, and whether they are approved and issued or 

not. Every Untitled Letter that is issued should bear the CMS-assigned 

number o
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r a sequential code number assigned by the issuing program office or 

center. If a program office or center assigned number is used, this number 

should be recorded in CMS to facilitate tracking.

2. Updating Firm Profile Status in eNSpect

When a profilable firm (i.e., domestic or foreign drug, biologics, or medical 

device facility) undergoes a CGMP or QS inspection, the inspected profile 

classes should be updated by the action office at each stage in the review 

process. When an Untitled Letter is issued as a result of the inspection, the 

date and type of letter issued should be entered in the Remarks field for the 

relevant profile classes. For profile procedures, see IOM Exhibit 5-14 or the 

Government-Wide Quality Assurance Program (GWQAP) intranet page.

4-3 USE OF STATE EVIDENCE FOR FDA WARNING 

LETTERS AND UNTITLED LETTERS

Evidence obtained by state personnel may be sufficient to support the issuance of 

Warning Letters and Untitled Letters if the standards and criteria used by state 

personnel provide reliable support for regulatory actions the agency may take 

consistent with the agency’s guidance on regulatory actions and laboratory 

procedures.

1. If state evidence involves inspectional observations made solely by state 

personnel, factors that indicate that the standards and criteria used are 

reliable for these purposes include, but are not limited to, the following:

a. The state inspector made the inspectional observations during an 

inspection conducted pursuant to an agency contract inspection 

program or a joint inspection program in which FDA participates; or

b. The state inspector made the inspectional observations after 

receiving training in relevant law and any specific requirements 

applicable to the inspection and the establishment or commodity 

being inspected; or

c. The state inspector received an “acceptable” rating if audited by a 

qualified FDA or state auditor under FMD 76, “State Contracts –

Evaluation of Inspectional Performance” (or other applicable audit 

program); or

d. The state inspector detected and documented the observations in the 

manner set forth in FDA’s inspectional procedures, such as the 

Investigations Operations Manual, guides to inspections, or 

comparable inspectional approaches.

2. If state evidence involves laboratory data, factors that indicate that the 

laboratory data and the methods and procedures used to collect and 

analyze the sample are valid and reliable include the following:
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a. The procedures involved in the sample collection have been 

analyzed and found to be reliable in that the sample was collected, 

handled, and analyzed using procedures that assure sample integrity 

and chain of custody and a sample size and test method the Director, 

Office of Regulatory Science (ORS),, determines to be appropriate; 

or

b. The Director, ORS, designates that the laboratory data from state 

facilities meet the criteria and standards appropriate for compliance 

decision-making; or

c. The Director, ORS, has reviewed and endorsed the state laboratory 

findings through an evaluation of the laboratory operations, methods, 

sampling, and evidence documentation.

3. Except for state inspections of retailers to determine compliance with the 

provisions of the Family Smoking and Tobacco Control Act and its 

implementing regulations, the program office must review and endorse the 

state evidence as meeting the criteria for the issuance of a Warning Letter 

or Untitled Letter in accordance with FDA procedures and agency 

compliance policy. Warning Letters and Untitled Letters relating exclusively 

to state inspections of retailers to determine compliance with the provisions 

of the Family Smoking and Tobacco Control Act and its implementing 

regulations will be drafted by the Center for Tobacco Products based on 

sufficient evidence collected and documented by state personnel.

4. The FDA product center with primary jurisdiction over the establishment or 

commodities inspected and the Office of Chief Counsel concurs with the use 

of the evidence obtained by state personnel.

5. This section is not applicable where a proposal for a Warning Letter or 

Untitled Letter is based on FDA-developed evidence to demonstrate the 

current condition of the commodity or establishment, and evidence obtained 

by state personnel is used to solely demonstrate prior compliance history.

4-4 EXHIBITS

Exhibit 4-1 Procedures for Clearing FDA Warning Letters and Untitled Letters

Exhibit 4-2 Warning Letter Close-Out Letter
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Exhibit 4-1 Procedures for Clearing FDA Warning Letters 

and Untitled Letters

Contents

1. Purpose

2. Scope

3. Background

4. Definitions

5. Responsibilities

6. Procedures

a. Timeframes

b. Procedures for the Review of Agency Warning and Untitled Letters

c. Licensed Products Letters

d. Enforcement Correspondence under an Audit Review

1. Purpose

To facilitate the review by the Office of Chief Counsel (OCC) of certain types of 

Warning Letters and Untitled Letters, prior to their issuance, for legal sufficiency 

and consistency with Agency policy.

2. Scope

These procedures apply to all of the agency components that are responsible for 

recommending, evaluating or issuing Warning Letters and Untitled Letters. 

Therefore, the applicability of these procedures is not limited to ORA and the 

Centers’ offices of compliance.

The OCC review provisions in these procedures apply only to Warning and Untitled 

Letters described below:

a. CFSAN

i. Any Warning or Untitled Letter involving a novel, controversial, 

or sensitive legal issue.

ii. Warning Letters involving medical foods.

iii. Warning Letters involving section 502(f)(1) drug misbranding 

charges.

iv. Warning Letters involving section 403(a) false or misleading 

food labeling.
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v. Warning Letters involving section 403 (r) (1) (A) (unauthorized 

nutrient content claim) or section 403 (r) (1) (B) (unauthorized 

health claims) charges.

vi. Warning Letters for dietary supplements with a new drug 

charge based in whole or in part on promotional use of 

scientific studies to market the product for disease uses.

vii. Warning Letters with violations of the general CGMP 

regulations.

viii.Warning and Untitled Letters with violations of the dietary 

supplement CGMP regulations.

ix. Warning Letters with adulteration and/or misbranding charges 

related to cosmetics.

In addition, cyber letters (letters resulting from web sites promoting 

dietary supplements with drug claims) will be reviewed under the audit 

review program in 6.4 with OCC reviewing every 10th letter.

b. CDRH

i. Any warning or untitled letter involving a novel, controversial, 

or sensitive legal issue.

ii. Advertising/promotion warning/untitled letters.

iii. Warning/untitled letters with unapproved device charges under 

section 501(f)(1)(B) if the firm contests that the product is a 

device or any other warning/untitled letter in which the firm 

contests that the product is a device.2

iv. Warning/untitled letters with section 502(a) charge-labeling of 

the device is false or misleading.

v. Warning/untitled letters with 502(j) charge-device is dangerous 

to health when used in the manner or with the frequency or 

duration prescribed, recommended or suggested in the 

labeling thereof.

vi. Warning/untitled letters with section 502(o) chargenotice/information of modification of the device not provided to 

FDA.

vii. Warning/untitled letters with section 502(o) chargenotice/information of new intended use of the device not 

provided to FDA.

2 The term “contests ” in this list means that FDA has had prior contact with the firm, e.g., through 

an inspection, a 483 response, a prior issuance of an untitled letter, email, or telephone, and the 

firm has asserted that its product is not a “device.”
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viii.Warning/untitled letters with section 502(t) (3)-firm has failed 

or refused to comply with a requirement under section 522.

ix. Warning and untitled letters involving bioresearch monitoring 

not covered by the December 8, 2005 agreement between 

OCC and CDRH’s Office of Compliance.

c. CVM

i. Any Warning or Untitled Letter involving a novel, controversial, 

or sensitive legal issue.

ii. Warning Letters involving bioresearch monitoring.

iii. Warning Letters with violations of 21 CFR 589.2000 (ruminant 

feed ban) and/or 21 CFR 589.2001 (new animal feed ban).

iv. Warning and Untitled Letters involving advertising and 

promotion.

v. Warning Letters with section 502(a) false or misleading 

labeling drug misbranding charges.

vi. Warning Letters related to turtles.

vii. Warning and Untitled Letters involving new animal drug 

compounding. 

d. CBER

i. Any Warning or Untitled Letter involving a novel, controversial, 

or sensitive legal issue.

ii. Warning Letters and notice of initiation of disqualification 

proceedings and opportunity to explain (or “NIDPOEs”) 

involving clinical investigators and IRBs.

iii. Warning Letters involving advertising or promotion, except for 

those involving only straightforward omission of risk (e.g., no 

risk information whatsoever).

iv. Warning and Untitled Letters involving product jurisdiction.

v. Warning and Untitled Letters involving unregistered or 

unlicensed blood banks.

e. CDER

i. Any Warning or Untitled Letter involving a novel, controversial, 

or sensitive legal issue.

ii. Warning Letters involving clinical investigators and IRBs.

iii. Warning Letters involving advertising or promotion, except for 

those involving only straightforward omission of risk (e.g., no 

risk information whatsoever).
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iv. Warning and Untitled Letters involving compounding.

v. Warning and Untitled Letters involving unapproved new drugs, 

except health fraud, over-the-counter drugs subject to final 

monographs, and Warning Letters that contain both GMP and 

unapproved new drug charges.

f. ORA

Any Warning or Untitled Letter involving a novel, controversial, 

or sensitive legal issue.

3. Background

On November 29, 2001, then Deputy Secretary of the Department of Health and 

Human Services directed “...the Food and Drug Administration (FDA) to submit all 

Warning Letters and Untitled Letters to FDA’s OCC prior to their issuance so that 

they can be reviewed for legal sufficiency and consistency with Agency policy.” To 

implement this directive, a cross-agency working group established procedures to 

integrate OCC review into the agency’s existing procedures for the review of 

enforcement correspondence. These procedures were implemented in March 

2002. In August/September of 2009, the OCC review provisions of these 

procedures were modified, on an interim basis, to apply only to the Warning and 

Untitled Letters described in section “2. Scope.” The 2009 interim procedures were 

evaluated as described in section 5.1 and finalized in December 2010.

4. Definitions

For the purpose of these procedures:

a. A Warning Letter is a correspondence that notifies regulated industry 

about violations that FDA has documented during its inspections or 

investigations. Typically, 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 (the Act), its implementing 

regulations and other federal statutes. Warning Letters should only 

be issued for violations of regulatory significance, i.e., those that may 

actually lead to an enforcement action if the documented violations 

are not promptly and adequately corrected. A Warning Letter is one 

of the Agency’s principal means of achieving prompt voluntary 

compliance with the Act.

b. An Untitled Letter is an initial correspondence with regulated industry 

that cites violations that do not meet the threshold of a Warning 

Letter. Untitled Letters are intended to cover those circumstances 

where the Agency has a need to communicate with regulated 

industry about violations that do not meet the threshold of regulatory 

significance as described above. The three types of letters related to 
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licensed products that are issued by CBER and CDER, pursuant to 

subsection 6.3 of Exhibit 4-1 do not necessarily fall within this 

definition of an Untitled Letter; however, they are still Untitled Letters 

that are covered by the scope of these procedures.

5. Responsibilities

a. FDA’s Office of Policy, Planning, Legislation and Analysis conducted 

a qualitative and quantitative evaluation of the OCC review provisions 

in the 2009 interim procedures. OCC, in coordination with other 

agency components, reviewed the results of this evaluation and 

concluded that the interim procedures should be finalized.

Any refinements to these procedures that become identified through 

periodic evaluation or otherwise, that may facilitate the review, 

streamline or focus the process, or enable better management of the 

workload, while maintaining the overall intent, are implemented through 

established, internal agency review procedures. In addition, FDA will 

monitor the timeframes to determine whether they need to be modified 

based on the agency’s experience with these procedures.

b. Each Office involved in implementing these procedures is 

responsible for documenting additional internal procedures as 

needed.

c. Violation letters are tracked using MARC-CMS (or CMS). CMS 

provides the capability to enter and track Warning and Untitled 

Letters through the approval process. The action office (i.e., the 

Program office or Center initiating the recommendation) is 

responsible for entering all violation letters into CMS; as well as 

updating data related to their submissions. The issuing office of the 

violation letter is also responsible for ensuring that a PDF copy of the 

final, signed violation letter is added into CMS.

Instructions for using CMS are available in the User’s Guide link within 

the application and further information is available within the link to 

Frequently Asked Questions.

d. When a violation letter is the result of a CGMP or QS inspection of a 

domestic or foreign drug, biologics, or medical device facility, the 

firm’s profile status information in eNSpect is to be appropriately 

updated at each stage in the review process. The action office (i.e., 

the Program office or Center initiating the recommendation) is 

responsible for entering the Final Profile Status in eNSpect. (See 

Chapter 4 “Firm Profile Updates in eNSpect” for more information.)
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6. Procedures

a. Timeframes

i. Warning Letters

The agency did not establish new timeframes for ORA and the Centers. 

In these procedures, the agency recommits to the established 

timeframes at each level of review. To ensure the applicability of 

evidence to the present situation, the agency will strive to issue Warning 

Letters within four months from the appropriate reference date. 

Examples of the appropriate reference date are: the last day of the 

inspection, the date of sample analysis, or the date of evidence 

collection.

If a Program or Office enters a formal agreement with another Center, 

such as a Concept of Operations (CONOPS), the agreement's timelines 

supercede this procedure. Recommendations to the Center and 

Warning Letter time frames for Human Drug Inspections (Surveillance 

and For-Cause Inspections) which fall under the review of CDER, can be 

found in FDA’s INTEGRATION OF FDA FACILITY EVALUATION AND 

INSPECTION PROGRAM FOR HUMAN DRUGS: A CONCEPT OF 

OPERATIONS. If the agency anticipates pursuing further enforcement 

action after issuance of the Warning Letter but prior to a follow-up 

inspection or other verification activities, an expedited timeframe for 

Warning Letter issuance may be warranted to ensure applicability of the 

evidence to the present situation (i.e., within four months from the 

appropriate reference date).

The timeframe for OCC review, when OCC review is required, is fifteen 

(15) working days. If OCC does not respond to Direct Reference 

Warning Letters and those issued pursuant to foreign inspections within 

this timeframe, the Program office or Center can presume concurrence 

and may send the letter out without additional input. All other categories 

of letters requiring OCC review should await an OCC decision prior to 

being issued. For all categories of Warning Letters receiving a decision 

by OCC, OCC will either concur, concur with changes, not concur with 

written reasons, or flag the letter because it raises significant issues and 

questions, e.g., jurisdictional issues or insufficient evidentiary support.

The period for OCC review officially begins once OCC has received the 

full packet of materials that serve as support for the agency’s issuance of 

the Warning Letter. If the basic elements of the case are not provided 

(the basic elements are identified in the Program office and center 

responsibility sections of these procedures), OCC will return the 

materials to the originator. If, as a part of their review, OCC asks for an 

exhibit or attachment that accompanied the Establishment Inspection 
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Report (EIR) or Form FDA 483 response, a copy of the document should 

be sent to OCC electronically, via fax or by mail.

ii. Warning Letter Responses

When OCC review of the Warning Letter was required, and it is 

reasonably clear from the Warning Letter response that the individual or 

firm is going to contest the findings as set out in the Warning Letter, 

OCC should be consulted and provided with the relevant documents. 

This is not necessary when the disputed issues are scientific or 

technical.

iii. Untitled Letters

There are no agency timeframes for the issuance of Untitled Letters. 

However, pursuant to these procedures, the working group established 

timeframes for the review of Untitled Letters. In most cases, the 

timeframes for Warning Letters are tripled for the review of Untitled 

Letters. The exceptions to this rule are the letters for licensed products 

that are issued by CBER or CDER pursuant to subsection 6.3 of this 

exhibit. To ensure the applicability of evidence to the present situation, 

the agency will strive to issue Untitled Letters within six months from the 

last day of the inspection, the date of sample analysis, or the date of 

evidence collection.

When OCC’s review of an Untitled Letter is required, OCC will either 

concur, concur with changes, not concur with written reasons, or flag the 

letter because it raises significant issues and questions, e.g., 

jurisdictional issues or insufficient evidentiary support. However, the 

default provisions do not apply to Direct Reference Untitled Letters and 

Untitled Letters issued pursuant to a foreign inspection. The period for 

OCC review officially begins once OCC has received the full packet of 

materials that serve as support for the agency’s issuance of the Untitled 

Letter. If the basic elements of the case are not provided (the basic 

elements are identified in the Program office and Center responsibility 

sections of these procedures), OCC will return the materials to the 

originator. If, as a part of their review, OCC asks for an exhibit or 

attachment that accompanied the EIR or Form FDA 483 response, a 

copy of the document should be sent to OCC electronically, via fax or by 

mail.

b. Procedures for the Review of Agency Warning and Untitled Letters

All Warning Letters and Untitled Letters must be entered into CMS, 

where they are available for review.
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i. General Procedures for Direct Reference Warning and 

Untitled Letters

a. Program office Responsibilities

1. When OCC review of a Warning or Untitled Letter is 

required:

• Submit a draft “final” Warning Letter via CMS to 

OCC for concurrence, within 15 working days after 

the completion of an inspection, the sample 

analysis, or date of evidence collection.

• Submit a draft “final” Untitled Letter via CMS to OCC 

for concurrence within 45 working days after the 

completion of an inspection, the sample analysis, or 

date of evidence collection.

• To facilitate OCC’s review of the Warning or Untitled 

Letters, ensure that the violation letter documents 

within CMS include the Form FDA 483, the 

endorsement page of the EIR or the FACTS 

coversheet, the narrative portion of the EIR, and, if 

applicable, the summary of any sample analysis.

• If there is no Form FDA 483 or EIR, send the 

evidence to OCC that supports the issuance of the 

letter.

• If the Program office receives the Form FDA 483 

response prior to submitting the draft “final” Warning 

or Untitled Letter to OCC, a copy of the Form FDA 

483 response (without the exhibits or the 

attachments) and the Program office’s assessment 

of the response should accompany the draft “final” 

Warning or Untitled Letter.

• If the Program office receives the Form FDA 483 

response while OCC is reviewing the draft “final” 

Warning or Untitled Letter, the Program office 

should notify the attorney that is conducting the 

review. A copy of the Form FDA 483 response 

(without the exhibits or the attachments) and the 

Program office’s assessment of the response 

(including whether the response has changed the 

Program office’s view on whether to issue the letter) 

should also be submitted to the assigned attorney 

electronically, via fax, or by mail and also added into 

the case file for the proposed action within CMS. 

The review clock will stop when OCC is notified and 
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restart upon OCC’s receipt of the Form FDA 483 

response and the Program office’s assessment. Any 

changes to the proposed letter as a result of the 

FDA-483 response will be discussed with the 

initiating office.

• If OCC concurs, or if OCC does not review the draft 

“final” Warning Letter within 15 working days, issue 

the letter.

• If OCC concurs with the draft “final” Untitled Letter, 

issue the letter.

• If the Program office receives the Form FDA 483 

response after OCC has concurred with the 

issuance of the draft “final” Warning or Untitled 

Letter, you should issue the letter.

In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Program Office will work with OCC as necessary to 

quickly address OCC’s concerns.

2. Upon issuance, add a PDF signed copy of the Warning 

or Untitled Letter into the Final Outcome tab for the 

action within CMS. Distribute additional copies in 

accordance with any applicable Compliance Program 

and RPM Chapter 4.

b. OCC Responsibilities

1. Review any draft “final” Warning Letter and Untitled 

Letter requiring OCC review within 15 working days.

2. If concurrence, send concurrence to the Director of the 

Compliance Branch and the compliance officer who 

proposed the action, along with a copy of the draft 

“final” letter with any edits (the Program office can then 

issue the letter).

3. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Program office, 

and state in writing the reason for nonconcurrence.

c. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified 

by the Program office, Center or OCC. 
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ii. General Procedures for Warning and Untitled Letters Pursuant 

to a Foreign Inspection

a. Center Responsibilities

1. Within 15 working days after the receipt of the EIR, the 

Center will determine if a Warning Letter is 

appropriate.

2. Within 45 working days after the receipt of the EIR, the 

Center will determine if an Untitled Letter is 

appropriate.

3. When OCC review of a Warning or Untitled Letter is 

required:

• Send a copy of the draft “final” letter via CMS to 

OCC for concurrence.

• To facilitate OCC’s review of the Warning or Untitled 

Letters, ensure that the violation letter documents 

within CMS include the Form FDA 483, the 

endorsement page of the EIR or the FACTS 

coversheet, the narrative portion of the EIR, and, if 

applicable, the summary of any sample analysis.

• If there is no Form FDA 483 or EIR, send the 

evidence to OCC that supports the issuance of the 

letter.

• If the agency receives the Form FDA 483 response 

prior to submitting the draft “final” Warning or 

Untitled Letter to OCC, a copy of the Form FDA 483 

response (without the exhibits or the attachments) 

and the agency’s assessment of the response 

should accompany the draft “final” Warning or 

Untitled Letter.

• If the agency receives the Form FDA 483 response 

while OCC is reviewing the draft “final” Warning or 

Untitled Letter, the Center should notify the attorney 

that is conducting the review. A copy of the Form 

FDA 483 response (without the exhibits or the 

attachments) and the agency’s assessment of the 

response (including whether the response has 

changed the agency’s view on whether to issue the 

letter) should also be submitted to the assigned 

attorney electronically, via fax, or by mail, and 

should also be added into the case file for the 

proposed action within CMS. The review clock will 
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stop when OCC is notified and restart upon OCC’s 

receipt of the Form FDA 483 response and the 

agency’s assessment. Any changes to the proposed 

letter as a result of the FDA-483 response will be 

discussed with the initiating office.

• If OCC concurs, or if OCC does not review the draft 

“final” Warning Letter within 15 working days, issue 

the letter.

• If OCC concurs with the draft “final” Untitled Letter, 

issue the letter.

• If the agency receives the Form FDA 483 response 

after OCC has concurred with the issuance of the 

draft “final” Warning or Untitled Letter, the letter 

should be issued.

• In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Center will work with OCC and the programs and 

divisions in ORA as necessary to quickly address 

OCC’s concerns.

4. Upon issuance, add a PDF signed copy of the Warning 

or Untitled Letter into the Final Outcome tab for the 

action within CMS. 

b. OCC Responsibilities

1. Review any draft “final” Warning Letter and Untitled 

Letter requiring OCC review within 15 working days.

2. If concurrence, send concurrence to the Center along 

with a copy of the draft “final” letter with any edits (the 

Center can then issue the letter).

3. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center, and state 

in writing the reason for nonconcurrence.

c. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified 

by the Program office, Center or OCC. 

iii. Warning and Untitled Letters that Require Center Concurrence

a. Program office Responsibilities
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1. Within 15 working days after the completion of the 

inspection, the sample analysis, or collection of 

evidence, submits a recommendation and a draft 

“final” Warning Letter to the Center through CMS.

2. Within 45 working days after the completion of the 

inspection, the sample analysis, or collection of 

evidence, submit a recommendation and a draft “final” 

Untitled Letter to the Center through CMS.

3. To the extent that this information is not included in the 

recommendation, and to facilitate the Center’s review 

of the Warning or Untitled Letters, ensure that the 

violation letter documents within CMS include all 

evidence necessary to support issuance of the letter or 

other relevant information. For example, the Form FDA 

483, the endorsement page of the EIR or the FACTS 

coversheet, the narrative portion of the EIR, the 

relevant exhibits, product labels and labeling, and, if 

applicable, the summary of any sample analysis.

4. If the Program office receives the Form FDA 483 

response prior to submitting the draft “final” Warning or 

Untitled Letter recommendation, a copy of the Form 

FDA 483 response (without the exhibits or the 

attachments) and the Program office’s assessment of 

the response should accompany the draft “final” 

Warning or Untitled Letter.

5. If the Program office receives the Form FDA 483 

response while the draft “final” Warning or Untitled 

Letter is being reviewed, the Program office should 

notify the Center and, for letters requiring OCC review, 

the attorney that is conducting the review, as 

appropriate. The review clock will stop when OCC is 

notified and restart upon OCC’s receipt of the Form 

FDA 483 response and the agency’s assessment. A 

copy of the Form FDA 483 response (without the 

exhibits or the attachments) and the Program office’s 

assessment of the response (including whether the 

response has changed the Program office’s view on 

whether to issue the letter) should also be submitted to 

the appropriate reviewer(s) electronically, via fax, or by 

mail and also added into the case file for the proposed 

action within CMS. The review clock will stop when 

OCC is notified and restart upon OCC’s receipt of the 

Form FDA 483 response and the agency’s 

assessment. Any changes to the proposed letter as a 
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result of the FDA-483 response will be discussed with 

the initiating office.

6. If the Center approves the recommendation and OCC 

review is not required, issue the letter.

7. When OCC review of a Warning or Untitled Letter is 

required:

• If OCC concurs, issue the letter.

• If the agency receives the Form FDA 483 response 

after OCC has concurred with the issuance of the 

draft “final” Warning or Untitled Letter, the letter 

should be issued.

• In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Center will work with OCC and the programs and 

divisions in ORA as necessary to quickly address 

OCC’s concerns.

8. Upon issuance, add a PDF signed copy of the Warning 

or Untitled Letter into the Final Outcome tab for the 

action within CMS. Distribute additional copies in 

accordance with any applicable Compliance Program 

and RPM Chapter 4.

b. Center Responsibilities

1. Within 15 working days after the receipt of the 

recommendation, the accompanying documents, and 

the draft “final” Warning Letter, the Center should 

review and approve or nonconcur with the issuance of 

the letter. The Center will issue the approval memo 

within the 15 working day timeframe and add a copy of 

the Center decision document for the violation letter 

into the Center documents tab in CMS.

2. Within 45 working days after the receipt of the 

recommendation, the accompanying documents, and 

the draft “final” Untitled Letter, the Center should 

review and approve or nonconcur with the issuance of 

the letter. The Center will issue the approval memo 

within the 45 working day timeframe and add a copy of 

the Center decision document for the violation letter 

into the Center documents tab in CMS.

3. When OCC review of a Warning or Untitled Letter is 

required:
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• If the recommendation is approved, the Center will 

send its concurrence and the draft “final” letter with 

any edits to OCC for concurrence. The Center’s 

“final” letter with any edits should be added to the 

Center documents tab in CMS and should clearly 

identify via the document description any letter that 

require OCC review and concurrence. For instance, 

the description field within CMS should indicate 

“FOR OCC REVIEW.”

• To facilitate OCC’s review of the Warning or Untitled 

Letters, ensure that the violation letter documents 

within CMS include the Form FDA 483, the 

endorsement page of the EIR or the FACTS 

coversheet, the narrative portion of the EIR, and, if 

applicable, the summary of any sample analysis.

• If there is no Form FDA 483 or EIR, send the 

evidence to OCC that supports the issuance of the 

letter.

4. If the Warning Letter recommendation is not approved, 

the Center will notify the Director of the Compliance 

Branch and OCC if the letter required OCC review, of 

its decision within 15 working days. The Center will 

also issue a memorandum to the Director of the 

Compliance Branch that states its reasons for 

nonconcurrence within 30 working days, or as soon as 

possible. The Center will add a copy of its Center 

decision memorandum for the violation letter into the 

Center documents tab in CMS.

5. If the Untitled Letter recommendation is not approved, 

the Center will notify the Director of the Compliance 

Branch, and OCC if the letter required OCC review, of 

its decision within 45 working days. The Center will 

also issue a memorandum to the Director of the 

Compliance Branch that states its reasons for 

nonconcurrence within 60 working days, or as soon as 

possible. The Center will add a copy of its Center 

decision memorandum for the violation letter into the 

Center documents tab in CMS.

c. OCC Responsibilities

1. Once the Center has approved the recommendation, 

review any draft “final” Warning Letter requiring OCC 

review within 15 working days. 
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2. Once the Center has approved the recommendation, 

review any draft “final” Untitled Letter requiring OCC 

review within 45 working days.

3. If concurrence, send concurrence to the Director of the 

Compliance Branch and the program office’s 

compliance officer who proposed the action, along with 

a copy of the draft “final” letter with any edits (the 

Program office can then issue the letter).

4. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center involved 

and the Program office, and state in writing the reason 

for nonconcurrence.

d. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified 

by the Program office, Center or OCC. 

iv. Warning and Untitled Letters that Issue Directly from the 

Center

a. Center Responsibilities

1. Make the decision to issue a Warning Letter or an 

Untitled Letter

2. When OCC review of a Warning or Untitled Letter is 

required:

• Submit a draft “final” Warning Letter or Untitled 

Letter via CMS to OCC.

• To facilitate OCC’s review, ensure that the violation 

letter documents within CMS include the Form FDA 

483, the endorsement page of the EIR or the 

FACTS coversheet, the narrative portion of the EIR, 

and, if applicable, the summary of any sample 

analysis.

• If there is no Form FDA 483 or EIR, send the 

evidence to OCC that supports the issuance of the 

letter.

• If the agency receives the Form FDA 483 response 

prior to submitting the draft “final” Warning or 

Untitled Letter to OCC, a copy of the Form FDA 483 
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response (without the exhibits or the attachments) 

and the agency’s assessment of the response 

should accompany the draft “final” Warning or 

Untitled Letter.

• If the agency receives the Form FDA 483 response 

while OCC is reviewing the draft “final” Warning or 

Untitled Letter, the Center should notify the attorney 

that is conducting the review. A copy of the Form 

FDA 483 response (without the exhibits or the 

attachments) and the agency’s assessment of the 

response (including whether the response has 

changed the agency’s view on whether to issue the 

letter) should also be submitted to the assigned 

attorney electronically, via fax, or by mail, and also 

added into the case file for the proposed action 

within CMS. The review clock will stop when OCC 

is notified and restart upon OCC’s receipt of the 

Form FDA 483 response and the agency’s 

assessment. Any changes to the proposed letter as 

a result of the FDA-483 response will be discussed 

with the initiating office.

• If OCC concurs, the Center can issue the letter.

• If the agency receives the Form FDA 483 response 

after OCC has concurred with the issuance of the 

draft “final” Warning or Untitled Letter, the letter 

should be issued.

• In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Center will work with OCC as necessary to quickly 

address OCC’s concerns.

•

3. Upon issuance, add a PDF signed copy of the Warning 

or Untitled Letter into the Final Outcome tab for the 

action within CMS. Send a copy to the Compliance 

Branch where the recipient of the letter is located and 

distribute additional copies in accordance with any 

applicable Compliance Program and RPM Chapter 4.

b. OCC Responsibilities

1. Review any draft “final” Warning Letter requiring OCC 

review within 15 working days.
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2. Review any draft “final” Untitled Letter requiring OCC 

review within 45 working days.

3. If concurrence, send concurrence to the Center along 

with a copy of the draft “final” letter with any edits (the 

Center can then issue the letter).

4. If nonconcurrence or the letter is flagged because it

raises significant issues, contact the Center, and state 

in writing the reason for nonconcurrence.

v. Letters that Issue Directly from the Centers Promotion and 

Advertising Staffs

a. Center Responsibilities

1. Make the decision to issue a Warning Letter or an 

Untitled Letter. 

2. When OCC review of a Warning or Untitled Letter is 

required:

• Send a copy of the draft “final” letter via CMS to 

OCC for concurrence.

• To facilitate OCC’s review, ensure that the violation 

letter documents within CMS include the evidence 

that supports the issuance of the letter.

• If OCC concurs, issue the letter.

• In the case of nonconcurrence by OCC or the letter 

is flagged by OCC because it raises significant 

issues, the Center will work with OCC to quickly 

address OCC’s concerns.

3. Upon issuance, add a PDF signed copy of the Warning 

or Untitled Letter into the Final Outcome tab for the 

action within CMS. Distribute additional copies in 

accordance with any applicable Compliance Program 

and RPM Chapter 4.

b. OCC Responsibilities

1. Review any draft “final” Warning Letter requiring OCC 

review within 15 working days.

2. Review any draft “final” Untitled Letter requiring OCC 

review within 45 working days.

3. If concurrence, send concurrence to the Center along 

with a copy of the draft “final” letter with any edits (the 

Center can then issue the letter).
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4. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center and state 

in writing the reasons for nonconcurrence.

c. Licensed Products Letters

Violation Letters associated with licensed biological therapeutic 

drugs may fall under CBER or CDER responsibility. Contact the 

Centers if the jurisdiction is not clear.

Recommendations and other correspondence related to 6.3.1 –

6.3.3 (below) that are associated with CDER products should be 

forwarded to CDER, Office of Compliance, and Office of 

Manufacturing Quality. Recommendations and correspondence 

related to CBER products should be referred to CBER, OCBQ, 

DCM.

i. License Suspension

a. Center Responsibilities

1. Within three (3) working days after receiving 

information that a danger to health exists, the Center 

will gather the pertinent evidence, convene a Health 

Hazard Evaluation meeting with the applicable product 

office, and draft a Letter of Suspension.

2. If the determination is made that a danger to health 

exists, a draft “final” Letter of Suspension will be 

submitted by the Center via CMS to OCC within the 3 

working day period.

• To facilitate OCC’s review, ensure that the 

documents within CMS include the Health Hazard 

Evaluation and the pertinent evidence that 

establishes that a danger to health exists.

• If OCC concurs, the Center’s Office of Compliance 

and the Office of the Center Director will process 

and issue the letter.

• In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Center will work with OCC to quickly address OCC’s 

concerns.

3. Upon issuance, add a PDF signed copy of the letter 

into the Final Outcome tab for the action within CMS. 

Distribute additional copies in accordance with any 

applicable Compliance Program and RPM Chapter 4.
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b. OCC Responsibilities

1. Review the draft “final” letter within 5 working days.

2. If concurrence, send concurrence to the appropriate 

Center along with a copy of the draft “final” letter with 

any edits.

3. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center, and state 

in writing the reason for nonconcurrence.

c. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified by 

the Program office, Center or OCC. 

ii. License Revocation (For Cause)

a. Center Responsibilities

1. Within 30 working days after receipt of a 

Recommendation for a License Revocation, the Center 

will evaluate the recommendation to determine 

whether the issuance of a letter requesting the 

revocation of a license is appropriate.

2. If the issuance of a letter is appropriate, submit a draft

“final” letter via CMS to OCC for their concurrence.

3. To facilitate OCC’s review of the letter, ensure that the 

documents within CMS include the recommendation 

and any additional supporting documents.

4. If OCC concurs, issue the letter.

5. In the case of nonconcurrence or the letter is flagged 

because it raises significant issues, the Center will 

work with OCC to quickly address OCC’s concerns.

6. Upon issuance, add a PDF signed copy of the letter 

into the Final Outcome tab for the action within CMS.

b. OCC Responsibilities

1. Review the draft “final” letter within 30 working days.

2. If concurrence, send concurrence to the Center along 

with a copy of the draft “final” letter with any edits.

3. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center, and state 

in writing the reason for nonconcurrence.
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c. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified 

by the Program office, Center or OCC. 

iii. Notice of Intent to Revoke

a. Center Responsibilities

1. Within 30 working days after the receipt of a 

Recommendation for a Notice of Intent to Revoke 

(NOIR), the Center will evaluate the recommendation 

to determine whether the issuance of a (NOIR) letter is 

appropriate.

2. If the issuance of a NOIR is appropriate, submit a draft 

“final” NOIR letter and any accompanying 

documentation via CMS to OCC for their concurrence.

• If OCC concurs, issue the letter.

• In the case of nonconcurrence or the letter is 

flagged because it raises significant issues, the 

Center will work with OCC.

3. Upon issuance, add a PDF signed copy of the letter 

into the Final Outcome tab for the action within CMS.

b. OCC Responsibilities

1. Review the draft “final” letter within 30 working days.

2. If concurrence, send concurrence to the Center, along 

with a copy of the draft “final” NOIR letter with any 

edits.

3. If nonconcurrence or the letter is flagged because it 

raises significant issues, contact the Center and state 

in writing the reason for nonconcurrence.

c. OSPOP DE Responsibilities

DE will facilitate the discussion to quickly address 

significant issues, policy misalignment, novel, political, 

appearance or other controversial issues when notified 

by the Program office, Center or OCC. 

d. Enforcement Correspondence Under an Audit Review

Periodically, the agency may determine, through the periodic evaluations 

or otherwise, that certain Untitled and Warning Letters may be reviewed 

by OCC on an audit basis rather than a letter-by-letter review. The 
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agency may institute such an audit review under those circumstances in 

which policy is clear and well established, and model letters have been 

developed and cleared through OCC for use by the originating 

organization. Specific areas and criteria for audit review will be 

developed for the relevant letters.

If, during the evaluation or otherwise, any problems are identified in the 

use of the models, quality of issued letters, conformance with the audit 

requirements or other criteria in this procedure, audit review may revert 

back to full letter-by-letter review.

i. Introduction

Audit letters are automatically identified by CMS, using the audit 

schedules in 6.4.1 based on the nationwide count of that category of 

letter. The system will automatically indicate those letters subject to 

OCC review while the remaining letters in that audit category may be 

issued without such review. The model letters must be followed for 

all letters under this audit review program issued on or after the 

associated effective date.

If the same model is used for both Warning Letters and Untitled 

Letters, the audit schedule must be followed for each type of letter. 

This means that Untitled Letters and Warning Letters are to be 

counted separately to identify the audit letter to be submitted for OCC 

review using the procedures in this document.

At the discretion of the issuing office, letters that represent unique 

circumstances that warrant OCC review may continue to be 

submitted for review through the routine procedures in this document, 

in addition to the required submission of audit letters.

ii. Program office Responsibilities

Use the relevant model letter for all letters to be issued under the 

audit program. Once the action is added into CMS, the program 

office must identify the OCC audit program under which the letter 

falls in order to determine whether the letter is subject to audit 

submission to OCC. For letters that require Center concurrence, the 

program office should likewise identify that the proposed action letter 

falls within one of the OCC audit programs and follow the routine 

procedures in this document. For direct reference letters, submit 

audit letters to OCC for review using the procedures in this 

document. The other letters may issue without OCC review but must 

still be added into CMS in order for the agency to keep accurate 

accounting for the issuance of the letter.
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Program offices must continue to be diligent to ensure the high 

quality and timeliness of any letters that are issued and must 

otherwise follow the appropriate procedures in the RPM, Compliance 

Programs, or elsewhere.

Conformance with these procedures and use of the model letter is 

required. Audit review can be rescinded if warranted.

iii. Center Responsibilities

Use the relevant model letter for all letters to be issued under the 

audit program. Once the action is added into CMS, the Center must 

identify the OCC audit program under which the letter falls in order to 

determine whether the letter is subject to audit submission to OCC. 

In most instances, this information should be completed by the 

recommending program office; however, Centers will review as well 

to ensure an audit program is identified when appropriate. For letters 

for which the Center is responsible for obtaining OCC concurrence, 

submit audit letters to OCC for review using the procedures in this 

document. The other letters may issue without OCC review.

When a Center submits an “audit letter” to OCC for review, the 

transmittal memo approving the recommendation will contain the 

notation “Audit Letter – OCC concurrence is required” under the 

heading “Warning Letter –Approved.” This identifies the letter as one 

that requires OCC review and concurrence under the audit review 

program before it can be issued.

Centers must continue to be diligent to ensure the high quality and 

timeliness of any letters that are issued and must otherwise follow the 

appropriate procedures in the RPM, Compliance Programs, or 

elsewhere.

Conformance with these procedures and use of the model letter is 

required. Audit review can be rescinded if warranted.

iv. OCC Responsibilities

Review Untitled Letter and Warning Letter recommendations 

submitted by a Program office or Center, representing the audit 

letters of that type to be issued by that Program office or Center on or 

after the effective date of the model (shown below) in accordance 

with the routine procedures in this document. Determine conformity 

with the model letter. Report any perceived problems to OSPOP DE.

v. OSPOP DE Responsibilities
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DE will facilitate the discussion to quickly address significant issues, 

policy misalignment, novel, political, appearance or other 

controversial issues when notified by the Program office, Center or 

OCC. 

vi. Model Letters and Audit Schedules

The following model letters and audit schedules have been approved 

for use under this audit review program. The links to these letters can 

be found in the Warning Letter page on the ORA’s intranet page.

Center Type of Letter Audit Schedule

CFSAN CFSAN Dietary Supplement Cyber Every

Letters (resulting from web sites 

promoting dietary supplements with drug Tenth Letter

claims) with:

Disease Claims

Disease and Structure-Function Claims

The effective date for use of these letters 

is August 6, 2009.
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Exhibit 4-2 Warning Letter Close-Out Letter

Mr. John Doe, 

President J.D. Laboratories, Inc. 

Somewhere, USA

Dear Mr. Doe:

The Food and Drug Administration has completed evaluation of (your /your firm’s) 

corrective actions in response to our Warning Letter [insert WL # and Date]. Based on 

our evaluation, it appears that you have addressed the violation(s) contained in this 

Warning Letter. Future FDA inspections and regulatory activities will further assess the 

adequacy and sustainability of these corrections.

This letter does not relieve you or your firm from the responsibility of taking all 

necessary steps to assure sustained compliance with the Federal Food, Drug, and 

Cosmetic Act and its implementing regulations or with other relevant legal authority. The 

Agency expects you and your firm to maintain compliance and will continue to monitor 

your state of compliance. This letter will not preclude any future regulatory action should 

violations be observed during a subsequent inspection or through other means.

Sincerely,

Official [issuing program/office]

bcc: Establishment File

Home District of Corporate HQ (or of receiving firm if issued by a Center) FOI 

Office for Posting (typically no redaction needed; electronic through CMS

CMS case file (electronic copy)