CHAPTER 4

ADVISORY ACTIONS

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CONTENTS

SUBCHAPTER - WARNING LETTERS
Purpose
Procedures
Issuance
Center Concurrence 
Time Frames
Follow-up
Profile Update
Format
Distribution
Classification
WL to Importers and Foreign Firms
FOI (Release of WL)
Center for Biologics Evaluation and Research
Center for Drug Evaluation and Research
Center for Devices and Radiological Health
Center for Food Safety and Applied Nutrition
Center for Veterinary Medicine
Quality Assurance for Warning Letters
Exhibits

SUBCHAPTER - UNTITLED LETTERS
Agency Policy on Issuance
Untitled Letters Issued to Industry 
     on Illegal Promotional Activities

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SUBCHAPTER

WARNING LETTERS

PURPOSE

The purpose of this chapter is to specify the agency's enforcement procedures governing the use of Warning Letters.

BACKGROUND

Various forms of letters containing warnings of violations have been used throughout the history of FDA. However, such letters were sparingly used until 1967, when District Directors were authorized to issue such correspondence. A proposed regulation was published in 1978 that would have formally defined the agency's procedures and prescribed the use of two forms of Warning Letters (Notice of Adverse Findings Letters and Regulatory Letters).

The proposal was withdrawn in 1980; however, the criteria for such letters were placed in the RPM and used by the agency until May 1991. On May 23, 1991, the agency implemented the single Warning Letter system to replace the two letter warning system. The Warning Letter system placed more authority, responsibility, and flexibility at the district level concerning enforcement strategy decisions than previous procedures.

Warning Letter - A written communication from FDA notifying an individual or firm that the agency considers one or more products, practices, processes, or other activities to be in violation of the Federal FD&C Act, or other acts, and that failure of the responsible party to take appropriate and prompt action to correct and prevent any future repeat of the violation, may result in administrative and/or regulatory enforcement action without further notice.

PROCEDURES

When it is consistent with the public protection responsibilities of the agency and depending on the nature of the violation, it is FDA's practice to afford individuals and firms an opportunity to voluntarily take appropriate and prompt corrective action prior to the initiation of enforcement action. Warning Letters are issued for the purposes of achieving this voluntary compliance and establishing prior notice (see definitions in RPM Chapter 10 and the RPM section on "Prior Notice". The use of the Warning Letter and the prior notice policy are based on the expectation that a majority of individuals and firms will voluntarily comply with the law. The agency position is that Warning Letters should only issue for violations of regulatory significance; i.e., those violations that may actually lead to enforcement action if not promptly and adequately corrected.

The Warning Letter was developed and initiated 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, and/or prosecution to achieve correction. Despite the significance of the violations, there are a number of circumstances which may preclude the agency from pursuing any further enforcement action following the issuance of a Warning Letter. For example, the violation may be serious enough to warrant the issuance of a Warning Letter and subsequent seizure; however, if the seizable quantity fails to meet the agency's threshold value, the agency may choose not to pursue a seizure. In this instance, the Warning Letter would appropriately document prior warning if adequate corrections are not made and enforcement action is warranted at a later time.

Responsible officials in positions of authority in regulated firms have a legal duty to implement whatever measures are necessary to ensure that their products, practices, processes, or other activities are in compliance 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 will 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 prior to taking enforcement action, except in a few specifically defined areas. When acting under the authority of the Radiation Control for Health and Safety Act (RCHSA), FDA is required by law to provide a written notification to manufacturers when the agency discovers products that fail to comply with a performance standard or that contain a radiation safety defect. Due to the legal requirements of the RCHSA, minor variations on the procedures specified below 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, the agency does not consider Warning Letters to be final agency action on which FDA can be sued.

There are instances when issuance of a Warning Letter is not appropriate, and, as previously stated, issuance of such a 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 continuous conduct of a similar or substantially similar nature during which time the individual and/or firm have 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.

In certain situations, the agency may also take other actions as an alternative to, or concurrently with, the issuance of a Warning Letter. Additional instructions concerning the issuance of Warning Letters in specific product areas are located in various agency compliance programs and compliance policy guides.

AGENCY POLICY ON THE ISSUANCE OF WARNING LETTERS

Warning Letters should be issued only for violations of "regulatory significance." The threshold for determination of what constitutes "regulatory significance" is that failure to adequately and promptly achieve correction to the Warning Letter may be expected to result in enforcement action. It is recognized that despite the seriousness of the violations there are a number of circumstances which may mitigate against the Agency pursuing further regulatory action following the issuance of a Warning Letter. For example, the violation may be serious enough to warrant the Warning Letter and subsequent seizure. If, however, the seizable quantity fails to meet the Agency's threshold value, the Warning Letter would be appropriate to document prior warning if adequate corrections aren't made and subsequent enforcement action is warranted, i.e., injunction or prosecution.

WARNING LETTERS TO OTHER GOVERNMENT AGENCIES

All government establishments should be held to the same standards as non-governmental establishments. However, although the public health standards are identical, the process utilized to ensure compliance with these standards may vary. The Agency believes that government establishments will achieve and maintain a higher rate of voluntary compliance with FDA regulations compared to non-government establishments. Therefore, the most efficient use of our limited enforcement resources is to utilize the enforcement process described below:

Prior to the issuance of a Warning Letter to any government agency, the issuing office should make a documented effort to obtain correction by discussing the violations with the responsible government officials. If this discussion with the responsible officials does not result in assurances of correction, a Warning Letter should be promptly issued to the government establishment's headquarters/office as discussed below.

If assurances of correction are provided at the meeting, a follow-up inspection should be scheduled, within a reasonable time frame consistent with the noted violations, to confirm that correction of the violations has occurred. If during the follow-up inspection, the previously reported deviations continue to exist, a Warning Letter should be issued as discussed in the following section.

FEDERAL AGENCIES

Federal agencies whose violations meet all the requirements for Warning Letters, and for which administrative sanctions (e.g. license suspensions, etc.) are available as enforcement follow-up, should be issued Warning Letters addressed to the government establishment's headquarters office.

For violative inspection of Federal agencies that meet all of the requirements for warning letters, and for which the only viable enforcement follow-up actions are seizure, injunction, or prosecution, warning letter recommendations should be referred by the appropriate Center to the Division of Compliance Policy for review and concurrence prior to issuance.

STATE AND LOCAL GOVERNMENTS

State and local governments whose violations meet all of the requirements for warning letters should be issued warning letters addressed to the government establishment's headquarters office.

ISSUANCE

The Warning Letter is the agency's principal means of notifying regulated industry of violations (prior notice) and of achieving prompt voluntary correction. Warning Letters can be issued at the discretion of the district director without center or other headquarters review or concurrence, except in specific program areas that require prior center concurrence. (See Center Concurrence.) Because the circumstances in each case will vary, and district directors may reach different decisions on the issuance of Warning Letters in similar circumstances, it is recognized that Warning Letters may not be issued with rigid consistency.

In reaching a decision to issue a Warning Letter directly, district directors should consider the following basic factors:

CENTER CONCURRENCE

The following specific areas require center concurrence for the district director to issue Warning Letters, or Warning Letters are issued directly by the center.

ALL CENTERS

1. Labeling violations - except areas where specific guidance has been provided, e.g., Compliance Programs, Compliance Policy Guides, Drug Health Fraud Bulletins.
2. Computer application and software violations.
3. Bioresearch monitoring program violations.
4. Product advertising violations.

Note: Warning Letters will continue to be issued directly by the centers in certain areas such as product advertising, OTC drug monographs and Bioresearch Monitoring Program.

CENTER FOR DRUG EVALUATION AND RESEARCH

1. New drug charges - includes unapproved changes in processes or formulations and recommendations to withhold approvals of applications or supplements.
2. Narcotic treatment program violations.
3. Adverse drug reaction reporting violations.
4. Novel and unusual tamper-resistant packaging violations.
5. Prescription Drug Marketing Act violations.
6. Investigational drug use violations.
7. GMP charges involving bulk drugs.

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

1. Donor re-entry violations (e.g., HBsAg, anti-HIV-1).
2. Violations relating to drug GMPs.
3. Violative inspections of federal government agencies.
4. Viral marker test run deficiencies.* (See below)
5. Violations in areas where specific guidance has not been provided.* (See below)
6. Human tissue transplantation - the issuance of a Warning Letter to a firm following the issuance of an Order for Recall, Retention, and Destruction is not usually appropriate since enforcement action will have already been taken. If a district identifies circumstances in which a Warning Letter seems to be appropriate, the recommendation should be submitted to CBER for review.

*Viral marker testing violations: The districts no longer need Center concurrence regarding viral maker 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: The Center would not be in a strong position to issue a Warning Letter when there is no policy or agency policy on an issue that is not clear. Therefore, before recommending a Warning Letter to the Center, we encourage the district to contact the policy team within CBER's Office of Compliance to discuss issues where specific guidance has not been provided. Contact: CSO Steve Ripley, HFM-635, (301)-594-3074.

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

1. All 502(j) danger to health violations.
2. Medical device reporting violations which cite either failure to report unanticipated (temporary) serious injuries as defined in 803.3(h)(3)(ii) or malfunctions as defined in 803.3(c). Center medical/technical expertise is necessary to make these evaluations.
3. Restricted device violations.
4. Radiation Control for Health and Safety Act violations - except sunlamp products and x-ray assemblers.
5. Violation of requirements for post market surveillance studies.
6. Any violation of device tracking regulation requirements other than failure of the firm to implement any form of a tracking system.
7. All suspected violations of the user reporting regulations.
8. Failure to submit a 510(k)/PMA supplement for modifications of a previously cleared device.

CENTER FOR VETERINARY MEDICINE

1. Product approval violations.
2. Tissue residue violations where no tolerance has been established, and/or which involve the use of compounded products.
3. Feed contaminant violations where no tolerance has been established.
4. Adverse drug reaction reporting violations.
5. Low acid canned pet food violations requiring technical review.

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

1. Pesticide and chemical contamination violations where no action level or tolerance has been established.
2. Special dietary food violations - includes medical foods, infant formula, and vitamin/mineral supplements.
3. Low acid canned food violations requiring technical review.
4. Food and color additive violations where no specific guidance has been provided.
5. Nutrition violations.

MULTIPLE CENTER REVIEW

When the districts are aware that the issues in a warning letter will require multiple center review, the warning letter recommendation should be submitted to each Center involved. However, when the district is unaware that the issues involve more than one Center, then the centers will review the warning letter serially. Each center's 15 working day review time limit will begin at the time the submission is received at that Center.

TIME FRAMES

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

Within fifteen (15) working days after receipt of the Warning Letter recommendation, the center should review and approve the issuance of a Warning Letter and notify the district office of its decision. If the warning letter is to be disapproved, the center will so notify the district office of its decision within 15 days of receipt, and will issue a memorandum stating its reasons within 30 days or as soon thereafter as possible.

FOLLOW-UP

The issuing district or center will evaluate the response and determine its adequacy. If the response is inadequate, or if no response is received, the district/center will initiate follow-up action as necessary to achieve correction. If the response appears adequate, the district/center will verify that the commitments have been fulfilled and that correction has been achieved, and will notify other appropriate agency units.

PROFILE UPDATE

The District or Center must promptly update the firm profile system when a drug or medical device Warning Letter is issued. The profile system is also to be updated again when it is determined that correction has been achieved, or when further enforcement action is recommended or taken. In the cases of Warning Letters issued under Bioresearch Monitoring Program, corrective actions may not be verified until the next inspection as requested by the Center.

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) encountered and the response expected of the recipient of the Warning Letter. Nevertheless, the elements listed below are common to Warning Letters:

1. Titled "WARNING LETTER."
2. Issued by the district director, division director, or higher agency official. Some program areas will require Center concurrence prior to issuance.
3. Issued to the responsible individual who, based on currently available evidence, appears to be most closely related to the violation, to that person's superior, and to the highest known official in the organization. Each person in the organization issued a copy is identified on the Warning Letter.
4. The dates of the inspection and a description of the violative condition, practice, and/or product in brief but sufficient detail to provide "prior notice" and permit the respondent to take corrective action. Citation of the section of the law and/or regulation violated is not required.
5. A request for correction and a written response within a specific period of time after date of receipt of the letter, usually fifteen (15) working days. At the discretion of the district, the recipient may be offered an opportunity to discuss the content of the letter with district officials or, when appropriate, with Center officials.
6. A statement in drug and medical device Warning Letters (except warning letters issued to IRBs, clinical investigators, sponsors, and/or monitors involved in clinical trials) that: "Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when considering the award of contracts."
7. Instructions, as appropriate, that the response include (1)each step that has been or will be taken to completely correct the current violation(s) and to prevent the recurrence of similar violations; (2) the time within which correction will be completed; (3) any reason why the corrective action has not been completed within the response time; and (4) any documentation necessary to show that correction has been achieved.
8. A warning statement that failure to achieve prompt correction may result in enforcement action without further notice. Examples of such actions may be cited. It will not contain a commitment to take enforcement action (promise to sue).
9. A designated district or center official to whom the response should be addressed.
10. Delivered promptly (usually by certified mail, return receipt requested) with receipt documented.

DISTRIBUTION

Warning Letters should be distributed as follows:

1. Original - Addressee(s)
2. One redacted copy to HFI-35 for public display in accordance with FOI regulations.
3. One copy each to:

o Each person identified on the Warning Letter
o HFA-224
o Division of Compliance Policy (HFC-230)
o Center Compliance unit (via special mail or fax)

CDER - HFD-300
CBER - HFM-620
CDRH - HFZ-300
CVM - HFV-236
CFSAN - HFS-605
DIOP - HFC-170 (Imports only)

o Appropriate district office, for all Center issued Warning Letters.
o Medical Products Quality Assurance Staff (HFC-240) (Copy HFC-120 with all drug and medical device Warning Letters regardless of whether GWQAP issues are involved).
o Local Distribution, as required (i.e., factory file, WL file, resident post and appropriate federal and state agencies).

4. Offices or individuals identified as blind copies (bcc) on credit page (note: credit page with drafting, clearance record, and blind copies must not be sent to HFI-35).

Delivery - Warning letters should be sent to ensure overnight delivery and receipt of delivery (return receipt requested) should be documented.

Acknowledgement of Response to a Warning Letter -It is the Agency's general policy that responses received to warning letters should be acknowledged with an appropriate written response by the district or center that issued the warning letter.

Follow-up Enforcement Action - Once a firm has been issued a warning letter, provided the firm continues to operate out of compliance, districts/centers should evaluate further enforcement options. A second warning letter should not be issued for the same violation.

CLASSIFICATION

A Warning Letter constitutes official agency action and all inspections will be classified Official Action Indicated (OAI) when a Warning Letter is issued. This procedure provides greater consistency and uniformity in our classification system and our regulatory policy. Inspections should not be down classified from OAI due to failure to meet the 15 working day requirement for issuance of a Warning Letter. It is recognized that some OAI classifications should not have mandated follow-up without additional violations, such as tissue residue violations.

WARNING LETTERS TO IMPORTERS AND FOREIGN FIRMS

IMPORTER WARNING LETTERS

Warning letters for import violations may be issued at the discretion of the District Director without Center or other headquarters review or concurrence, except in certain program areas that require prior Center concurrence.

Warning letters may also be issued to importers of FDA regulated products who engage in business practices that appear designed to evade the lawful regulation of imports. The "Priority Enforcement Strategy for Problem Importers," chapter offers guidance for the proper use of warning letters, and other enforcement actions, against importers.

Generally, it is not appropriate to take enforcement action against a customs broker. The owner/consignee/importer is normally the responsible party for imported goods. However, if the broker is the owner/consignee/importer identified on the import documents, or has authority over the product through prior arrangement with the importer, it may be appropriate to issue a warning letter to the broker. Assurance must be made that the broker is responsible for the violation.

On March 6, 1992, the Director of the Division of Import Operations and Policy (DIOP HFC-170) issued a memo that included three examples of warning letters that could be used for importer violations. Districts were also requested to send copies of all warning letters issued to importers to DIOP so that a master list can be generated. This list is maintained in Import Alert #00-17 and is updated as importer responses or new warning letters are received.

Questions regarding the issuance or use of a warning letter involving an importer, consignee, owner, or broker of imported goods should be directed to DIOP, Policy & Enforcement Branch (HFC-172) at (301) 443-6553.

IMPORT BROKERS

By statute (19 U. S. C. Section 1641), the United States Customs Service (Customs) has the responsibility for ensuring that brokers comply with the law. Customs, not FDA, has the authority to follow through on any threats of further regulatory action against violators. It is inappropriate for FDA to issue a warning letter, per se, to customhouse brokers. In those cases in which a broker fails to fulfill his statutory obligations as a broker, and FDA concludes that a warning is appropriate, the most that FDA should do is send an untitled letter to the broker informing him of the violation and warning that any future violation will be reported to Customs. However, there are some cases in which it may be appropriate to send a warning letter to a broker. Where the broker is functioning as the importer of record and violates a provision of the FD&C Act, then a warning letter may be appropriate. In such a case, the warning letter is issued to the broker in his capacity as importer of record of the imported merchandise.

It is often difficult to distinguish between a broker performing his duties as a broker or as an importer of record. The only guidance the FD&C Act or its implementing regulations offers on the definition of owner or consignee is found in 21 CFR Section 1.83(a). That section defines an owner or consignee as "the person who has the rights of the consignee under the provisions of Sections 483, 484, and 485 of the Tariff Act of 1930, as amended (19 U.S.C. Sections 1483, 1484, and 1485)." [21 CFR Section 1.83(a)]. Section 483 of the Tariff Act was repealed in 1983. Under Sections 484 and 485, a consignee's rights consist primarily of filing any documentation required to allow foreign merchandise entry into the United States. [19 U.S.C. Sections 1484, 1485].

The former Section 483 of the Tariff Act provided that the consignee of imported merchandise was the consignee declared on the bill of lading or air waybill, unless the consignee conferred its rights to other persons through endorsements on such documents. [19 U.S.C. Section 1483 (repealed 1983)]. The current Section 484(a)(2)(C) provides that the documentation required to make entry of merchandise "shall be filed either by the owner or purchaser of the merchandise or, when appropriately designated by the owner, purchaser, or consignee of the merchandise, a person holding a valid license under Section 1641 of this title." [19 U.S.C. Section 1484(a)(2)(C)]. While the person "appropriately designated" (i.e., a custom broker licensed under 19 U.S.C. Section 1641) is often the importer of record, Sections 484 and 485 of the Tariff Act recognize, as did the former Section 483, that neither the consignee nor the importer of record is necessarily the true owner of the imported merchandise. Thus, under Sections 484 and 485, Customs entry may be made only by the importer of record (i.e., the owner or purchaser, or a broker/designee). [Id.; 19 U.S.C. Section 1485 (a)].

In most cases, the broker will not be the party responsible for causing the violation of the import provisions of the FD&C Act. While the broker files the entry documentation, he exercises little, if any, control over the merchandise itself. The owner/consignee/importer usually controls the movement of the merchandise and, therefore, bears the legal responsibility for complying with the FD&C Act.

A safe and easy approach to determining the proper addressee of a warning letter is to direct the letter to the person or entity identified on the entry documents as the importer. Under Sections 484 and 485 of the Tariff Act, the importer of record always has the rights of the consignee. In other words, one must be an owner, consignee, or the authorized agent of either(e.g. the customs broker engaged to make entry) to be the importer of record. If there are other individuals with an interest in the merchandise but FDA is unsure of the extent of the interest, the importer of record should be able to identify those individuals and/or notify them of the violation. If FDA is aware of other persons or entities with an interest in the merchandise, the Agency should send courtesy copies of the warning letter to them as well as the broker.

FOREIGN FIRMS

With regard to foreign companies, the same principle discussed above applies. A warning letter may be appropriate if FDA maintains some kind of regulatory control over the company and is prepared to exercise that control, if necessary. Firms are placed on automatic detention because of repeatedly offering violative products for import. Unless the foreign firm is under the regulatory purview of the FDA, as declared in the applicable sections of the FD&C Act, issuing warning letters should be discussed with our General Counsel. For foreign manufacturers of drugs and drug products, CDER/OC issues Warning Letters based on their review and concurrence with recommendations by FDA investigators in the foreign inspection reports.

FREEDOM OF INFORMATION (FOI)

Warning letters will be on public display at the Freedom of Information Staff office.

RELEASE OF WARNING LETTERS

1. Do not accept telephone requests for warning letters. FOI requests for warning letters should be sent to the FOI Staff (HFI-35) for response. Under exceptional circumstances the district may want to release a warning letter. In these cases the letter can be released by the district/center however, there must be assurance that the original letters have been received by the addressee and the FOI request sent to HFI-35.
2. Send a purged copy of all warning letters to (HFI-35) at the time the letter issues. Note: The Director, Freedom of Information Staff has asked that the person purging the letter place their name or initials and the date the letter was purged for release directly on the purged copy for future reference.

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

The following are applicable CBER programs:

1. CP 7342.001 - INSPECTION OF LICENSED AND UNLICENSED BLOOD BANKS

2. CP 7342.002 - INSPECTION OF SOURCE PLASMA ESTABLISHMENTS

Part VI of both of these programs provides numerous references, contacts, and attachments applicable to these products, and Attachment B on both programs lists deviations which may warrant consideration of regulatory/administrative follow-up, e.g., warning letter.

The organizational unit in the CBER Office of Compliance which handles warning letter recommendations is the Regulatory Actions Team, HFM-610. They can be reached at (301) 594-2006.

Warning Letters

1. All correspondence to licensed establishments must be addressed to the Responsible Head with a copy sent to the highest official in the establishment. For unlicensed establishments, correspondence should be addressed to the most responsible individual, e.g., blood bank director or hospital administrator.
2. The lists of significant deviations (following) serve as guides for determining the recommended course of action. Any significant deviation, if well documented and representative of a continual pattern of operation, as opposed to an occasional deviation, may warrant the issuance of a warning letter. Additionally, warning letters may be indicated when there are deviations which may not affect the donor's health or the integrity of the product, but because they continually occur, may reflect an overall inadequately operated establishment.
3. The following specific areas require center concurrence for the District Director to issue a warning letter, otherwise, the warning letters are issued directly by the district: Donor re-entry violations; invalidation of viral marker test run deficiencies; labeling violations (except areas where specific guidance has been provided, e.g., Compliance Programs, Compliance Policy Guide (CPG), Drug/Health Fraud Bulletins); computer application and software violations; product advertising violations, and violative inspections of federal government agencies.
In areas where a specific guidance has not been provided, we encourage the district offices to contact the policy team within CBER's Office of Compliance before recommending a Warning Letter to the Center. Please contact: Stephen Ripley, HFM-635, 301-594-3074.
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 effected or the firm has failed to respond, the district should consider appropriate follow-up.
4. Submit copies of all warning letters and any correspondence between the firm and the district to Division of Case Management (HFM-610).

Violations must be evaluated to determine if they warrant administrative or regulatory action or both. To assist in this determination, Attachments A and B of CP 7342.001 are lists of significant deviations from the GMP regulations. These two lists contain deviations which are sufficiently serious that if they are allowed to continue, might jeopardize donor health or might compromise product safety or integrity. The deviations on these lists apply to both unlicensed and licensed establishments. Any deviation listed has the potential to become a health hazard, and all deviations must be corrected as quickly as possible after responsible personnel have been made aware of them.

Federal/State Relations

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, however, encouraged; especially where it is known that a state or local jurisdiction has a regulatory program. Exchange of information should occur with all levels of State government whenever feasible.

Deviations Which May Warrant Consideration of Regulatory/Administrative Follow-Up General

A. Changing or altering blood labels or records so as to falsify, but not constituting a danger to health or is not a current practice. [606.160]

B. Shipment of unlicensed blood or blood products in interstate commerce for sale, barter, or exchange. [42 U.S.C. 262(a)]

C. Inadequate or filthy facilities. [606.40; 640.4(b)]

D. Personnel inadequately trained or supervised in the operations they perform but not to an extent that constitutes a danger to health. [606.20(b); 640.3(a); 640.4(a)]

E. Records of the performance of any significant step in the collection, processing, compatibility testing, storage and distribution of each unit of product are significantly incomplete or inaccurate. [606.160(a)(b)(c) and (e)].

F. A history of similar or substantially similar deficiencies about which the manufacturer has been advised.

Specific

A. Donor Suitability:

1. Specific deviations from the regulations or non-adherence to Standard Operating Procedures (SOP) in: (1) providing donors with the AIDS educational material; (2) medical history questions to be asked of donors; (3) determining what makes a donor unacceptable for donation; and/or (4) not performing hemoglobin, blood pressure, or temperature determinations. [640.3; 606.20(b)]. Note: Autologous donations that will not be for allogenic (homologous) use or further manufacturing may differ from donor suitability determinations applied to allogenic donations, however, the personnel must follow the firm's SOP established for autologous donations.
2. No written procedures for determining donor suitability, including the exclusion of high-risk donors in regard to AIDS. [606.100(b)(1) and (2); 640.3(b)(c)(e)(f)].
3. Donor suitability records are incomplete or inaccurate. [606.160(a)(1) and (b)(1)].
4. No records available from which unsuitable donors may be identified so that products from such individuals will not be distributed. [606.160(e)].

B. Blood Collection:

1. Arm preparation technique is inadequate or deviates significantly from the firm's SOP. [640.4(f)].
2. Container not permanently sealed in an acceptable manner. [640.2(c)].
3. Container, pilot, and laboratory samples are incompletely identified so as to relate them to the individual donor. [606.140(c); 606.160(c); 640.4(e) and (g)(3)].
4. Unapproved container used for collection of whole blood. [640.2(c); 640.4(c)].

C. Processing:

1. Laboratory tests for the determination of ABO, Rh, HBsAg and other viral markers not performed on laboratory samples collected from the donor at the time of filling final container, except in unusual situations. [640.5; 610.40(b)].
2. Anti-HIV and/or HBsAg test(s) not performed with an approved (licensed) test kit or as otherwise allowed in Sections 610.40 and 610.45.
3. Deviations in the performance of tests or interpretation of results according to manufacturer's directions and specifications, e.g., use of out-dated reagents; mixing reagents from different master lots; failure to run the proper number of controls concurrently with the test; failure to conduct necessary retests. [610.40; 610.45; 606.65(e)].
4. Records of test results significantly incomplete or inaccurate. [606.160(b)(2)(i)].

Note: Refer to Compliance Program 7342.001 for a list of licensed manufacturers of HBsAg and anti-HIV test kits.

D. Storage:

1. Blood or blood components not stored at proper temperatures. [606.100(b)(10)].
2. Failure to maintain daily temperature records when blood and blood components are in storage. [606.160(b)(3)(iii)].
3. Failure to have or follow a system which would prevent the issuance of any products not suitable for use. [606.40(a)(6)].

E. Components (Red Blood Cells, Plasma, Platelets, Cryoprecipitated AHF):

1. Components prepared by a method which deviates significantly from the regulations or the firm's SOP. [640.16(b); 640.24(a); 640.30(a); 640.52(a)].
2. Records of component preparation are significantly incomplete or inaccurate. [606.160(a)(1), (b)(2)(ii), (b)(2)(iii)].

F. Compatibility Testing:

Records of test results are significantly incomplete or inaccurate. [606.160(b)(4)(i)].

G. Adverse Reactions and Fatalities:

1. Failure to investigate adverse reactions and maintain appropriate records. [606.170(a)].
2. The Center for Biologics Evaluation and Research not advised of death(s) resulting from complications related to blood collecting or transfusion. [606.170(b)].

H. Errors or Accidents:

Errors or accidents in the manufacture of blood and/or blood products (licensed facilities) which might affect their safety, purity, and/or potency not reported to CBER. [600.14(a)].

I. Distribution and Receipt:

Distribution and receipt procedures (system) of each unit can not be readily determined to facilitate its recall if necessary. [606.165(a)].

J. Computerization:

Contact CBER (HFM-610 or HFM-650) for guidance.

Use of Current Good Manufacturing Practice (CGMP): Regulations for Finished Pharmaceuticals for Regulatory Actions for Blood Establishments

Since the workshop concerning General Principles of Quality Assurance for Blood Establishments (January 21-22, 1992), there has been considerable discussion as to the applicability of the drug CGMPs (21 CFR Part 211) to manufacturing operations and systems within blood establishments. CBER and ORA partially addressed the issues through clarification statements contained in the recently reissued CP 7342.001 (Inspection of Licensed and Unlicensed Blood Banks) and a new section to the Investigations Operations Manual (IOM) Chapter 560 - Biologics.

The Part 211 CGMP's are applicable to blood establishments. We recognize that with the increase in complexity of blood establishment operations due to the implementation of additional testing procedures for viral markers and to automated or computerized operations, blood establishments must place more attention on process and systems controls during the manufacture of blood and blood components. As a result, CBER and ORA issued the "Draft Guideline for Quality Assurance in Blood Establishments" addressing the specific process and system control expectations for blood establishments. These process control expectations will be based on requirements contained in both 21 CFR Parts 211 and 606.

In order to provide for uniform application and enforcement regarding deficiencies from 21 CFR Part 211 CGMPs, CBER review and concurrence is required for warning letters relating to deviations from Part 211. Direct reference authority does not include citing blood establishments for deviations from Part 211 CGMPs in warning letters.

Advertising and Promotional Labeling Staff Procedural Guide

The Advertising and Promotional Labeling Staff (APLS) 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 FD&C Act and regulations for labeling and advertising by notifying the manufacturer in writing of the violations. If significant problems in the advertising or promotional labeling are discovered that could pose a potential health hazard, or if other violations persist, APLS will work with the Office of Compliance to implement appropriate compliance action as necessary.

Warning Letters to Tissue Establishments

Since enforcement action will have already been taken, it is not usually appropriate to issue a warning letter for violations involving human tissue for transplantation when an Order for Recall, Retention, and Destruction has been issued. If a district identifies circumstances in which a warning letter seems to be appropriate, the recommendation should be submitted to CBER for review.

Direct Warning Letter recommendations to the attention of:

Office of Compliance
Division of Case Management, HFM-610
Steven Masiello, Director
301-594-2006

Direct Warning Letter questions to the attention of:

Regulatory Actions Team, HFM-610
Cecily Kois Kaufman, Team Leader
301-594-2006

CENTER FOR DRUG EVALUATION AND RESEARCH

GLOSSARY OF STANDARD CHARGES

PREAPPROVAL INSPECTIONS/PENDING APPLICATIONS - WITHHOLD APPROVAL

Warning letters are not to be used by the districts as a follow-up to a preapproval inspection of pending drug or device applications (Antibiotic Form 6, ANDAs, NDA, PMAs) if no other FDA regulated products are marketed by the firm.

Warning letters may be used by the districts for preapproval inspections of drug and device facilities when other FDA regulated products are marketed by the firm. These letters should include a disapproval statement stating "due to the deficiencies listed on the attached FDA-483 we are recommending to the Center that approval of the application(s) be withheld," and a statement that "federal agencies are advised of the issuance of all warning letters about drugs so that they may take this information into account when considering the award of contracts.

GRANDFATHER NEW DRUG CHARGE -- usually for drug which claims to have been on the market pre-1938 or pre-1962.

505(a)         The articles are new drugs 
               within the meaning of Section 201(p)
               of the Act and approval of an 
               application filed under Section 
               505(b) is not effective for such 
               drugs and a Notice of Claimed Investigational
               Exemption under Section 505(i) and Part
               12 of the Code of Federal Regulations
               (CFR) 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.

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 we have documented the interstate movement of a component as a 301(k) sample then we may charge that the product was misbranded while held for sale:

502(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) and no approval of an application
filed pursuant to Section 505(b) is effective for this drug.

A 502(f)(1) charge may be used for any OTC drug if the product fails to bear adequate directions for use and the product is also a new drug.

When the product is not a new drug, the simple misbranding charge should read:

502(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." 

PRESCRIPTION DRUG WHERE YOU HAVE NO LABELING BEARING DIRECTIONS FOR USES.

502(f)(1)     The article(s), (DRUG NAME),
              is subject to the provisions of 
              Section 503(b)(1) and it is not exempt 
              from 502(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.

REGISTRATION AND LISTING: The charge is misbranding under section 502(o) but the violation is failure to register and list.

502(o)          The articles, (DRUG NAMES), are 
misbranded in that they were manufactured in an
establishment not duly registered under Section
510 of the Act and the articles have not been
listed as required by Section 510(j).

Prescription 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)       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 as follows:

For prescription drug:

503(b)(4)       The article of drug, (DRUG NAME),
is subject to 503(b)(1) and is misbranded
in that its label fails to bear the statement,
"Caution: Federal law prohibits dispensing without prescription."

For an OTC drug that is not entitled to bear the Federal caution (prescription) statement.

The article of drug, (Drug name), is not subject to 503(b)(1) and is misbranded in that its label bears the statement 'Caution: Federal law prohibits dispensing without a prescription' and it is not entitled to bear such statement.

The above charge is applicable to articles marketed with prescription legend when in fact they are OTC drugs.

The following straight UNAPPROVED NEW DRUG charge may be used when there is interstate movement of the finished labeled drug product.

505(a)          The article of drug, (DRUG NAME),
is a drug within the meaning of Section 201(g)
of the Act which may not be introduced or delivered
for introduction into interstate commerce under
Section 505(a) of the Federal Food, Drug, and 
Cosmetic Act, since it is a new drug within the
meaning of Section 201(p) of the Act and no
approval of an application filed pursuant
to Section 505(b) is effective for such drug. 

Note: The Nontraditional Drug Compliance Branch (HFD-304) has distributed at least 19 Health Fraud Bulletins and District Offices should refer to them guidance and contact points.

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

For Level 1 noncompliances, the issuance of a Warning Letter for a facility inspection does not necessitate the district submitting the letter to CDRH for concurrence. Under other circumstances, where numerous Level 3 noncompliances are found, but no single noncompliance is severe enough to warrant a Warning Letter, a Warning Letter may be sent with CDRH concurrence. A Warning Letter will also be sent when an uncertified facility has been found to be operating without a certificate. When Warning Letters are to be issued for any situation not specifically identified as a Level 1 noncompliance, the draft Warning Letter should be submitted to the Office of Compliance, CDRH for concurrence with a recommendation memorandum. If a facility has been shown to be operating uncertified, a Warning Letter can be issued to the facility and will not require CDRH concurrence. If a Warning Letter is being considered for failure to correct Level 2 noncompliances after a follow-up reinspection, a recommendation should be submitted to CDRH for concurrence. (See Compliance Program 7382.014 for other case guidance.)

RECOMMENDED WORDING FOR CHARGES

Below is a listing of charges that we commonly use, which should be used by all compliance officers to achieve uniformity. Please note the change made to the Section 502(o) charge concerning removal of the order required by Section 513(i)(l)(A) for premarket notifications. OGC is of the opinion that this reference is to support a Section 501(f)(1) charge for lack of a PMA.

Adulteration Charges

Section 501(f)(1)(B) [21 U.S.C. 351(f)(1)(B)] in that it is 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] or an approved application for an investigational device exemption under Section 520(g) [21 U.S.C. 360j(g)].

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.

Section 501(h) [21 U.S.C. 351(h)] in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the Good Manufacturing Practice (GMP) for Medical Devices Regulation, as specified in Title 21, CFR Part 820.

Misbranding Charges

Section 502(a) [21 U.S.C. 351(a)] in that the labeling for the device, namely (state the name of the labeling, i.e., the ABC Catalog) contains statements which represent or suggest that the device is adequate and effective (quote the misbranding statement), which representations or suggestions are false or misleading or otherwise contrary to fact because the device is not adequate or effective for such purposes.

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.

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 _______(i.e., such purposes,etc.).

Section 502(f)(2) [21 U.S.C. 352(f)(2)] in that the labeling for the device fails to bear adequate warnings against use in those pathological conditions where its use may be dangerous to health.

Section 502(j) [21 U.S.C. 352(j)] in that the device is dangerous to health when used in the manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof. (NOTE: this charge cannot be used if the device does not have any labeling.)

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 the FDA as required by Section 510(k) [21 U.S.C. 360(k)].

Section 502(o) [21 U.S.C. 352(o)] MODIFICATION OF THE DEVICE - a notice or other information respecting the modification to the device was not provided to the FDA as required by 21 CFR 807.81(a)(3)(i).

Section 502(o) [21 U.S.C. 352(o)] NEW INTENDED USE OF THE DEVICE - in that a notice or other information respecting new intended use of the device was not provided to the FDA as required by 21 CFR 807.81(a)(3)(ii).

Section 502(t)(2) [21 U.S.C. 352(t)(2)] in that your firm failed to submit information to the Food and Drug Administration as required by the Medical Device Reporting (MDR) Regulation, as specified in 21 CFR Part 803.

On May 4, 1995, CDRH amended Compliance Program Guidance Manual 7382.830, Inspection of Medical Device Manufacturers, to incorporate the criteria for linking Class I and II 510(k) submissions, certain PMA supplements, and Export Certificates with Good Manufacturing Practice (GMP) requirements. These revisions are included in Exhibits 4-8 through 4-15.

UNTITLED LETTERS TO X-RAY ASSEMBLERS

CDRH and ORA have decided that individual x-ray test letters to x-ray assemblers should now be issued only as untitled letters and not as warning letters. Individual x-ray test letters are a requirement of the Radiation Control for Health and Safety Act and must issue regardless of whether the Agency is prepared to take follow-up enforcement action. Warning letters may be issued to x-ray assemblers for "pattern of violations" situations where the Agency is prepared to take enforcement action if the violations continue. If you have specific cases to discuss or need further information on this change contact the Office of Compliance, HFZ-300, 301-594-4692.

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

FOODBORNE BIOLOGICAL HAZARDS

CITATIONS TO VIOLATIONS UNDER FOOD ECONOMICS (Requirement and Citation[s])

Type size of mandatory information - 21 CFR 101.2(c), 101.105(i), 403(f) FD&C

Statement of identity on PDP - 21 CFR 101.3, 403(g), 403(i)(1) FD&C

Ingredient statement; common or usual name and order of predominance - 21 CFR 101.4, 403(i)(2) FD&C

Name and POB of manufacturer, packer/distributor - 21 CFR 101.5(a), 403(e)(1) FD&C

Nutrition labeling - 21 CFR 101.9, 403(a)(1) and 201(n) FD&C

English labeling - 21 CFR 101.5(c), 403(f) FD&C

Statement of presence of artificial flavors, colors, and preservatives - 21 CFR 101.22(c), 403(k) FD&C

Conformity to standard of identity standardized food - 21 CFR Applicable Standard , 403(g)(2) FD&C

Labeling of optional ingredients - 21 CFR Applicable Standard, 403(g)(2) FD&C

Product substitution - 402(b)(2) FD&C

Short weight - 403(e)(2) FD&C

Quantity of contents statement separately stated on PDP - 4(a)(2) FPLA, 21 CFR 101.105

Serving size statement - 4(a)(4) FPLA 21 CFR 101.8

Quantity of contents statement in avoirdupois pounds and ounces - 4(a)(3)(A)(i) FPLA, 21 CFR 101.105

NUTRITION LABELING AND EDUCATION ACT (NLEA) (SECTION 403 OF THE FD&C ACT)

Regulatory/Administrative Action

The Agency has stated that a firm will have made a "Good Faith Effort" to comply when its label complies with the January 6, 1993 regulations and in so doing may deviate from a requirement placed in the regulations by the August 18, 1993 technical amendments. A firm will not be required to change its label if it complies with the January 6 regulations, but deviates from the effective regulations due to changes made in the August 18 technical amendments.

All recommendations for regulatory actions except for failure to bear nutrition labeling (Criterion A below) must be submitted to CFSAN, Division of Enforcement (HFS-607) for review and concurrence prior to issuance. Include three (3) original product labels with each recommendation.

Districts should recommend issuance of warning letters to firms whose product(s) meets one or more of the following criteria:

1. non-exempt products that fail to bear nutrition labeling;
2. products bearing health claims or nutrient content claims that have not been authorized by FDA; and
3. products that fail to bear information required by NLEA that was not required previously, e.g., ingredient declaration on standardized foods, percent juice, names of certified colors.

Warning letters for these types of violations should consist of a description of the type of major violation and a disclaimer paragraph stating that there may be other violations other than those indicated in the letter. This type of warning letter should not include a description of any other violation that may be on the label.

Warning letter recommendations should be submitted for product labels with format deviations on the Nutrition Facts Panel. Label deficiencies for non-NLEA requirements should also be included in this warning letter.

Warning letter recommendations based on nutrient analysis in support of charges for violations of health claims or nutrient content claims requirements must include a copy of the collection report, three (3) original product labels, and the analytical worksheet. Warning letter recommendations should be submitted for violations of non-NLEA requirements, provided they are egregious, such as lack of an ingredient listing or significantly misleading product name.

STANDARD LANGUAGE FOR WARNING LETTERS FOR NLEA VIOLATIONS

Incorporate one or more of the following five paragraphs as appropriate. This is agreed upon language for issuing abbreviated warning letters:

1. This product is considered to be misbranded in that it fails to bear nutrition labeling as required by 21 U.S.C. 343(q)(1) and 21 CFR 101.9 and is not exempt under 21 U.S.C. 343(q)(5) from this requirement and has been labeled on or after May 8, 1994.
2. This product is misbranded under 21 U.S.C. 343(r)(1)(B) [or (A) in the case of nutrient content claims] in that it bears the health claim (nutrient content claim) "____" which has not been authorized by FDA. See 21 CFR 101.14 and Subpart E of Part 101 for authorized health claims; and 21 CFR 101.13 and Subpart D of Part 101 for authorized nutrient content claims.
3. This product is misbranded under 21 U.S.C. 343(i) in that it is fabricated from two or more ingredients, one of which is a standardized food but fails to bear the common or usual name of each ingredient in the standardized food as set forth in 21 CFR 101.4(b).
4. This product is misbranded under 21 U.S.C. 343(i) in that it is a food which purports to be a beverage containing vegetable or fruit juice and fails to bear a statement with appropriate prominence on the information panel of the total percentage of such fruit or vegetable juice contained in the food.
5. This product is misbranded under 21 U.S.C. 343(i) in that it contains a color or colors required to be certified without naming each.

Incorporate the following paragraph in each warning letter:

The above violations concern certain new labeling requirements and are not meant to be an all inclusive list of deficiencies on your labels. Other label violations can subject the food to legal action. It is your responsibility to assure that all of your products are labeled in compliance with all applicable statutes enforced by FDA.

CENTER FOR VETERINARY MEDICINE

CP 7371.004 - MEDICATED FEEDS

CGMP Deviations

Recommend formal administrative action, and regulatory action, if appropriate, when CGMP violations demonstrate that the methods, facilities, or controls being used present an actual or probable adverse impact on the safety, identity, strength, quality, or purity of the finished product. These are significant CGMP violations that support an Official Action Indicated (OAI) inspection classification. The following course of follow-up action should be considered:

1. On the initial CGMP inspection classified OAI, issue a warning letter. The district has the discretion to determine whether a warning letter is appropriate based on the circumstances of the specific case. In accordance with the delegation of authority, each letter concerning OAI inspections must contain the following elements:

a. Approval of all pending and future Medicated Feed Applications (MFAs) will be refused until the CGMP deviations are corrected.
b. A statement that the letter constitutes official notice of CGMP violations as required under Section 512(m)(4)(B)(ii) of the Federal, Food, Drug, and Cosmetic Act.

2. If the CGMP re-inspection is violative and classified OAI, recommend:

a. Issuance of a notice of opportunity for a hearing proposing withdrawal of existing MFA's,* and/or
b. Regulatory action, (e.g., injunction and/or mass seizure of medicated feeds and *** drug components).

*NOTE: Issuance of the official notice under Section 512(m)(4)(B)(ii), item a. (2) above, is a prerequisite of this action.

Examples of significant CGMP violations that warrant OAI classification and the above course of follow-up action include:

• Failure to conduct adequate clean-out procedures which have or could result in unsafe contamination of the finished product.
• Scales or metering devices used to determine the amount of drug ingredient in the product are inaccurate or are operating in a manner that has caused or could be expected to cause incorrect or erratic drug levels in the medicated feed.
• Lack of daily drug inventory records or failure to make a daily comparison between the actual amount of drug used and the theoretical amount of drug used or failure to take corrective action when significant discrepancies are detected.
• A pattern of failure to perform medicated feed assays according to the schedule in 225.58.
• Lack of follow-up action to determine and correct the cause of medicated feeds not meeting assay specifications.
• Failure to properly label medicated feeds; for example, lack of withdrawal instructions on labeling or operating in a manner that would favor a label mix-up.
• Failure to have master records or production records, or such records are lacking elements that can reasonably be expected to cause an adverse effect on the finished product.
• If CGMP deviations are identified which do not support an OAI classification, the district has the discretion to determine what type of follow-up (e.g., meeting with the firm) is appropriate and who should be delegated the responsibility for conducting such follow-up activity.

Non-CGMP Violations

Below are several examples of non-CGMP violations that warrant issuance of warning letters as the initial action:

1. *Lack of MFA's for drugs requiring MFA's for use in finished feeds.
2. *Use of unapproved drugs, or unapproved combinations or levels of approved drugs.
3. Failure to register as a drug manufacturer when using drug(s) requiring MFA's (See CPG 7126.30 - Failure to Register).
4. Illegal distribution of Type A medicated articles.

*These violations fall within the specific areas that require center concurrence prior to issuance of a warning letter.

Import

Detain or refuse entry of medicated feeds which appear to be in violation of the Act and regulations. Release, with comments, feeds with minor violations.

Inspection Classification and MFA Approval/Denial

Firms with CGMP deviations as described under Administrative/Regulatory Sanctions, will be classified under PAC 71004 as Official Action Indicated (OAI). These firms and CVM will be advised by the district office that approval of pending and future MFA's will be refused until the CGMP deviations are corrected.

Firms with CGMP deviations as described under item C, Voluntary Action Indicated (CP 7371.004), will be classified under PAC 71004 as either NAI, or VAI. MFA approval by CVM will not be affected by classifications.

GUIDANCE FOR SALMONELLA IN ANIMAL FEED

In 1990 when CVM announced a goal of salmonella negative in animal feed and feed ingredients, we realized that salmonella contamination was a widespread problem in the feed industry. Further, we realized that because of the nature of the business and the source of some of the ingredients that the stated goal would not be easily achieved.

A recent FDA survey of 154 animal protein and vegetable protein processors (less than 50% of this one segment of agribusiness) indicated that on the day of sampling over 70 (45%) of the firms had product on hand that was salmonella positive. Deciding which firm(s) should be identified for regulatory action and what action to take is obviously difficult, as is the matter of dealing with adulterated product on the market.

To address this problem, while permitting a vital part of agribusiness to operate and still move toward a salmonella negative goal, CVM is working with the United States Animal Health Association, academia, and industry to develop and implement Hazard Analysis Critical Control Point (HACCP) based quality assurance programs within the feed industry. It is the Center's hope that industry will embrace HACCP and begin systematically reviewing their manufacturing processes to address the source(s) of salmonella contamination. Our desire for the implementation of HACCP programs does not mean that the Center is opposed to regulatory action at this time, rather it means we should be selective in choosing the cases.

CVM is revising the regulatory action guidance regarding salmonella contamination in feed. CPGs 7126.07 and 7126.13 have been revoked. While guidance has not been finalized, we can state that we will be giving considerable weight to a firm's efforts to remedy production and handling problems to decrease the incidence of salmonella. Prime candidates for regulatory attention will be those firms that show a high incidence of positives and little regard for identifying problems and making improvements. [Concerning salmonella positive protein on the market, the field should notify firms in writing to review their operation in an effort to identify and correct possible contamination sources. CVM is developing example letters fitting various situations and including a 704(d) notification of analytical results.]

CVM will continue to support regulatory action against feed, ingredients, or pet food presenting a hazard to human or animal health. The strongest cases can be made for salmonella contamination of retail size containers which can be expected to be taken into the home where contamination could be expected to extend to cooking utensils and food preparation surfaces, thereby exposing humans to the contaminant. Imports found positive for salmonella may be detained without Center concurrence.

QUALITY ASSURANCE FOR WARNING LETTERS

IDENTIFICATION OF WARNING LETTERS

To facilitate the tracking of warning letters, it is suggested that every warning letter issued by a district or center office should bear a sequential code number. This code number should identify the fiscal year issued, the district or center issuing, and the appropriate sequential number for warning letters issued by that office.

WARNING LETTER MONITORING

To monitor and evaluate the effectiveness of warning letters it is suggested that the following information, at a minimum, be maintained by each district and center office for all warning letters issued.

General Information

1. Name of firm (and CFN #)
2. Location of firm (city & state)
3. Date warning letter issued
4. Date establishment inspection (EI) concluded

Time Frame Information

1. Number) working days (WD) after completion of the inspection or, if applicable, a sample analysis for the district or the center to issue the warning letter directly, or for the district to submit the warning letter to the center for concurrence.

Note: When a warning letter is issued in response to an inspection, test, or other action not conducted by the district issuing the warning letter, the 15 working day time frame for the issuing district begins upon receipt of the inspection report or other document which is the basis for the issuance of the warning letter. Examples of this situation are warning letters issued by a district based on inspectional or other activities conducted by cooperating state agencies (e.g., medicated feed inspections) or warning letters issued at the request of a center.

2. (Number) working days (WD) after receipt of the warning letter for the center to review and concur or not concur in the issuance of a warning letter, and notify the district of its decision.

Compliance Information

1. Response
___Yes (Y), ___No (N), or ___Pending (P)

Use pending (P) for situations such as:

* The firm's response time has not yet expired.
* The firm's response was inadequate and continuing to correspond.
* The firm's response is under review by the center.

2. Correction adequate
___Yes (Y), ___No (N), or ___Pending (P)

Use pending (P) for situations such as:

* Scheduled reinspection has not occurred.
* Sample analysis or analysis is pending.
* Met with firm and awaiting response.

3. Follow-up action on no response or inadequate correction

(a) If follow-up action is completed, briefly state the type of action taken (i.e., seizure, injunction, civil penalty, disqualification).
(b) If follow-up action is in-process or has not been initiated, briefly state the type of action in-process or planned.

4. Provide any additional information, if necessary to explain the follow-up action completed or planned, or to clarify particular circumstances involved in handling the case.

The above information will be periodically requested by the Division of Compliance Policy (HFC-230).

QUALITY AUDITS

In order to improve quality control/quality assurance of regulatory actions such as warning letters, it is important for the Agency to define quality standards and institutionalize the process to allow assessment of quality. To assist in this standardization of quality for warning letters, the Division of Compliance Policy has developed 17 criteria points.

The audit form, see Exhibit 21, can assist in insuring uniformity in the issuance of warning letters. Through use of an audit, strengths and weakness can be addressed and plans for correction implemented.

EXHIBITS

Imports

4-1 Sample Warning Letter (WL) - Violative Shipments
4-2 Sample WL Language (WLL) - Failure to Hold Entry Misrepresentation

Sample WLL - Distribution Prior to Release
Sample WLL - Misrepresentation
Sample WLL - Standard of Identity/Foreign Language

Biologics

4-3 Sample WL - Blood or Plasma
4-4 Sample WLL - Computer Software

Sample WLL - Source Plasma

Drugs

4-5 Sample WL - Misbranded
4-6 Sample WL - Tamper-Resistant Packaging
4-7 Sample WLL - Sterile drugs/CGMP

Sample WLL - DESI Drug/NDAs and ANDAs
Sample WLL - Homeopathic Drugs

Devices

4-8 Sample WL #1 - GMPs and MDR
4-9 Sample WL #2 - GMPs and MDR
4-10 Sample WL #3 - GMPs and MDR
4-11 Sample WL #4 - GMPs and MDR
4-12 Sample WL #5 - GMPs and MDR
4-13 Sample WL #6 - GMPs and MDR
4-14 Sample WL #7 - GMPs and MDR
4-15 Sample WL #8 - GMPs and MDR
4-16 Sample WL #9 - X-Ray Assemblers

Foods

4-17 Sample WLL - Standard of Identity

Cosmetics

4-18 Sample WLL - Color Additives

Veterinary Medicine

4-19 Sample WL - Medicated Feed Mill
4-20 Sample WLL - GMP Veterinary Drug

Other

4-21 WL Audit Report Form

-------------------------

SUBCHAPTER

UNTITLED LETTERS

AGENCY POLICY ON ISSUANCE

There are some specific circumstances in which the agency has a need to communicate with regulated industry about documented violations that do not meet the threshold of regulatory significance. Therefore, when circumstances warrant the issuance of an untitled letter to a member of an FDA- regulated industry, the letter should be in a format that clearly distinguishes it from a Warning Letter. The essential elements of this untitled letter are:

1. Not titled;

2. May be issued by any appropriate agency compliance official;

3. No 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;

4. No warning statement that failure to take prompt correction may result in enforcement action;

5. No mandated district follow-up;

6. Time frames for correction are not specified; and

7. A written response may be an option, but is not necessary.

The following types of correspondence should be issued as untitled letters and not as warning letters:

1. Letters sent to an entire industry, such as the letter on excessive glazing of seafood. Letters issued to put an entire industry "on notice" should be untitled letters.

2. The district may issue a brief untitled letter with the FDA-483 attached to assure that top management of a firm (i.e. president, CEO, etc.) has a copy of the FDA-483 when the original FDA-483 was not issued to top management during the inspection. Since this correspondence is only a brief transmittal letter it is not considered a warning letter. If significant deviations are found, a warning letter should be sent and not an untitled letter.

UNTITLED LETTERS ISSUED TO INDUSTRY ON ILLEGAL PROMOTIONAL ACTIVITIES

If a center is willing to support further Agency regulatory action if the violative practice doesn't cease, a warning letter and not an untitled letter should be issued for illegal promotional activities such as the promotion of a device or drug which has not been approved by FDA for commercial distribution and making representations that the device or drug is safe or effective for such purposes. If the center is not prepared to support regulatory action should a firm ignore a letter issued for illegal promotional activities, neither a warning letter nor an untitled letter should be used. An alternate approach would be to alert the district office of the violation and request that they bring the promotional activity to the attention of the firm on the next scheduled visit. This way if the district inspection reveals additional problems, this violation may be included as part of their regulatory action plan, should the firm fail to make appropriate corrections. If the problem is deemed to be more urgent the district could also request a meeting with the firm to discuss the violations.