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Compliance Program
Manual for FDA Staff

PART V

REGULATORY/ADMINISTRATIVE FOLLOW-UP

 

A. QUALITY SYSTEM/GMP REGULATORY/ADMINISTRATIVE FOLLOW-UP

1. Compliance Decision

a. Situation I

The district has documented evidence indicating that one or more major deficiency with the Quality System regulation has resulted in the inspection being classified as Official Action Indicated (OAI). Examples that may be considered include:
    • Total failure to define, document, or implement a quality system or one of the seven subsystems, for example, absence of Management Controls Subsystem.
    • A deficiency in one or more element(s) of the subsystems. The QSIT Guide provides guidance addressing what are major Quality System requirements.
    • The existence of products which clearly do not comply with the manufacturer’s specifications and/or the Quality System regulation and which were not adequately addressed by the Corrective and Preventive Actions Subsystem (CAPA) program.
    • Noncorrection of major deficiencies from previous inspection(s).

NOTE: The determination of OAI should be based on evidence of quality system, or subsystem(s) deficiencies, that when considering all pertinent factors, may result in the production of nonconforming and/or defective finished devices by the establishment.

If any major deficiencies exist, the district is expected to classify the EIR as OAI and, based on the significance (risk) of the device and the findings, the district should consider which administrative and/or regulatory action to initiate. Such actions include, but are not limited to, issuance of a Warning Letter, injunction, detention, seizure, civil penalty and/or prosecution. See Regulatory Procedures Manual for further guidance.

If any of these deficiencies exist for foreign manufacturers, based on the significance (risk) of the device and the findings, a Warning Letter and/or Warning Letter with Detention without Physical Examination will be considered by CDRH/OC.

IMPORTANT NOTE: If a serious health hazard is identified, and the firm is not cooperative in conducting a voluntary recall, an FDA mandated recall (Section 518(e) of the FD&C Act), administrative detention/seizure or injunction should be considered as the initial action to bring the situation under prompt control.

b. Situation II

The inspection documents QS/GMP deficiencies of a quantity and/or type to conclude that there is minimal probability -- in light of the relationship between quality system deficiencies observed and the particular product and manufacturing processes involved -- that the establishment will produce nonconforming and/or defective finished devices. The Form FDA-483, Inspectional Observations, will serve to inform the establishment of any objectionable findings.

2. Sampling Records

The Guide to Inspections of Quality Systems, also called the QSIT Guide, includes instructions for sampling records for review. Sampling is an important tool for reducing the time spent reviewing records while being able to make statistically based inferences about the significance of the findings.

During Level 1 and 2 inspections, an investigator can terminate review of the records if objectionable conditions are observed before the entire sample is reviewed. The investigator can make the Form FDA-483 observation that the objectionable condition was found and move on to the next part of the inspection. However, QSIT Guide instructions caution that not reviewing the entire sample may result in the loss of additional information which may be useful in understanding the potential prevalence of the objectionable condition, or the failure to identify other objectionable conditions.

During Level 3 inspections, however, the investigator and the compliance officer should work together closely to plan how sampling will be conducted. It is important for the compliance officer to be confident that the level of sampling will be sufficient to document the deficiency and support the anticipated regulatory action. During Level 3 OAI follow-up inspections, it is recommended that the investigator review the entire sample of records to provide a complete picture of any deficiencies identified during sampling. The EIR should reflect the following information:
    • The type of records reviewed;
    • The sampling table used, Table 1 or 2;
    • The row used, row A, B, C, D, E or F;
    • The size of the sample;
    • The number of records actually reviewed (may be the same as or different from the size of the sample); and
    • The results of sample review.

Note: Statistical support is available from CDRH, Office of Surveillance and Biometrics.

3. Contract Sterilizers and Device Manufacturers – Deciding Responsibility When Taking Regulatory Action
    1. The following is provided as guidance for deciding which party is to be held responsible when a device manufacturer uses a contract sterilizer to perform terminal sterilization on its devices:
    • Contract sterilization is considered an extension of the finished device manufacturer's process. The manufacturer is ultimately responsible for assuring that validation, sterilization operations, and quality assurance checks associated with the sterilization of its products are appropriate, adequate and correctly performed.
    • Contract sterilizers are considered manufacturers for the purpose of applying the Quality System Regulation in that they meet the definition as described in Section 820.3(o). Contract sterilizers are subject to those parts of the Quality System Regulation that apply to the operations they perform for finished device manufacturers.
    • While the finished device manufacturer bears overall responsibility for the safety and effectiveness of the finished device, both the contract sterilizer and the finished device manufacturer are legally responsible for assuring the effectiveness of the sterilization process. The written agreement, between the manufacturer and contract sterilizer, required by 21 CFR 801.150(e), may be referenced to determine how the two parties have defined their respective responsibilities.

b. When deviations are observed, proposed regulatory actions should reflect and identify the shared responsibilities between the contract sterilizer and finished device manufacturer. In some situations, it may be appropriate to initiate regulatory action against both the contract sterilizer and the device manufacturers:
    • Appropriate action should be considered against the contract sterilizer in areas for which it has the prime responsibility under the written agreement. It may be necessary to inspect more than one customer to develop supporting documentation to demonstrate the particular sterilization firm does not appear to have adequate overall process controls.
    • When an inspection of a contract sterilizer finds violations in areas that are the responsibility of the finished device manufacturer (such as validation, biological indicators, package seal testing, etc.), these deviations are to be reported to the home district of the manufacturer. Regulatory action consistent with the action of choice for the contract sterilizer should also be considered for the finished device manufacturer.
    • Because the finished device manufacturer is ultimately responsible for the contractor's activities, serious deficiencies found at the contract sterilization operations will probably indicate consideration of regulatory action against the device manufacturer also. Copies of Warning Letters issued to the contract sterilizer should be sent to the home districts of the finished device manufacturers for placement in the firm's jacket. These documents should be used as a basis for the next scheduled inspection of the device manufacturer.
    • When a possible health hazard situation exists due to the contract sterilizer's operation; or an administrative or legal action is contemplated against a device processed by the contract sterilizer, the home district of all finished device manufacturers should schedule an immediate follow-up inspection at all affected device manufacturers.

4. Violative Devices Sold to Government Agencies

It is agency policy to treat products sold to the federal government in the same manner as products sold to commercial accounts. Consequently, when FDA recommends against acceptance of a device by a government agency because that device, or its manufacturer, is in violation of the FD&C Act, FDA should also recommend appropriate regulatory/administrative action against the same or similar device sold to commercial accounts.

If an establishment has shipped a violative product to a Government agency, apppropriate regulatory action consistent with the nature of the violation(s) may be taken even though there have been no shipments to commercial customers. Formal regulatory action in connection with a violative shipment may not be necessary in some cases. (For example, the establishment promptly corrects the violative condition, and the Agency would not require further action if the matter involved a product shipped to a non-government customer). However, where corrections are not or cannot be made promptly, the main concern is preventing the subsequent shipment of the product to another customer. When the product has been shipped solely to a Government agency and is under control of that agency and there is no threat to the public, the ORA/Medical Products Quality Assurance (MPQA) staff should ascertain the intention of the agency holding the goods (e.g., will they return or destroy the goods; will they request FDA to initiate seizure, etc.). If the procuring agency requests FDA action, ORA/MPQA staff will refer the matter to the home district for their consideration of an appropriate recommendation.

5. Administrative and Judicial Actions

Actions which may be considered include: FDA requested recall, FDA mandated recall, Warning Letter, seizure, injunction, prosecution, civil penalties and detention.

Corrective action proposals should be submitted by a responsible official of the establishment in writing, detailing the action(s) to be taken to bring the violative process or product into compliance within a specified time frame. Voluntary correction does not preclude the initiation of administrative and/or judicial action.

Special Note: Please review Warning Letter Pilot when reviewing corrective actions.

In determining whether quality systems deviations are sufficient to support legal action, consideration should be given to the significance of the device, the establishment's quality history, and whether the problem is widespread or continuing.

a. Warning Letters

Issuance of all Warning Letters should follow Chapter 4 of the Regulatory Procedures Manual (RPM) (see Attachment C for Model Warning Letters). Districts have DIRECT REFERENCE AUTHORITY for Warning Letters for Quality System, MDR death and serious injury, Tracking, and Correction and Removal violations.

Regarding direct reference authority for Correction and Removal violations: Warning Letters should only be issued once the districts have checked with their District Recall Coordinator to confirm that the recall is Class I or II.

Districts should obtain CDRH concurrence before issuing Warning Letters related to refurbishing/reconditioning of used devices, reprocessing of single use devices, MDR reporting of malfunctions or violations of Part 11 relating to of Electronic Records and Electronic Signatures.

If the district determines that issuance of the Warning Letter has resulted in corrective action by the establishment, the district should, within five (5) working days after confirmation, update the establishment's profile data in FACTS.

b. Violative Follow-Up Inspections

As stated in Part III of this Compliance Program, the post-inspection activities serve to advise manufacturers that the conditions identified by the investigator may be symptomatic of system problems, and that the manufacturer is responsible for investigating, identifying, and correcting system problems. The model Warning Letters further direct the establishment to discuss in its response how it will address the system problems related to the conditions identified by the investigator.

After issuance of a Warning Letter for Quality System violations, the next inspection should be a Level 3 QSIT inspection, as explained in Part III. When investigators identify the same or additional conditions that meet the criteria for Situation I, the district should consider subsequent enforcement actions, such as seizure, injunction, prosecution, or civil penalties. During Level 3 QSIT inspections, the investigator should work closely with the district compliance officer to assure that appropriate coverage is provided and deviations properly documented.

c. The Recidivist Policy -- Enforcement Strategy For Establishments With Repeated Violative Inspections

(1) Some establishments have a high rate of recidivism. They have developed a pattern of correcting violative conditions in response to Warning Letters or other administrative/regulatory actions, and usually maintain those corrections long enough to pass the follow-up inspection. When FDA next inspects the establishment (sometimes, as a follow-up to a recall), the investigator identifies similar conditions that again meet the criteria for Situation I. This tendency toward recidivism is often due to the failure of the establishment to have a strong quality policy and basic manufacturing and quality assurance systems which meet the requirements of the Quality System regulation.

(2) When dealing with another violative inspection for such an establishment, the district should consider using the following strategy:

(a) Issue a Warning Letter that follows the model Warning Letter in Attachment C. This Warning Letter requests the manufacturer to submit to the district (for up to 2 years if the district believes that it is necessary) an annual certification by an outside expert consultant stating that it has conducted a complete audit of the establishment's manufacturing, quality assurance (and if applicable, design control) systems relative to the requirements of the Quality System regulation. The manufacturer should submit a copy of the consultant's report, and certification by the establishment's CEO that he or she personally has received and reviewed the consultant's report and that the establishment has made all corrections identified in the report. To keep the process on track, schedules, milestones, update reports and other similar activities should be established between the firm and FDA, or by the firm after issuance of the Recidivist Warning Letter.

(b) Compliance Officers have the option of limiting the review of the certification only to the extent necessary to confirm that the consultant and the establishment have met the requirements set forth in the Warning Letter. Compliance Officers may also request a technical evaluation of the consultant's report by the appropriate branch within the Office of Compliance (OC) at CDRH. Compliance Officers have no obligations, however, to send to the establishment comments regarding the adequacy of the consultant's report or the establishment's corrections.

(c) Follow-up inspections will normally be conducted 3 – 6 months after the establishment certifies that it has completed all corrections.

The district may update the profile data as soon as the establishment has certified that it has completed all corrections recommended by the consultant.

(d) If the follow-up inspection indicates that the corrections are satisfactory, the district should notify the establishment that it has no objections to the corrections, and remind the establishment that it should continue to submit to the district, in accordance with the schedule specified in the Warning Letter, certification by an outside expert consultant that it has conducted an updated audit, certification by the establishment's CEO that any corrections noted to be necessary by the consultant have been made, and that it remains in compliance with the requirements of the Quality System regulation. The establishment should continue to submit copies of the audit results.

(3) If conditions identified by the follow-up inspection meet the criteria for Situation I, the district should consider action per A.1. above.

(4) If the evidence indicates that the consultant's or establishment's certifications are fraudulent, the district is encouraged to advise and seek assistance from the Office of Criminal Investigations. When there is clear evidence that the establishment falsified its status report to the district, the district should initiate appropriate action under 18 USC, 1001.

d. Recalls

If the district believes that prompt removal of a violative product from channels of commerce is necessary, it should proceed in accordance with the requirements of Part 806 of the Act and established recall procedures found in Chapter 7 of the RPM and 21 CFR, Part 7 (Enforcement Policy), Subpart C (Recalls). In the event of serious adverse health consequences or a death, CDRH may order a firm to discontinue further distribution and advise customers of the problem, and may

 

subsequently order the recall of a device to the user level in accordance with Section 518(e) of the Act.

e. Administrative Detention/Seizure
    1.  

Prior to invoking an administrative detention, for a period of 20 or 30 days, the district director should have reason to believe: (1) the device is misbranded or adulterated; (2) the establishment holding the device is likely to quickly distribute or otherwise dispose of the device; and (3) detention is necessary to prevent use of the device by the public until appropriate regulatory action may be taken by the Agency. District Directors should consult via telephone with CDRH, the Division of Compliance Management and Operations (DCMO) and the Office of Chief Counsel (CC) concerning administrative detention. NOTE: Telephone contact with CDRH should be directed to the appropriate Case Expert/Division Director in OC responsible for the subject device, both of which can be found in Part VI, C. Program Contacts. Concurrence should be given by the Director, OC, CDRH, based on a recommendation by the OC staff.

The district should immediately recommend seizure of the detained devices to assure continued control of the violative product after the 20/30 days of administrative detention expire.

A seizure action can be recommended without administrative detention to remove violative devices from commercial distribution, either at the manufacturer, distributor, repacker or a device user location.

f. Injunction

If an establishment has a continuing pattern of significant deviations in spite of past warnings, injunction will usually be the recommended action of choice. If a serious health hazard exists, the recommendation should include a request for a temporary restraining order (TRO) to prevent the distribution of devices that have been manufactured under the violative conditions documented by the inspection report (see RPM Chapter 6). The recommendation should be accompanied by copies of all necessary documents, e.g., complete inspection reports, Warning Letters issued, sample analyses reports, establishment's response(s) to Warning Letters and/or Form FDA-483. In the absence of physical samples, the inspectional evidence should clearly show that the establishment has substantially deviated from the requirements of the Quality System regulation. These deviations should be well documented and should show continuing system deficiencies, not just an isolated event.

 

 

 

 

g. Citation

A citation should be recommended, if appropriate, as stated in Chapter 5 of the RPM.

h. Prosecution

The criteria stated in Chapter 6 of the RPM are the criteria for consideration of prosecution of individuals in violation of the requirements of the Quality System regulation.

i. PMA Disapproval/Withdrawal

Refer to Compliance Program 7383.001, Part V.

j. Detention without Physical Examination

In general, detention without physical examination should be recommended by the Office of Compliance whenever there is clear documented evidence to suggest that the foreign manufacturer is producing or is likely to produce nonconforming and/or defective devices or the device presents a hazard to health.

k. Civil Money Penalties

Section 303(g)(1)(B)(i) of the Act states that civil money penalties shall not apply to QS/GMP violations "unless such violation constitutes (I) a significant or knowing departure from such requirements, or (II) a risk to public health." Section 303(g)(1)(B)(iii) further stipulates that civil penalties shall not apply to "section 501(a)(2)(A) which involve one or more devices which are not defective." For additional information, see the draft Guidance for FDA Staff on Civil Money Penalties Policy published in the Federal Register, June 8, 1999.

    1. NAI and VAI Post-Inspection Notification Letters

For examples of NAI and VAI Post-Inspection Notification Letters see Attachment C.

NOTE: General information concerning Post-Inspection Notification Letters is referenced in Chapter 5, section 529, of the IOM.

 

 

 

6. Facilitating Review of Regulatory Recommendations

    1. The district should contact the appropriate CDRH/OC Case Expert/Division Director by phone when the district believes they have an OAI situation for which a recommendation for seizure, injunction, civil penalties, or prosecution may be appropriate. CDRH fully supports the concept of "Up Front" loading so as to be fully aware of a potential situation and provide guidance on how to proceed. At the discretion of the district, notification to CDRH may occur prior to an inspection, while the inspection is ongoing, or after issuance of the Form FDA-483. Notification would typically be made by a compliance officer, but could be made by the investigator and/or district management. A list of the Case Experts, their phone numbers, and respective Device Panel responsibilities, are shown in PART VI, C. Program Contacts. The CDRH/OC organization chart also shown in PART VI, C. Program Contacts should be consulted for Division Director identification.

b. When the district knows a regulatory action will be recommended as a result of the inspection, it should FAX a copy of the issued Form FDA-483 to the appropriate division in OC. The review process can begin within CDRH while the EIR and recommendation are being written by the district. A copy of the Form FDA-483 annotated with exhibit numbers, and EIR page numbers, helps the reviewers.

c. It is the responsibility of district management to ensure that the documentation and evidence presented with each legal action recommendation is sufficient to justify and support each charge. The material submitted should include only the basic documentation needed to support each QS/GMP charge/example.

d. All necessary samples and other supporting documentation should be tabbed and their location cross referenced in the recommendation in order to assist in a timely review. It is highly recommended that you provide a table that cross references the violation with the Form FDA-483 item number, the inspection report page number and the exhibit number.

e. All significant questions, problems, or other weaknesses in the evidence regarding the recommended action should be stated, along with pertinent district comments. Otherwise, reviewers may miss a problem entirely until after litigation is commenced. Deficiencies/observations should be presented in descending order of importance.

f. The recommendation should begin with the most serious deviation from the regulations with reference to the EIR pages, exhibits and sample results that document the violation. Each charge should be parenthetically referenced in the recommendation memorandum and the page location of the supporting evidence given. Each deviation should be related to its effect on device quality in light of overall controls, and should be separated according to the type of manufacturing activity.

g. Physical samples are not required to support QS/GMP deviations, and should not be routinely collected for QS/GMP cases. If the district should reference violative documentary or physical samples as evidence to support QS/GMP deviations, the results should be tied to the QS/GMP deviation to show a cause/effect relationship.

h. Information regarding previous warning and other past or ongoing regulatory actions should be referenced along with a description of corrective actions. If the recommendation or current EIR references a previous report, the district should either copy the cited EIR pages, or summarize the information.
    1. All legal action recommendations shall be sent to CDRH/HFZ-306 for processing.

 

  1. MDR REGULATORY/ADMINISTRATIVE FOLLOW-UP

(SEE ATTACHMENT E)

The district should consider issuing a Warning Letter when the following MDR violations were observed during the inspection. This list only provides examples and is not all-inclusive.
    • Firm fails to report, within five workdays, after becoming aware that a reportable MDR event necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health.
    • Firm fails to submit an MDR death report.
    • Firm fails to submit an MDR serious injury report.
    • Firm fails to develop, maintain and implement written MDR procedures.

When the firm has already received a Warning Letter for MDR violations and still fails to comply with the MDR regulation, then the district should consider recommending a seizure, injunction, civil money penalty or prosecution.

All failures to comply with MDR should be listed on the FDA-483.

SPECIAL NOTE: Warning Letters based on failure to report malfunctions should have CDRH review/concurrence.

 

  1. TRACKING REGULATORY/ADMINISTRATIVE FOLLOW-UP

(SEE ATTACHMEN F)

The district should consider issuing a Warning Letter when the following tracking violations were disclosed during the inspection. This list only provides examples and is not all-inclusive.
    • Firm distributes tracked device and does not have a tracking system.
    • Firm does not have written standard operating procedures for collection, maintenance and auditing of the data for its tracked device(s).
    • Firm's tracking system is not effective in locating tracked devices during recall/notification.
    • Firm does not perform audits of their tracking system.

When the firm has already received a Warning Letter for tracking violations and still fails to comply with the tracking regulation, then the district should consider recommending a seizure, injunction, civil money penalty or prosecution.

All failures to comply with the tracking regulation should be listed on the FDA-483.

 

  1. CORRECTIONS AND REMOVALS (CAR) REGULATORY/ADMINISTRATIVE FOLLOW-UP (SEE ATTACHMENT G)

The district should consider issuing a Warning Letter when the following CAR violation was disclosed during the inspection. This is only an example and is not all-inclusive.
    • Firm fails to submit a CAR report to the District within 10 working days of initiating a corrective action which would involve a Class I or II situation, or fails to submit an MDR Report (5 or 30 day) indicating a CAR action was being taken.

When the firm has already received a Warning Letter for CAR violations and still fails to comply with the CAR regulation, then the district should consider recommending a civil money penalty or prosecution.

All failures to comply with the CAR regulation should be listed on the FDA-483, once the investigator has confirmed with their District Recall Coordinator that the situation would likely be classified as a Class I or II recall situation.

 

  1. REGISTRATION AND LISTING REGULATORY/ADMINISTRATIVE FOLLOW-UP

Regulatory Procedure Manual, Chapter 4, states agency policy is that Warning Letters should only issue for violations of regulatory significance. Generally, registration and listing violations, as a sole finding, should not be the basis of a warning letter. However, when those violations are found in combination with other findings, such as quality system violations, they should be included on the Warning Letter, after CDRH concurrence.

 

F. RADIATION EMITTING DEVICE REGULATORY/ADMINISTRATIVE FOLLOW-UP

Refer to Part V in Compliance Programs 7386.001, 7386.002; and 7386.004 through 7386.007 for guidance on regulatory actions related to radiation emitting devices.

 

G. EXPORTS REGULATORY/ADMINISTRATIVE FOLLOW-UP

When violations meet the criteria for Situation I for those unapproved devices exported under Section 802, note that fact in the Warning Letter. Submit a copy of the Warning Letter to the Division of Program Operations (HFZ-305) with a recommendation to rescind all outstanding certificates of export.