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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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5-7 - ORDERS OF RETENTION, RECALL, DESTRUCTION AND CESSATION OF MANUFACTURING RELATED TO HUMAN CELL, TISSUE AND CELLULAR AND TISSUE-BASED PRODUCTS (HCT/Ps)

5-7 - ORDERS OF RETENTION, RECALL, DESTRUCTION AND CESSATION OF MANUFACTURING RELATED TO HUMAN CELL, TISSUE AND CELLULAR AND TISSUE-BASED PRODUCTS (HCT/Ps)

 5-7 - ORDERS OF RETENTION, RECALL, DESTRUCTION AND CESSATION OF MANUFACTURING RELATED TO HUMAN CELL, TISSUE AND CELLULAR AND TISSUE-BASED PRODUCTS (HCT/Ps)

 5-7-1 - Purpose

This section contains procedures for issuing an Order of Retention, Recall, Destruction and Cessation of Manufacturing (Order) related to human cell, tissue, and cellular and tissue-based products (HCT/Ps) pursuant to 21 CFR Part 1271.440, promulgated under section 361 of the Public Health Service Act (PHS Act) [42 U.S.C. 264].

 5-7-2 - Background

In February 1997, FDA proposed a new, comprehensive approach to the regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). FDA proposed a tiered, risk based approach under which some HCT/Ps would be regulated only under Section 361 of the PHS Act and the newly proposed regulations in order to prevent the introduction, transmission, and spread of communicable diseases. Other HCT/Ps would also be regulated as drugs, devices, and/or biological products.

Since that time, the agency has published multiple regulations to fully implement this approach. In January 2001, we issued regulations to create a new, unified system for registering HCT/P establishments and for listing their HCT/Ps (66 FR 5447). In May 2004, FDA issued regulations requiring most cell and tissue donors to be tested and screened for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases (69 FR 29786). In November 2004, FDA issued regulations requiring HCT/P establishments to follow current good tissue practice (CGTP), which governs the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps; recordkeeping; and the establishment of a quality program. The CGTP regulations also contain certain labeling and reporting requirements, as well as inspection and enforcement provisions (69 FR 68612). These regulations apply to HCT/Ps recovered on or after May 25, 2005. HCT/Ps that were recovered before this effective date are subject to 21 CFR Part 1270, and subparts A and B of Part 1271, as appropriate.

HCT/Ps that meet all of the criteria set forth in 21 CFR 1271.10(a) are subject to regulation solely under 21 CFR Part 1271 and section 361 of the PHS Act, so no premarket approval is required. HCT/Ps that do not meet all of the criteria in 21 CFR 1271.10(a) are regulated also as drugs, devices, and/or biological products.

Part 1271 contains six subparts:

Subpart A of Part 1271 – scope, purpose, and definitions
Subpart B of Part 1271 - registration
Subpart C of Part 1271 - screening and testing of donors to determine eligibility
Subpart D of Part 1271 - provisions on CGTP
Subpart E of Part 1271 - certain labeling and reporting requirements
Subpart F of Part 1271 - inspection and enforcement provisions.

The subparts apply as follows:

Subparts A through D apply to all HCT/Ps, i.e., to HCT/Ps regulated solely under section 361 of the PHS Act and Part 1271, as well as to those regulated as drugs, devices, and/or biological products. Subparts E and F, which pertain to labeling, reporting, inspection, and enforcement, apply only to those HCT/Ps regulated solely under section 361 of the PHS Act and Part 1271. However, with the exception of two provisions (Sec. Sec. 1271.150(c) and 1271.155), subparts D and E are not being implemented for reproductive HCT/Ps.

21 CFR 1271.440 authorizes FDA to issue Orders of Retention, Recall, Destruction, and Cessation of Manufacturing in certain circumstances. Such an order is intended for use in situations when needed to prevent the introduction, transmission, or spread of communicable diseases, and applies only to those HCT/Ps regulated solely under section 361 of the PHS Act and Part 1271.

 5-7-3 - General Considerations

The agency may consider an Order of Retention, Recall, Destruction, or Cessation of Manufacturing when any of the conditions specified in 21 CFR 1271.440(a) exist. Under this provision, an Order may be justified when the agency finds that there are reasonable grounds to believe that an HCT/P is a violative HCT/P because:

  1. The HCT/P was manufactured in violation of the regulations in Part 1271 and, therefore, the conditions of manufacture of the HCT/P do not provide adequate protections against the risk of communicable disease transmission; or
  2. The HCT/P is infected or contaminated so as to be a source of dangerous infection to humans; or
  3. An establishment is in violation of the regulations in Part 1271 and, therefore does not provide adequate protections against the risks of communicable disease transmission.

Based upon one or more of the above findings, the agency may order the retention, recall, and/or destruction of the violative HCT/P; take possession of and/or destroy the violative HCT/Ps; or order the establishment to cease manufacture until compliance with Part 1271 has been achieved.

NOTE: FDA will not issue an order for the destruction of reproductive HCT/Ps, nor will FDA carry out such destruction itself (21 CFR 1271.440(f)).

5-7-4 - Procedures for Orders of Retention, Recall, or Destruction of HCT/Ps

An Order of Retention, Recall, or Destruction of HCT/Ps may be appropriate in situations where there are significant concerns regarding the source or violative nature of the HCT/P, the adequacy of the screening and/or testing, or a failure of the establishment to fulfill stated commitments to gain control over violative HCT/Ps.

As soon as practicable after the possibility of issuing an Order of Retention, Recall, or Destruction is first identified, the district should contact the Chief, Blood and Tissue Compliance Branch (BTCB)/ Division of Case Management (DCM), in CBER’s Office of Compliance and Biologics Quality. It is important to make this initial contact during the inspection if possible; do not wait until the conclusion of the inspection to contact CBER. Discussions with CBER prior to submission of a recommendation will facilitate the processing of the recommendation.

The district should upload a copy of the FDA 483 (draft or final) into CMS along with any additional, preliminary information and/or documentation as quickly as possible and should notify (BTCB)/ DCM, for example by electronic mail. BTCB/DCM, will notify CBER’s Office of Cellular, Tissue, and Gene Therapies (OCTGT) and the Office of Chief Counsel (OCC) of the potential for an Order as appropriate.

If the district believes an Order of Retention, Recall, or Destruction is appropriate, complete documentation of the violative conditions should be collected, including an inventory of products on the premises as well as those products distributed (including names and addresses of consignees and HCT/Ps shipped to consignees) as of the last day of the inspection.

The district prepares and submits a written recommendation for an Order of Retention, Recall, or Destruction to CBER. Include the district director’s concurrence with recommendations for Orders. Transmit the Order recommendation, FDA 483, and all supporting documentation via MARCS-CMS or, where needed, by electronic mail.

All districts should identify Order recommendations as high priorities and make every effort to expedite submissions of the documents described above. BTCB/DCM reviews the information received, also as a high priority, and determines whether the inspectional findings support the issuance of an Order of Retention, Recall, or Destruction.

CBER may concur with issuance of an Order after reviewing the FDA 483 and supporting documentation, but before receiving the Establishment Inspection Report (EIR), if the violations are serious and if there are not adequate protections against risks of communicable disease transmission. It is essential that the district completes the EIR expeditiously and forwards it, along with the exhibits and additional supporting documentation, by uploading it into MARCS-CMS. In cases involving complex issues, CBER may need to review the completed EIR before deciding whether to concur with the recommendation to issue an Order.

BTCB/DCM transmits the FDA 483 and other available supporting documentation as needed to the Division of Human Tissues (DHT), OCTGT. If one or more of the conditions in 21 CFR 1271.440(a) (as described above in section 5-7-2) are present, DHT will confirm this in writing, signed by the Director, DHT (or designee).

If CBER concurs with the Order recommendation, and OCTGT has confirmed that one or more of the conditions in 21 CFR 1271.440(a) are present, BTCB/DCM drafts the Order of Retention, Recall, or Destruction.

The draft Order, FDA 483, and supporting documentation are uploaded into MARCS-CMS for OCC review. If OCC concurs with the issuance of the Order, BTCB/DCM prepares the Order for signature by the CBER Center Director and delivers it to the Office of the Center Director for signature.

On the date that the Order is signed, the Director, OCBQ attempts to contact the HCT/P establishment by phone to notify the establishment that the Order is in effect. A copy of the order will be sent to the establishment by fax if possible, as soon as possible, after this call has taken place.

Also on the date the Order is signed, BTCB/DCM forwards the Order via overnight delivery to the district office for delivery to the HCT/P establishment. It is preferable to have the original, signed Order hand-delivered to the HCT/P establishment by an FDA investigator. If this is not practicable, the original signed order can be sent to the HCT/P establishment via overnight delivery.

If CBER does not concur with the Order recommendation, BTCB/DCM will notify the district regarding this decision by telephone or electronic mail, and forward a memorandum to the responsible district official explaining the reasons for non-concurrence and describing other potential regulatory actions, if appropriate.

If OCC does not concur with the Order recommendation, OCC will provide a written statement of its rationale to CBER, with a copy to the district office.

5-7-5 - Follow-Up to Orders of Retention, Recall, or Destruction

The Order of Retention, Recall, or Destruction will ordinarily provide that the HCT/P be recalled and/or destroyed within five working days from the date of receipt of the Order. The district should promptly verify that the recall and/or destruction is carried out expeditiously, and the HCT/P establishment’s action should be monitored or witnessed, as appropriate, by an FDA investigator. The district should manage recalls as provided for in Chapter 7. The Order will require the HCT/P establishment to notify its consignees to return or retain affected HCT/Ps in their inventories.

As an alternative to proceeding with recall and/or destruction, other arrangements for ensuring the proper disposition of the HCT/P may be agreed upon by the person receiving the written Order and FDA. Such arrangements may include, among other things, providing FDA with records or other written information that adequately ensures that the HCT/P has been recovered, processed, stored and distributed in compliance with the regulations and that, except as provided under 21 CFR 1271.60, 1271.65, and 1271.90, the donor of the cells or tissue for the HCT/P has been determined to be eligible. If the violative HCT/Ps can be reconditioned to become suitable for implantation, transplantation, infusion, or transfer into a human recipient as a result of these corrective actions, the establishment may be authorized to release the HCT/P for distribution.

If alternative arrangements are proposed by the HCT/P establishment, the district and CBER should review the proposal concurrently. The HCT/P establishment must retain the violative HCT/Ps in quarantine status until FDA agrees that the appropriate corrective actions have been implemented and adequate documentation has been provided to FDA to address the issues identified in the Order of Retention, Recall, or Destruction.

If FDA orders the destruction of HCT/Ps, it is the firm’s responsibility to destroy all violative HCT/Ps and provide to FDA records documenting destruction. The district monitors the destruction of violative HCT/Ps and obtains destruction records.

The regulations provide the agency with the authority to take possession of and/or destroy the violative HCT/Ps. The district must notify BTCB/DCM if it believes that taking possession of HCT/Ps may be appropriate. If CBER agrees that taking possession of HCT/Ps is appropriate in a particular situation, CBER will provide guidance on procedures for handling and destroying the HCT/Ps safely.

The district will schedule a follow-up inspection as appropriate. If the district observes continued deviations, it should contact BTCB/DCM during the inspection. The district and CBER will jointly consider what action to take.

5-7-6 - Procedures for Orders of Cessation of Manufacturing

An Order of Cessation of Manufacturing may be appropriate in situations where there are significant concerns regarding one or more steps in the manufacture of HCT/Ps, or a failure of the establishment to fulfill stated commitments to gain control over or to bring the areas of manufacturing into compliance with the applicable regulations.

As soon as practicable after the possibility of issuing an Order of Cessation of Manufacturing is first identified, the district should contact the Chief, Blood and Tissue Compliance Branch (BTCB)/Division of Case Management (DCM), in CBER’s Office of Compliance and Biologics Quality. It is important to make this initial contact during the inspection if possible; do not wait until the conclusion of the inspection to contact CBER. Discussions with CBER prior to submission of a recommendation will facilitate the processing of the recommendation.

The district should transmit a copy of the FDA 483 (draft or final) as quickly as possible to BTCB/DCM by electronic mail, along with any additional, preliminary information and/or documentation. BTCB/DCM will notify CBER’s Office of Cellular, Tissue, and Gene Therapies (OCTGT) and the Office of Chief Counsel (OCC) of the potential for an Order as appropriate.

If the district believes an Order of Cessation of Manufacturing is appropriate, complete documentation of the violative conditions should be collected, including an inventory of products on the premises as of the last day of the inspection.

An Order of Cessation of Manufacturing will be effective immediately if FDA determines there are reasonable grounds to believe there is a danger to health. BTCB/DCM will consult, as necessary, with the appropriate scientific/medical staff to determine whether there are reasonable grounds to believe that there is a danger to health. This evaluation will be documented by BTCB/DCM, working with appropriate scientific/medical staff. If a determination is made that a danger to health exists, the district will be advised immediately.

The district prepares and submits a written recommendation for issuance of an Order of Cessation of Manufacturing to CBER. Include the district director’s concurrence with recommendations for Orders. Transmit the Order recommendation, FDA 483, and all supporting documentation via MARCS-CMS or, where needed, by electronic mail.

All districts should identify Order recommendations as high priorities and make every effort to expedite submissions of the documents described above. BTCB/DCM reviews the information received, also as a high priority, and determines whether the inspectional findings support the issuance of an Order of Cessation of Manufacturing.

CBER may concur with issuance of an Order after reviewing the FDA 483 and supporting documentation, but before receiving the Establishment Inspection Report (EIR) if the violations are serious and if there are not adequate protections against the risks of communicable disease transmission. It is essential that the district completes the EIR expeditiously and forwards it to BTCB/DCM, along with the exhibits and additional supporting documentation, by uploading it into MARCS-CMS. In cases involving complex issues, CBER may need to review the completed EIR before deciding whether to concur with the recommendation to issue an Order.

BTCB/DCM transmits the FDA 483 and other available supporting documentation as needed to the Division of Human Tissues (DHT), OCTGT. If one or more of the conditions in 21 CFR 1271.440(a) (as described above in section 5-7-2) are present, DHT will confirm this in writing, signed by the Director, DHT (or designee). If there are reasonable grounds to believe there is a danger to health, this must also be documented and signed by the Director, DHT (or designee).

If CBER concurs with the Order recommendation, and OCTGT has confirmed that one or more of the conditions in 21 CFR 1271.440(a) are present, BTCB/DCM drafts the Order of Cessation of Manufacturing.

The draft Order, FDA 483, and supporting documentation are uploaded into MARCS-CMS for OCC review. If OCC concurs with the issuance of the Order, BTCB/DCM prepares the Order for signature by the CBER Center Director and delivers it to the Office of the Center Director for signature.

On the date that the Order is signed, the Director, OCBQ attempts to contact the HCT/P establishment by phone to notify the establishment that the Order is in effect. A copy of the Order will be sent to the establishment by fax if possible, as soon as possible, after this call has taken place.

Also on the date the Order is signed, BTCB/DCM forwards the Order via overnight delivery to the district office for delivery to the HCT/P establishment. It is preferable to have the original, signed Order hand-delivered to the HCT/P establishment by an FDA investigator. If this is not practicable, the original signed order can be sent to the HCT/P establishment via overnight delivery.

If CBER does not concur with the Order recommendation, BTCB/DCM will notify the district regarding this decision by telephone or electronic mail, and forward a memorandum to the responsible district official explaining the reasons for non-concurrence and describing other potential regulatory actions, if appropriate.

If OCC does not concur with the Order recommendation, OCC will provide a written statement of its rationale to CBER, with a copy to the district office.

5-7-7 - Follow Up to Orders of Cessation of Manufacturing

When FDA determines there are reasonable grounds to believe there is a danger to health, an Order of Cessation of Manufacturing is effective immediately. In other situations, the Order of Cessation of Manufacturing is effective after one of the following events, whichever is later: 1) passage of five working days from the establishment’s receipt of the Order; or, 2) if the establishment requests a Part 16 hearing, a decision in the proceedings. The Order will specify the regulations with which the HCT/P establishment must achieve compliance and will ordinarily specify the particular operations covered by the Order. The establishment is permitted to implement corrective actions in order to resume operations. However, the firm may not resume any operations subject to the Order without written authorization from FDA.

The district and CBER should concurrently review all correspondence received subsequent to issuance of an Order of Cessation concurrently. All meetings between the FDA and the Order recipient should include the appropriate district and CBER personnel.

5-7-8 - Part 16 Hearing

The recipient of an Order may request a hearing by submitting a written request in accordance with 21 CFR Part 16 as described in the Order and in 21 CFR 1271.440(e). The recipient must make the request within five working days of receipt of a written Order of Retention, Recall, Destruction, and/or Cessation of Manufacturing, or within five working days of the agency’s possession of an HCT/P. The HCT/P establishment may request additional time (beyond five working days) to consider whether to request a hearing. Reasonable requests for additional time will usually be granted. OCC, the FDA Office of the Ombudsman, and the district office should be notified promptly upon receipt of a Part 16 hearing request, and for a request for additional time to request a hearing.

For an Order requiring destruction of HCT/Ps, a request for a Part 16 hearing places the portion of the Order requiring destruction of the violative tissue in abeyance, pending the outcome of the hearing. The portion of the Order requiring recall and retention of violative HCT/Ps, however, is not placed in abeyance or affected by the hearing request.

As described above, if an Order of Cessation of Manufacturing is not immediately in effect, it is effective after one of the following events, whichever is later: 1) passage of five working days from the establishment’s receipt of the Order; or, 2) if the establishment requests a Part 16 hearing, a decision in the proceeding. If a Part 16 hearing is requested but denied, or if the Presiding Officer concludes after a Part 16 hearing that the Order was properly issued, the procedures in section 5-7-6 will be followed to notify the HCT/P establishment of the requirement to cease manufacturing.