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].

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5-7-2 - Background

In February 1997, FDA proposed a new, comprehensive approach to the regulation of human cellular and tissue-based products (now called human cells, tissues, and cellular and tissue-based products or HCT/Ps). The agency announced its plans in two documents entitled "Reinventing the Regulation of Human Tissue'' and "A Proposed Approach to the Regulation of Cellular and Tissue-based Products'' (hereinafter "proposed approach document'') (62 FR 9721, March 4, 1997).

Since that time, the agency has published three final rules and one interim final rule to fully implement the proposed approach. On January 19, 2001, we issued regulations to create a new, unified system for registering HCT/P establishments and for listing their HCT/Ps (registration final rule, 66 FR 5447). Part of the definition of ``human cells, tissues, or cellular or tissue-based products'' became effective on January 21, 2004. On January 27, 2004 (69 FR 3823), we issued an interim final rule to except human dura mater and human heart valve allografts from the scope of that definition until all of the tissue rules became final. On May 25, 2004, FDA issued regulations requiring most cell and tissue donors to be tested and screened for relevant communicable diseases (donor-eligibility final rule, 69 FR 29786). On November 21, 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 new CGTP regulations also contain certain labeling and reporting requirements, as well as inspection and enforcement provisions (GTP final rule, 69 FR 68612).

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 those HCT/Ps described in Sec. 1271.10 and regulated solely under section 361 of the PHS Act, and 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 described in Sec. 1271.10 and regulated solely under section 361 of the PHS Act. 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 described in Sec. 1271.10 and regulated solely under section 361 of the PHS Act.

A new provision for enforcement was added at 21 CFR 1271.440 that includes 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.

HCT/Ps subject to the provisions of 21 CFR Part 1271 include, but are not limited to, bone, ligaments, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.

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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)(1) to (3) exist. The conditions include an agency finding that:

1. There are reasonable grounds to believe that an HCT/P is a violative HCT/P because it was manufactured in violation of the regulations in this part and, therefore, the conditions of manufacture of the HCT/P do not provide adequate protections against the risk of communicable disease transmission; or

The HCT/P is infected or contaminated so as to be a source of dangerous infection to humans; or

An establishment is in violation of the regulations in this part and, therefore does not provide adequate protections against the risks of communicable disease transmission.”

In addition to the conditions noted above, the agency may issue an order of cessation of manufacturing until compliance with the regulations has been achieved, as stated in 21 CFR 1271.440(a)(3), when the FDA determines there are reasonable grounds to believe there is a danger to health. An order to cease manufacturing would be issued where violations create an urgent situation involving a communicable disease, because 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. An order to cease manufacturing is a remedial action taken to put important protections in place to prevent communicable disease transmission.

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)).

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

If the inspection review unit is considering a recommendation for issuance of an Order of Retention, Recall, or Destruction, contact the Center for Biologics Evaluation and Research (CBER), Division of Case Management (DCM), during the inspection or soon after issuance of the FDA 483. Discussions with CBER prior to submission of a recommendation will facilitate the processing of the recommendation. Part V of CP 7341.002 provides examples of violative conditions that may warrant issuance of an Order of Retention, Recall, or Destruction.

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 tissue(s) shipped to consignees) as of the last day of the inspection.

The district prepares and submits a written recommendation, including a draft Order, to CBER (see Exhibit 5-19 for model order). The initial CBER contact is DCM, HFM-614, Chief, Blood and Tissue Compliance Branch at 301-827-6201or fax 301-594-0940. Include the district director’s concurrence with recommendations for Orders of Retention, Recall, or Destruction. Transmit the Order recommendation by electronic mail or fax. Also, send the FDA 483 via electronic mail or fax immediately. Forward a package including the recommendation, the FDA 483 and copies of all supporting documentation to HFM-614 via express delivery at the following address:

Food and Drug Administration
Center for Biologics Evaluation & Research
Office of Compliance and Biologics Quality
Division of Case Management (HFM-610)
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448

All districts should identify Order recommendations as high priorities and make every effort to expedite submissions to CBER.

CBER personnel review the information received and determine whether the inspectional findings support the issuance of an Order of Retention, Recall, or Destruction.

CBER (and OCC) 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. Complete the EIR expeditiously and forward it along with the exhibits and additional supporting documentation by express delivery to CBER. In some cases, CBER may need to review the completed EIR before deciding whether to concur with the recommendation to issue an Order.

If CBER concurs with the recommendation, DCM prepares a concurrence memorandum, and any appropriate edits to the draft Order of Retention, Recall, or Destruction forwarded by the recommending unit. This package is forwarded to the Office of Chief Counsel for review. If OCC concurs, CBER forwards the concurrence memorandum and the Order to the district office for issuance. It is preferable to have the original signed Order hand-delivered to the HCT/P establishment by an FDA investigator, however, it may be more efficient to fax the signed Order directly to the establishment and send the original signed Order via certified mail with return receipt requested.

If CBER does not concur with the Order recommendation, DCM will notify the district regarding the decision by telephone or electronic mail, and forward a memorandum to the responsible district official explaining the reasons for non-concurrence and providing other enforcement options, if appropriate.

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5-7-5 - Follow-Up for 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. Alternatively, 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. The district and CBER should review the reply 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. The firm must notify its consignees to return or retain affected HCT/Ps in their inventories until resolving the issues. If, however, the firm/individual agrees to retain, recall and/or destroy the violative HCT/Ps, the district should promptly verify that the recall and/or destruction is carried out expeditiously, and the firm’s action should be monitored or witnessed, as appropriate, by an FDA investigator. Manage recalls as provided for in Chapter 7.

It is the firm's responsibility to destroy all violative HCT/Ps. However, the regulations provide the Agency with the authority to take possession of and/or destroy the violative HCT/Ps. It is rare, however, for FDA to do so, and it must only be done as a last resort. The district does not take possession of any HCT/Ps without first notifying CBER. CBER will provide guidance on procedures for handling and destroying the HCT/Ps safely.

The district monitors the destruction of violative HCT/Ps and obtains destruction records. Incineration is the recommended method of destruction of biohazardous substances, and there are services that specialize in the removal and destruction of such material. These firms generally provide their clients with the appropriate records documenting the destruction of such materials.

The district will schedule a follow-up inspection as appropriate. If the district observes continued deviations, the district and CBER will jointly consider what action to take.

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

If the district believes the grounds for issuance of an Order of Cessation of Manufacturing, including a danger to health, exist contact CBER’s DCM, HFM-610, 301 827-6201 immediately, during the inspection, and provide specific, substantive information relating to the grounds for ordering cessation. Do not wait until the conclusion of the inspection to contact CBER. At that time, CBER assigns a consumer safety officer who will work with the investigators in case development.

The district should transmit a copy of the FDA 483 (draft or final) as quickly as possible to DCM by facsimile, electronic mail, or express delivery, along with any additional, preliminary information and/or documentation. To avoid delay, do not send documentation through the regular mail system if other means of transmission are available. If using overnight express delivery, send to:

Food and Drug Administration
Center for Biologics Evaluation & Research
Attn: Division of Case Management (HFM-610)
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448

DCM will consult, as necessary, with the appropriate scientific/medical staff to determine whether a danger to health exists. If a danger to health exists, the district will be advised and should submit a recommendation that includes the basis for the recommendation. Recommendations for issuance of Orders of Cessation of Manufacturing are given a high priority and districts are to act promptly. Include the concurrence of the District Director. Districts will make every effort to expedite the submission of a recommendation for an Order of Cessation of Manufacturing where the establishment’s practices present a danger to health.

CBER may concur with a recommendation for an Order of Cessation of Manufacturing after receiving the FDA 483 and associated documentation but before receiving the Establishment Inspection Report (EIR). In cases involving complex issues, CBER may need to review the completed EIR before reaching a decision. In either event, write the EIR promptly and forward by express mail service to DCM.

CBER may ask the district to obtain a complete inventory of the HCT/P products on the firm’s premises.

If CBER concurs with the recommendation for Order of Cessation of Manufacturing, CBER/DCM will prepare an Action Memorandum and an Order within three working days of receipt of the recommendation. Documentation will be forwarded to OCC for review as soon as available. Upon OCC concurrence, the Director, CBER, who notes the date and time of signature, signs the Action Memorandum and the Order of Cessation of Manufacturing. The Director, OCBQ or designee will immediately telephone the establishment and advise it of the Order of Cessation of Manufacturing. DCM will then send the Order to the establishment by facsimile and certified mail.

CBER will concurrently advise the district of FDA’s actions. In some situations, CBER may arrange to transmit a copy of the Order of Cessation of Manufacturing to the district for hand delivery to the establishment.

If CBER does not concur with the recommendation for Order of Cessation of Manufacturing, it communicates its decision to the district. DCM will prepare a memorandum explaining the reasons for the nonconcurrence. If CBER disagrees with the recommendation for Order of Cessation of Manufacturing based on the absence of a danger to health, and any of the conditions specified in 21 CFR 1271.440(a) exist, DCM will consider whether other enforcement actions may be appropriate and will discuss these options with the district.

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

When FDA determines there are reasonable grounds to believe there is a danger to health, Orders of Cessation of Manufacturing are 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) a decision in, and in accordance with Part 16, in the event the establishment requests a Part 16 hearing.

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.

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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 information provided with the Order. The recipient must make the request within five working days of receipt of a written order of retention, recall, destruction, and/or cessation (or within five working days of the agency’s possession of an HCT/P). CBER, the Office of Enforcement (OE), and the OCC should be notified promptly by both telephone and electronic mail upon receipt of a Part 16 hearing request. A request for a Part 16 hearing places that 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 in any way by the hearing request. FDA will provide an opportunity for an expedited hearing for an Order of Cessation of Manufacturing that is not stayed by the Commissioner of Food and Drugs.

If a hearing is granted, DCMO will determine the availability of a Presiding Officer (usually an RFDD), and will prepare a memorandum for the signature of the Associate Commissioner for Regulatory Affairs (ACRA) designating the Presiding Officer and the deciding official (usually the Deputy Commissioner for Operations) for each particular case. The Presiding Officer has administrative responsibility for the conduct of the hearing. OCC will appoint counsel for the district and CBER, and counsel for the Presiding Officer. OCC will inform DCMO so that it can identify such attorneys in the memorandum prepared for the ACRA. The district and the center will provide documents, witnesses, and other support for the hearing if requested by the district or the OCC attorney counseling the district.

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