**Class II Special Controls Guidance Document: Human Dura Mater; Draft
Guidance for Industry and FDA**

***Draft Guidance -- Not for Implementation***

**This guidance document is being distributed for comment purposes
only.**

**Draft released for comment on \[release date as stated in FR
Notice\]**

When final, this document supersedes "Guide for the Preparation of a
Premarket Notification Application for Processed Human Dura Mater" dated
October 14, 1999.

![](media/image1.png){width="0.9631944444444445in"
height="1.0763888888888888in"}

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Devices and Radiological Health**

**Plastic and Reconstructive Surgery Devices Branch**

**Division of General, Restorative, and Neurological Devices**

**Office of Device Evaluation**

**Preface**

**Public Comment:**

For 90 days following the date of publication in the Federal Register of
the notice announcing the availability of this guidance, comments and
suggestions regarding this document should be submitted to the Docket
No. assigned to that notice, Dockets Management Branch, Division of
Management Systems and Policy, Office of Human Resources and Management
Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061,
(HFA-305), Rockville, MD 20852.

**Additional Copies**

Additional copies are available from the Internet at:
<http://www.fda.gov/cdrh/%5Bspecific> address\], or CDRH
Facts-On-Demand. In order to receive this document via your fax machine,
call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-0111
from a touch-tone telephone. Press 1 to enter the system. At the second
voice prompt, press 1 to order a document. Enter the document number
(**054**) followed by the pound sign (#). Follow the remaining voice
prompts to complete your request.

**TABLE OF CONTENTS**

[1. Purpose 1](#purpose)

[2. Background 1](#background)

[3. The Content and Format of an Abbreviated 510(k) Submission
2](#the-content-and-format-of-an-abbreviated-510k-submission)

[4. Human Dura Mater 4](#human-dura-mater)

[5. Scope 6](#scope)

[6. Risks to Health 7](#risks-to-health)

[7. Donor Qualification 7](#donor-qualification)

[8. Qualification of Other Components
10](#qualification-of-other-components)

[9. Device Manufacturing: Processing Methods
10](#device-manufacturing-processing-methods)

[10. Device Manufacturing: Manufacturing Controls
10](#device-manufacturing-manufacturing-controls)

[11. Final Sterilization 12](#final-sterilization)

[12. Labeling 13](#labeling)

[References 14](#references)

#### Class II Special Controls Guidance Document: Human Dura Mater; Draft Guidance for Industry and FDA

***This document is intended to provide guidance. It represents the
Agency's current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind the Food
and Drug Administration (FDA) or the public. An alternative approach may
be used if such approach satisfies the requirements of the applicable
statute and regulations.***

# Purpose

This draft guidance document was developed as a special controls
guidance to support the classification of the human dura mater device
into class II. The device, as proposed, is intended to repair defects in
the dura mater. This draft guidance will be issued in conjunction with a
Federal Register notice announcing the proposal to classify this device
type. This guidance is issued for comment purposes only. If a final rule
to classify this device type is not issued, this guidance document will
not be issued as a special control.

When final, this draft guidance document will supersede the "Guidance
for the Preparation of a Premarket Notification Application for
Processed Human Dura Mater" dated October 14, 1999.

# Background

> FDA believes that special controls, when combined with the general
> controls, will be sufficient to provide reasonable assurance of the
> safety and effectiveness of human dura mater. Thus, a manufacturer who
> intends to market a device of this generic type should (1) conform to
> the general controls of the Federal Food, Drug & Cosmetic Act (the
> Act), including the 510(k) requirements described in 21 CFR 807
> Subpart E, (2) address the specific risks to health associated with
> human dura mater identified in this guidance and, (3) obtain a
> substantial equivalence determination from FDA prior to marketing the
> device, unless exempt from the premarket notification requirements of
> the Act (refer to 21 CFR 807.85).

This special control guidance document identifies the classification
regulations and product codes for the human dura mater (Refer to Section
5 -- **Scope)**. In addition, other sections of this special control
guidance document list the risks to health identified by FDA and
describe measures that, if followed by manufacturers and combined with
the general controls, will generally address the risks associated with
these human dura mater and lead to a timely 510(k) review and clearance.
This document supplements other agency documents regarding the specific
content requirements of a 510(k) submission. You should also refer to 21
CFR 807.87 and other agency documents on this topic, such as the
**510(k) Manual - Premarket Notification: 510(k) - Regulatory
Requirements for Medical Devices**,
[http://www.fda.gov/cdrh/manual/510kprt1.html]{.underline}.

Under "**The New 510(k) Paradigm - Alternate Approaches to Demonstrating
Substantial Equivalence in Premarket Notifications; Final
Guidance**[^1]," a manufacturer may submit a traditional 510(k) or has
the option of submitting either an Abbreviated 510(k) or a Special
510(k). FDA believes an Abbreviated 510(k) provides the least burdensome
means of demonstrating substantial equivalence for a new device,
particularly once a Class II Special Controls Guidance Document has been
issued. Manufacturers considering modifications to their own cleared
devices may lessen the regulatory burden by submitting a Special 510(k).

# The Content and Format of an Abbreviated 510(k) Submission

An Abbreviated 510(k) submission must include the required elements
identified in 21 CFR 807.87, including the proposed labeling for the
device sufficient to describe the device, its intended use, and the
directions for its use. In an Abbreviated 510(k), FDA may consider the
contents of a summary report to be appropriate supporting data within
the meaning of 21 CFR 807.87(f) or (g); therefore, we recommend that you
include a summary report. The report should describe how this special
control guidance document was used during the device development and
testing and should briefly describe the methods or tests used and a
summary of the test data or description of the acceptance criteria
applied to address the risks identified in this guidance document, as
well as any additional risks specific to your device. This section
suggests information to fulfill some of the requirements of 807.87 as
well as some other items that we recommend you should include in an
Abbreviated 510(k).

> **Coversheet**
>
> The coversheet should prominently identify the submission as an
> Abbreviated 510(k) and cite the title of this Class II Special
> Controls Guidance Document.
>
> **Proposed labeling**
>
> Proposed labeling should be sufficient to describe the device, its
> intended use, and the directions for its use. (Refer to Section 12 for
> specific information that we recommend including in the labeling for
> devices of the types covered by this guidance document.)
>
> **Summary report**

We recommend that the summary report contain:

-   Description of the device and its intended use. We recommend that
    the description include a complete discussion of the performance
    specifications and, when appropriate, detailed, labeled drawings of
    the device. You should also submit an \"indications for use\"
    enclosure.[^2]

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-   Description of device design requirements.

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-   Identification of the Risk Analysis method(s) used to assess the
    risk profile in general as well as the specific device's design and
    the results of this analysis. (Refer to Section 6 for the risks to
    health generally associated with the use of this device that FDA has
    identified.)

-   Discussion of the device characteristics that address the risks
    identified in this Class II Special Controls Guidance Document, as
    well as any additional risks identified in your risk analysis.

-   A brief description of the test method(s) you have used or intend to
    use to address each performance aspect identified in Sections 7-11
    of this Class II Special Controls Guidance Document. If you follow a
    suggested test method, you may cite the method rather than
    describing it. If you modify a suggested test method, you may cite
    the method but should provide sufficient information to explain the
    nature of and reason for the modification. For each test, you may
    either (1) briefly present the data resulting from the test in clear
    and concise form, such as a table, **[or]{.underline}** (2) describe
    the acceptance criteria that you will apply to your test
    results.[^3] (See also 21 CFR 820.30, Subpart C - Design Controls
    for the Quality System Regulation.)

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-   If any part of the device design or testing relies on a recognized
    standard, (1) a statement that testing will be conducted and meet
    specified acceptance criteria before the product is marketed, or (2)
    a declaration of conformity to the standard.[^4] [Please note that
    testing must be completed before submitting a declaration of
    conformity to a recognized standard]{.underline}. (21 USC
    514(c)(2)(B)). For more information, see FDA guidance, **Use of
    Standards in Substantial Equivalence Determinations; Final Guidance
    for Industry and FDA**,
    <http://www.fda.gov/cdrh/ode/guidance/1131.html>.

If it is not clear how you have addressed the risks identified by FDA or
through your risk analysis, we may request additional information about
aspects of the device's performance characteristics. We may also request
additional information if we need it to assess the adequacy of your
acceptance criteria. (Under 21 CFR 807.87(l), we may request any
additional information that is necessary to reach a determination
regarding substantial equivalence.)

As an alternative to submitting an Abbreviated 510(k), you can submit a
traditional 510(k) that provides all of the information and data
required under 21 CFR 807.87 and described in this guidance. A
traditional 510(k) should include all of your methods, data, acceptance
criteria, and conclusions. Manufacturers considering modifications to
their own cleared devices should consider submitting Special 510(k)s.

The general discussion above applies to any device subject to a special
controls guidance document. The following is a specific discussion of
how we recommend that you apply this Class II Special Controls Guidance
Document to a premarket notification for a human dura mater.

# Human Dura Mater

**A.** **Human Dura Mater and Creutzfeldt Jakob Disease**

-   In February 1987, the Center for Disease Control and
    Prevention (CDC) reported the first U.S. case of Creutzfeldt Jakob
    Disease (CJD) in an individual who had received a human dura mater
    graft. CJD is a rare, invariably fatal degenerative disease of the
    central nervous system characterized by progressive dementia. In
    1996, a nationwide CJD survey in Japan identified 43 cases
    associated with implantation of processed human dura mater. This
    increased the worldwide total of published cases of CJD associated
    with human dura mater use to 62. The great majority of these cases
    (59 out of 62) were related to the use of Lyodura, a particular
    brand of human dura mater manufactured in Germany. It should be
    noted that Lyodura was never cleared for commercial distribution in
    the U.S. and the import alert issued by FDA in June 1987 for this
    product continues to be in effect as of the publication date for
    this guidance.

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-   In March 1997, the World Health Organization (WHO) recommended that
    human dura mater grafts no longer be used, especially in
    neurosurgery, unless no alternative was available. At the same time,
    the Japanese Health and Welfare Ministry banned the use of human
    dura mater in brain surgery in Japan.

-   Because FDA established safeguards and guidelines in 1990 in an
    effort to minimize the possibility of CJD transmission by human dura
    mater device implantation and because there were no confirmed cases
    of CJD-transmission related to the use of human dura mater that was
    legally cleared for U.S. commercial distribution as of March 1997,
    the FDA did not restrict the distribution of human dura mater in the
    United States. However, the decision was made to hold public
    meetings of the FDA Transmissible Spongiform Encephalopathies
    Advisory Committee (TSEAC) to re-evaluate the safety of human dura
    mater grafts with respect to surgical use and CJD transmission.

-   On October 6, 1997, the TSEAC met to consider information provided
    by the FDA, industry, CDC, National Institutes of Health (NIH), the
    neurology medical community, and other internationally recognized
    experts and make recommendations concerning the clinical benefits
    and risks of CJD transmission associated with human dura mater
    grafts. At the conclusion of this meeting, the TSEAC recommended
    unanimously that neurosurgeons should avoid the use of human dura
    mater whenever possible. The committee also concluded, however, that
    the final decision regarding use of human dura mater should be left
    to the discretion of the treating neurosurgeon, as long as the human
    dura mater is procured and processed following certain safety
    measures.

-   Based upon the TSEAC's recommendations, on March 6, 1998, FDA sent
    letters to suppliers of human dura mater requesting that they
    implement specific measures to improve the safety of human dura
    mater.

-   At the April 16, 1998 TSEAC meeting, FDA presented proposed
    revisions to the TSEAC's recommendations offered during their
    October 6, 1997 meeting. These revisions took into consideration the
    responses from the human dura mater suppliers to the FDA letter of
    March 6, 1998. Those sponsor's responses raised concerns about the
    feasibility or necessity of some of the recommendations. Transcripts
    for TSEAC meetings are available at
    <http://www.fda.gov/cber/advisory/tse/tsearchives.htm>.

-   On January 18-19, 2001, the TSEAC also discussed criteria for
    determining the suitability of donors of human cells, tissues, and
    cellular and tissue-based products with regard to CJD and variant
    CJD (vCJD). The recommendations provided by the TSEAC at this
    meeting are also incorporated into this revised guidance document.

-   The recommendations and guidance presented in this document also
    considered the issues raised in a citizen petition to ban and recall
    all human dura mater devices that was submitted to FDA on August 15,
    2001, by Public Citizen.

-   While reagents for proteinase-resistant prion protein (PrP-RES)
    testing of brain tissue are available from certain research
    laboratories, testing is currently a research/investigational-use
    tool (Ref. 1). Because there is no FDA-approved or validated PrP-RES
    test that is marketed for screening donors for CJD, the FDA is not
    advocating its use at this time. However, when either a validated
    test becomes available or evaluation of available data demonstrates
    the utility of PrP-RES testing as an aid in determining that brain
    and dura mater tissues are not contaminated with CJD, incorporating
    PrP-RES testing into standard operating procedures will be
    recommended.

**B. Regulatory Authority**

-   Although not the primary purpose of this guidance document, FDA
    would also like to clarify the regulatory history of human dura
    mater. Human dura mater was in commercial distribution before the
    enactment of the Medical Device Amendments of 1976 to the Federal
    Food, Drug, and Cosmetic Act. The Neurological Devices Advisory
    Panel (the Panel) initially made a classification recommendation at
    the February 2, 1990 meeting. Because product classification was not
    finalized and new information about the safety of this device became
    available during the following nine years, FDA requested a second
    classification recommendation from the Panel on September 16, 1999.
    Regulation as a class II medical device was recommended at both
    Panel meetings. As of the date of issuing this guidance, processed
    human dura mater products continue to be regulated as unclassified
    medical devices via premarket notification.

-   In February 1997, FDA proposed a risk-based approach to the
    regulation of human cellular and tissue-based products (Ref. 2). To
    implement the proposed approach, FDA has published three proposed
    rules. "Human Cells, Tissues, and Cellular and Tissue-Based
    Products; Establishment Registration and Listing; Final Rule" has
    been finalized (Ref. 3). The two proposed rules "Suitability of
    Donors of Human Cellular and Tissue-Based Products; Proposed Rule"
    (Ref. 4), and "Current Good Tissue Practice for Manufacturers of
    Human Cellular and Tissue-Based Products; Proposed Rule" (Ref. 5),
    are in the process of being finalized.

-   FDA will redesignate the regulation of human dura mater from the
    medical device authorities to the human tissue regulations under the
    legal authority of Section 361 of the Public Health Service Act.
    However, the precise date of this transfer is dependent upon
    finalization of the above cited rules for "Suitability of Donors of
    Human Cellular and Tissue-Based Products; Proposed Rule" and
    "Current Good Tissue Practice for Manufacturers of Human Cellular
    and Tissue-Based Products; Proposed Rule."

-   Thus, FDA believes that human dura mater that meets the criteria in
    Section 1271.10 of the "Establishment Registration and Listing for
    Manufacturers of Human Cellular and Tissue-Based Products" may be
    appropriately and effectively regulated solely under Section 361 of
    the Public Health Service Act by controlling the potential
    infectious disease risks posed by transplantation. However, because
    human dura mater products are currently regulated as medical devices
    and will continue to be so regulated until all the tissue rules are
    finalized, FDA is providing the information below to help 510(k)
    applicants submit sufficient information to demonstrate a reasonable
    assurance of the safety and effectiveness for these devices as
    described in 21 CFR 860.7(g)(2) (Ref. 6).

# Scope 

The scope of this document is limited to the human dura mater device,
regulation number 21 CFR 882.xxxx (to be designated, if a final rule is
published), and product code LEM. A human dura mater device is human
pachymeninx tissue intended to repair defects in the dura mater.

**§ 882.xxxx Human dura mater.**

a.  Identification. Human dura mater is human pachymeninx tissue
    intended to repair defects in human dura mater.

b.  Classification. Class II (special controls). The special control for
    this device is FDA's "Class II Special Controls Guidance Document:
    Human Dura Mater; Guidance for Industry and FDA."

Human dura mater should not be confused with dura mater substitute
devices, which are classified under 21 CFR 882.5910, product code GXQ.

# Risks to Health

In the table below, FDA has identified the risks to health generally
associated with the use of the human dura mater addressed in this
document. The measures recommended to mitigate these identified risks
are given in this guidance document, as shown in the table below. You
should also conduct a risk analysis, prior to submitting your 510(k), to
identify any other risks specific to your device. The premarket
notification should describe the risk analysis method. If you elect to
use an alternative approach to address a particular risk identified in
this guidance document, or have identified risks additional to those in
the guidance, you should provide sufficient detail to support the
approach you have used to address that risk.

  ---------------------------------------- ------------------------------
  **Identified risk**                      **Recommended mitigation
                                           measures**

  Infection related to patient condition   Sections 7-11
  and treatment                            

  Transmission of spongiform               Sections 7-10, 12
  encephalopathies                         

  CSF leakage                              Sections 9-10

  Adverse tissue reactions                 Sections 9-11
  ---------------------------------------- ------------------------------

# Donor Qualification

**A. Serology Testing**

A blood specimen from all potential donors should be tested and found
negative for antibodies to pathogens of concern using FDA licensed or
approved screening tests. Today that list includes the human
immunodeficiency virus, Type 1 and Type 2 (anti-HIV-1 and anti-HIV-2),
hepatitis B surface antigen (HBsAg), and antibodies to the hepatitis C
virus (anti-HCV). Tests should be performed in a CLIA-certified
laboratory. Screening tests that have been licensed for testing
cadaveric blood should be used, when available.

**B. Evaluating risk factors for, and clinical evidence of, neurological
and infectious diseases through medical record review and donor history
interviews**

We recommend that each 510(k) describe the methods for evaluating the
possible presence of risk factors for, and clinical or physical evidence
of, neurologic or infectious disease. For example:

All available information, including a donor\'s medical records, autopsy
reports, or any physical assessment reports (e.g., medical examiner
report, police records) should be reviewed to determine donor
suitability. These records should be evaluated by an individual who is
qualified by profession, education, and training and who is familiar
with the intended use of human dura mater.

Interviews should also be performed with one or more individuals who can
provide reliable information (e.g., a donor\'s next of kin, a relative,
a member of the donor\'s household, an individual with an affinity
relationship with the donor, or the donor\'s primary treating physician)
concerning the donor\'s medical history and relevant social behavior.
The interview should determine whether the donor had signs or symptoms
of neurologic disease or engaged in certain activities or behaviors that
place a donor at a high risk for HIV or hepatitis infection.

The interview should also seek to determine whether the potential dura
mater donor traveled or resided in a BSE-identified country during the
time and for a duration that would defer an individual as a blood donor.
CBER's blood donor selection criteria regarding CJD are described in the
"Revised Preventive Measures to Reduce the Possible Risk of Transmission
of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease
(vCJD) by Blood and Blood Products" (Ref. 7). FDA believes that applying
the blood donor selection criteria when considering potential human dura
mater donors is appropriate given the current lack of information
available about the incidence and transmissibility of vCJD.

> The manufacturer should establish donor selection criteria and develop
> standardized methods for reviewing medical records and performing
> interviews. Such procedures should draw upon the appropriate standards
> of voluntary organizations (e.g., American Association of Tissue Banks
> and Eye Bank Association of America) as well as the recommendations,
> guidelines, and regulations of Public Health Service agencies (Refs.
> 8-17).
>
> We recommend that exclusion criteria include, but not be limited to,
> the following:
>
> *Regarding neurological screening*

-   donors diagnosed with CJD or a known family history (blood relative)
    of a person with non-iatrogenic CJD

-   donors who received injections of human pituitary-derived growth
    hormone (pit-hGH)

-   donors who received transplants of dura mater

-   donors diagnosed with any degenerative or demyelinating disease of
    the CNS (e.g., multiple sclerosis) or other neurologic diseases
    (e.g., senile dementia, Alzheimer's disease)

-   donors who died in a neurological/psychiatric hospital.

> *Other exclusion criteria*

-   donors who meet the exclusion criteria for potential infectious
    disease described in the "Guidance for Industry: Screening and
    Testing of Donors of Human Tissue Intended for Transplantation"
    (Ref. 15)

-   donors diagnosed with active infections at the time of death (e.g.,
    rheumatic fever, generalized septicemia or systemic infection,
    mycosis, tuberculosis)

-   donors diagnosed with diseases of unknown etiology

-   donors without adequate documentation of medical history.

**C. Physical Assessment**

The 510(k) should identify standardized donor selection criteria for
physically assessing a cadaver in a general autopsy. Exclusion criteria
based on clinical evidence of possible infectious or neurologic diseases
should include, but not be limited to, evidence of:

-   physical evidence for risk of sexually transmitted diseases, such as
    genital ulcerative disease, herpes simplex, and syphilis

-   physical evidence of anal intercourse, including perianal condyloma

-   physical evidence of non-medical percutaneous drug use, such as
    needle tracks

-   disseminated lymphadenopathy

-   oral thrush

-   blue or purple spots consistent with Kaposi\'s sarcoma

-   needle tracks, including examination of tattoos which may be
    covering needle tracks

-   unexplained jaundice, hepatomegaly, or icterus

-   if the body was rejected for routine autopsy due to infectious
    criteria or if the autopsy was done in an infectious disease control
    room or under any special precautions and the reasons for these
    procedures.

**D. Gross and Histological Examination of the Brain**

> The 510(k) should describe the procedures for performing a full
> autopsy on each donor\'s brain. Following fresh examination, the brain
> should be fixed, sliced, gross examination of the entire brain
> conducted, including multiple cross sections, and multiple samples of
> tissue obtained from different parts of the brain for histologic
> examination. This examination should be performed by a qualified
> pathologist after human dura mater collection. Potential donors should
> be excluded when any possible evidence of TSE-related changes is
> observed during gross and histological examination of the brain (Refs.
> 1, 18-20).

**E. Archiving of Donor Brain and Dura Mater Tissue**

FDA recommends that frozen (at a temperature equal to or less than
-70°C) and fixed samples of both donor brain and dura mater tissues
should be archived. The donor brain samples should include at least 5
grams of the frontotemporal region.

These samples should be retained for 10 years based on the current
scientific knowledge regarding the development of screening tests and
our expectation that, as the science evolves, screening tests may become
available within that time.

While archiving samples of donor brain and dura mater may not
immediately increase the assurance of dura mater graft safety,
comprehensive collection and storage of such tissues would permit
subsequent testing for TSE-induced changes when improved or new test
methods become available. In the event that a human dura mater-graft
recipient becomes ill with CJD, testing of archival donor material might
assist in determining whether the dura mater graft was the source of
infection.

# Qualification of Other Components

The source and purity of all other components and manufacturing
materials (e.g., preservatives) should be identified in the 510(k). Such
information may be supplied by reference to a Master File(s) if a letter
of cross-reference is included which authorizes FDA review of the
appropriate documents. Submission of a Certificate(s) of Analysis (CoA)
and/or a Materials Safety Data Sheet(s) (MSDS) for each device component
can also greatly simplify the 510(k) review.

# Device Manufacturing: Processing Methods

**A. Manufacturing Reagents**

The 510(k) should contain information about all reagents (e.g., organic
solvents) and processing methods used in device manufacture. Information
similar to that discussed above for device components, (i.e., reagent
source, purity, CoA and/or MSDS) can be very helpful in evaluating the
substantial equivalence of the proposed and legally marketed devices.
The 510(k) should also identify the concentration in the final device of
any manufacturing reagent that is potentially toxic.

**B. CJD Disinfection**

> Careful control of donor selection and dura mater retrieval procedures
> constitute critical safety practices for human dura mater. While
> histological examination of the brain may detect most infected
> tissues, it may not identify all CJD-infected grafts. Therefore,
> treatment of each product with a generally accepted disinfection
> technique should be performed to provide an additional assurance of
> device safety. The TSEAC recommended treating human dura mater with
> 1.0 N sodium hydroxide (NaOH). This recommendation was based on a
> study in an animal model in which 1.0 N NaOH treatment reduced CJD
> infectivity (Ref. 18). Each application should provide information
> about the methods for disinfection with NaOH or another procedure that
> has been validated to significantly reduce CJD infectivity. Such data
> should also demonstrate that subsequent rinsing steps are sufficient
> to reduce the concentration of residual NaOH (or another disinfectant)
> to a non-cytotoxic level and that the human dura mater retains its
> clinical utility.

# Device Manufacturing: Manufacturing Controls

Because product specifications and end-product testing alone are
insufficient to control critical characteristics of this product, the
manufacturer should carefully monitor donor selection, tissue collection
procedures, device processing, packaging, and distribution to achieve a
reasonable assurance of product safety. The 510(k) should provide
evidence that sufficient controls for device manufacture are in place to
assure the safety of the final product. The manufacturer should provide
the following information about manufacturing controls:

**A. Excision Procedures**

Written procedures should require aseptic conditions for handling of all
tissues. Tissue recovery should be performed within 24 hours of death
and with sufficient temperature control to limit the effects of
autolysis.

**B. Excision Facilities**

The manufacturer should provide information concerning how the excision
facility (morgue) meets the minimum standards of a surgical operating
room. Such information should describe, but not be limited to, whether
the excisional facility has:

-   air filtration

-   stainless steel furniture

-   washable walls

-   refrigeration for cadaver storage

-   hypothermia blankets to cool the cadaver during the procedure

-   single use or disposable instruments and processing aids for each
    donor.

**C. Batch Processing**

> Human dura mater grafts from different donors should not be co-mingled
> during tissue collection or product manufacture. The 510(k) should
> describe efforts to eliminate opportunities for cross-contamination
> during tissue collection and processing as well as the procedures
> employed to prohibit batch processing of material from different
> donors. For example, procedures should require the use of only
> disposable processing materials and surgical instruments during the
> recovery and processing of dura mater allografts. Because FDA is
> unaware of any procedure or reagent that is validated to totally
> inactivate the CJD-causing agent, FDA would welcome any information
> that justifies an alternative approach to the sole use of disposable
> processing materials and surgical instruments.

**D. Record Keeping/Tissue Tracking**

> As described in 21 CFR 820.60 subpart F, each manufacturer must
> establish and maintain procedures for identifying the product during
> all stages of receipt, production, distribution, and application. The
> 510(k) should describe the methods and record keeping procedures for
> tracking each lot of final product directly back to the tissue donor
> as it relates to donor medical records and device manufacturing
> records.
>
> Although not required to be submitted as part of the 510(k), the
> manufacturer should maintain the following data as part of the donor
> medical records:

-   the record of the time of death and certification of the time of
    tissue recovery

-   the results of post-mortem examination and serological studies
    sufficient to evaluate the potential of communicating infectious,
    malignant, and/or neurological disease or to detect diseases of
    unknown etiology

-   the record of compliance with the written procedures for recovery.

> For additional information regarding device manufacturing records, the
> manufacturer should refer to 21 CFR 820 subpart M (Quality System
> Regulations).
>
> For additional information regarding the tracking regulation, the
> manufacturer should refer to 21 CFR 821 and Section 519(e) of the
> Federal Food, Drug, and Cosmetic Act), which was issued on December
> 14, 1998. A manufacturer should also refer to "Guidance Document on
> Medical Device Tracking (1999)" for additional information on
> procedures for accurately tracking medical devices.

# Final Sterilization

For devices labeled as sterile, a sterility assurance level (SAL) of
10^‑6^ is recommended. All sterility data should be obtained by methods
consistent with a recognized standard or guidance for assessing the
ability of the manufacturing and sterilization processes to inactivate
bacteria, fungi and yeast (e.g., **Updated 510(k) Sterility Review
Guidance K90-1; Final Guidance for Industry and FDA**,
<http://www.fda.gov/cdrh/ode/guidance/361.html>). In addition, the
manufacturing methods should demonstrate that the sum of the log
clearance of virus from manufacturing and sterilization processes are at
least six logs greater than the concentration of virus anticipated in
the unprocessed source material. Studies determining the viral
inactivation properties may be performed with on selected scaled down
versions of specific manufacturing and the sterilization processses
using appropriate model viruses. FDA recommends review of the "Viral
Safety Evaluation of Biotechnology Products Derived from Cell Lines of
Human or Animal Origin" (Ref. 21) for information about the design of
such studies and the selection of model viruses.

Regarding final sterilization procedures, the 510(k) should describe:

-   the method of sterilization

-   the validation method for the sterilization cycle

-   the SAL to be achieved

-   the method for monitoring the sterility of each production lot.

If radiation sterilization is used, the sterilizing dose and methods for
monitoring exposure level should be specified. If ethylene oxide (EtO)
sterilization is performed, the application should describe the methods
by which residual levels of ethylene oxide, ethylene chlorohydrin, and
ethylene glycol are determined and the amount of EtO and residues
remaining on/in the device. Because EtO and its decomposition products
may be very neurotoxic, specifications for EtO residuals should be set
at a non-cytotoxic level. Review of "Guidance for ANSI/AAMI/ISO 10993-7:
1995, Biological evaluation of medical devices-Part 7: Ethylene oxide
sterilization residuals" is recommended.

# Labeling

The premarket notification should include labeling in sufficient detail
to satisfy the requirements of 21 CFR 807.87(e). The following
suggestions are aimed at assisting you in preparing labeling that
satisfies the requirements of 21 CFR 807.87(e).[^5]

> **[Prescription Device]{.underline}**
>
> In accordance with 21 CFR 801.109, this device must bear the following
> caution statement: "Caution: Federal law restricts this device to sale
> by or on the order of a physician."
>
> **[Graft]{.underline}**
>
> The labeling should include information so that the graft recipient is
> notified in writing that she/he has received a human dura mater graft
> implant.
>
> **[Tissue Sourcing]{.underline}**
>
> The labeling should permit information on tissue sourcing to be
> maintained in the recipient's hospital record.
>
> **[Alternatives]{.underline}**
>
> Because the WHO and the TSEAC have stated potential concerns related
> to potential CJD and vCJD transmission, product labeling should remind
> practitioners to consider the risks and benefits of human dura mater
> implantation, including the use of alternative products and
> procedures.

# References

1.  Kretzschmar, H.A., Ironside, J.W., DeArmond, S.J., and Tateishi, J.,
    "Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease," *Arch.
    Neurol.* 1996; **53**:913-920.

2.  "Proposed Approach to Regulation of Cellular and Tissue-Based
    Products" - 2/28/97. <http://www.fda.gov/cber/gdlns/CELLTISSUE.pdf>.

3.  "Establishment Registration and Listing for Manufacturers of Human
    Cellular and Tissue-Based Products" (66 FR 5447, January 21, 2001),
    available at <http://www.fda.gov/cber/guidelines.htm>.

4.  "Suitability Determination for Donors of Human Cellular and
    Tissue-Based Products" (64 FR 52696, September 30, 1999).

5.  "Current Good Tissue Practice for Manufacturers of Human Cellular
    and Tissue-Based Products; Inspection and Enforcement" (66 FR 1508,
    January 8, 2001).

6.  "The Commissioner may require that a manufacturer, importer, or
    distributor make reports or provide other information bearing on the
    classification of a device and indicating whether there is
    reasonable assurance of the safety and effectiveness of the device
    or whether it is adulterated or misbranded under the act." (21 CFR
    860.7(g)(2))

7.  "Revised Preventive Measures to Reduce the Possible Risk of
    Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant
    Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products,"
    8/27/01, available at http://www.fda.gov/cber/gdlns/cjdvcjd.htm.

8.  FDA Recommendations to Blood Establishments for "The Management of
    Donors and Units that are Initially Reactive for Hepatitis B Surface
    Antigen (HBsAg)," 12/2/87.

9.  FDA Recommendations to Blood Establishments for "Donor Suitability
    Related to Laboratory Testing for Viral Hepatitis and a History of
    Viral Hepatitis," 12/22/93.

10. PHS Guideline for Preventing Transmission of HIV through
    Transplantation of Human Tissue and Organs, *MMWR*: **43**: 1-17,
    1994.

11. PHS Guideline for Screening Donors of Blood, Plasma, Organs, Tissue
    and Semen for Evidence of Hepatitis B and Hepatitis C, *MMWR*:
    **40**:1-17, 1991.

12. FDA Recommendations to Blood Establishments for "Deferral of Current
    and Recent Inmates of Correctional Institutions as Donors of Whole
    Blood, Blood Components, Source Leukocytes, and Source Plasma,"
    6/8/95.

13. FDA Recommendations to Blood Establishments for "Precautionary
    Measures to Further Reduce the Possible Risk of Transmission of
    Creutzfeldt-Jakob Disease by Blood and Blood Products," 8/8/95.

14. FDA Recommendations to Blood Establishments for "Deferral of Blood
    and Plasma Donors based on Medications," 7/28/93.

15. FDA Guidance for Industry: Screening and Testing of Donors of Human
    Tissue Intended for Transplantation, July 1997.

16. FDA Revised Recommendations to Blood Establishments for "Testing
    Whole Blood, Blood Components, Source Plasma and Source Leukocytes
    for Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV),"
    4/23/92.

17. FDA Revised Recommendations to Blood Establishments for "The
    Prevention of Human Immunodeficiency Virus (HIV) Transmission by
    Blood and Blood Products," 4/23/92.

18. Diringer, H. and Braig, H.R., "Infectivity of Unconventional Viruses
    in Dura Mater," *Lancet* 1989 Feb 25;1(8635):439-40

19. Johnson, R.T. and Gibbs, C.L., "Creutzfeldt-Jakob Disease and
    Related Transmissible Spongiform Encephalopathies," *NEJM*, **339**,
    1994-2004 (1998).

20. Lantos, P.L., Bhatia, K., Doey, L.J., al-Sarraj, S., Doshi, R.,
    Beck, J. and Collinge, J. "Is the neuropathology of new variant
    Creutzfeldt-Jakob disease and kuru similar?" *Lancet* 1997 Jul
    19;350 (9072):187-8

21. Viral Safety Evaluation of Biotechnology Products Derived from Cell
    Lines of Human or Animal Origin" \<1050\> USP 24

[^1]: <http://www.fda.gov/cdrh/ode/parad510.html>

[^2]: Refer to
    [http://www.fda.gov/cdrh/ode/indicate.html](http://www.fda.gov/cdrh/ode/indicate.pdf)
    for the recommended format.

[^3]: If FDA makes a substantial equivalence determination based on
    acceptance criteria, the subject device should be tested and shown
    to meet these acceptance criteria before being introduced into
    interstate commerce. If the finished device does not meet the
    acceptance criteria, and thus differs from the device described in
    the cleared 510(k), FDA recommends that submitters apply the same
    criteria used to assess modifications to legally marketed devices
    (21 CFR 807.81(a)(3)) to determine whether marketing of the finished
    device requires clearance of a new 510(k).

[^4]: See Required Elements for a Declaration of Conformity to a
    Recognized Standard (Screening Checklist for All Premarket
    Notification \[510(K)\] Submissions),
    [http://www.fda.gov/cdrh/ode/reqrecstand.html]{.underline}.

[^5]: Although final labeling is not required for 510(k) clearance,
    final labeling must also comply with the requirements of 21 CFR 801
    before a medical device is introduced into interstate commerce. In
    addition, final labeling for prescription medical devices must
    comply with 21 CFR 801.109. Labeling recommendations in this
    guidance are consistent with the requirements of part 801.