[Federal Register Volume 66, Number 5 (Monday, January 8, 2001)]
[Proposed Rules]
[Pages 1508-1559]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-447]



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Part VIII





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 1271



Current Good Tissue Practice for Manufacturers of Human Cellular and 
Tissue-Based Products; Inspection and Enforcement; Proposed Rule

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / 
Proposed Rules

[[Page 1508]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1271

[Docket No. 97N-484P]


Current Good Tissue Practice for Manufacturers of Human Cellular 
and Tissue-Based Products; Inspection and Enforcement

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing new 
regulations to require manufacturers to follow current good tissue 
practice, which includes methods used in, and the facilities and 
controls used for, the manufacture of human cellular and tissue-based 
products; recordkeeping; and the establishment of a quality program. 
The agency is also proposing new regulations pertaining to labeling, 
reporting, inspections, and enforcement that will apply to 
manufacturers of those human cellular and tissue-based products that 
the agency is proposing to regulate solely under the authority of the 
Public Health Service Act (PHS Act) and not as biological drugs or as 
devices. The agency's actions are intended to improve protection of the 
public health while permitting significant innovation and keeping 
regulatory burden to a minimum.

DATES: Submit written comments on the proposed rule by May 8, 2001. 
Submit written comments on the information collection provisions by 
February 7, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit written comments on the information 
collection provisions to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington, 
DC 20503, Attn: Wendy Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Introduction

    FDA is in the process of establishing a comprehensive new system 
for regulating human cellular and tissue-based products. In an earlier 
related rulemaking, the agency proposed to define a human cellular or 
tissue-based product as a ``product containing or consisting of human 
cells or tissues that is intended for implantation, transplantation, 
infusion, or transfer into a human recipient * * *'' (``Suitability 
Determination for Donors of Human Cellular and Tissue-based Products,'' 
proposed rule (64 FR 52696, September 30, 1999), hereinafter ``donor-
suitability proposed rule''). ``Transfer'' is a term used with respect 
to reproductive cells and tissues, and has also been defined in another 
related proposal (``Establishment Registration and Listing for 
Manufacturers of Human Cellular and Tissue-based Products,'' proposed 
rule (63 FR 26744 at 26754, May 14, 1998), hereinafter ``registration 
proposed rule'').
    Examples of human cellular and tissue-based products include 
cadaveric ligaments, skin, bone, dura mater, heart valves, corneas, 
blood hematopoietic stem cells, manipulated autologous chondrocytes, 
and spermatozoa. Certain exclusions from the definition of human 
cellular and tissue-based products may be applicable and have been 
discussed in earlier rulemakings (registration proposed rule, 63 FR 
26744 at 26748; donor-suitability proposed rule, 64 FR 52696 at 52700).
    The regulations now being proposed would require all human cellular 
and tissue-based products to be manufactured in compliance with current 
good tissue practice (CGTP). The proposal also contains provisions 
relating to establishment inspection and enforcement, as well as 
certain labeling and reporting requirements, which would be applicable 
to those human cellular and tissue-based products that the agency is 
proposing to regulate solely under the authority of section 361 of the 
PHS Act and not as biological drugs or devices.
    The agency also requests consultation from the States on any 
preemption issues raised by the proposed CGTP rule, specifically with 
regard to: (1) the need for CGTP requirements to prevent communicable 
disease transmission through human cellular and tissue-based products; 
(2) alternatives that would limit the scope of such national 
requirements or otherwise preserve State prerogatives and authority; 
and (3) any other issues raised by this proposed rule that could affect 
State laws and authorities.

A. Background

    In February 1997, FDA proposed a new, comprehensive approach to the 
regulation of human cellular and tissue-based products. The agency 
announced its regulatory plans in two documents: ``Reinventing the 
Regulation of Human Tissue'' and ``A Proposed Approach to the 
Regulation of Cellular and Tissue-based Products'' (hereinafter 
``proposed approach document''). FDA requested written comments on its 
proposed approach and, on March 17, 1997, held a public meeting to 
solicit information and views from the interested public (62 FR 9721, 
March 4, 1997).
    Since that time, the agency has published two proposed rules that 
would implement aspects of the proposed approach. On May 14, 1998, the 
agency proposed regulations that would create a new, unified system for 
registering establishments that manufacture human cellular and tissue-
based products and for listing their products (registration proposed 
rule at 63 FR 26744). On September 30, 1999, FDA proposed regulations 
that would require most cell and tissue donors to be tested and 
screened for relevant communicable diseases (donor-suitability proposed 
rule at 64 FR 52696 at 52719).
    With the present rulemaking, the agency is completing the set of 
proposals that would implement the new regulatory scheme. In the 
proposed approach document, the agency stated that it would require 
that cells and tissues be handled according to procedures designed to 
prevent contamination and to preserve tissue function and integrity. 
Thus, the agency is now proposing to require that establishments that 
manufacture human cellular or tissue-based products comply with CGTP, 
which would include, among other things, proper handling, processing, 
labeling, and recordkeeping procedures. In addition, the proposed 
regulations would require each establishment to maintain a ``quality 
program'' to ensure compliance with CGTP.
    The proposed CGTP regulations would be contained in title 21 CFR in 
new part 1271, along with provisions relating to establishment 
registration and donor suitability that have been proposed previously. 
Subpart A of part 1271 would set forth scope and purpose as well as 
definitions. Subpart B of part 1271 would contain registration 
procedures. Subpart C of part 1271 would set forth provisions for the 
screening and testing of donors in order to determine their 
suitability. Subpart D of part 1271 would contain the provisions on 
CGTP now being proposed. Subpart E of part 1271 would contain certain 
labeling and reporting requirements and subpart F of part 1271

[[Page 1509]]

would contain the inspection and enforcement provisions applicable to 
those human cellular and tissue-based products regulated solely under 
the authority of section 361 of the PHS Act. The agency proposes to 
revoke part 1270 (21 CFR part 1270), which will be superseded by new 
part 1271.

B. The Tiered, Risk-Based Regulatory Approach

    The proposed approach document set out a tiered regulatory scheme, 
under which human cellular and tissue-based products would be subject 
to an appropriate level of regulation based on the degree of risk and 
the necessity for FDA review. Certain human cellular and tissue-based 
products (e.g., tissues that are more than minimally manipulated) would 
be regulated as biological drugs or medical devices under the Federal 
Food, Drug, and Cosmetic Act (the act) and/or section 351 of the PHS 
Act (42 U.S.C. 262), and thus would be subject to premarket review 
procedures, among other requirements. FDA is proposing to regulate 
other human cellular and tissue-based products solely under the 
authority of section 361 of the PHS Act (42 U.S.C. 264), which 
authorizes the agency to issue regulations to prevent the introduction, 
transmission, or spread of communicable diseases. (These products are 
referred to in this document as ``361 products.'')
    The proposed tissue regulations would apply to a wide range of 
human cells and tissues. To simplify terminology, the proposed 
regulations refer generally to all human cells and tissues, including 
reproductive tissue, as ``products,'' and refer to persons who recover, 
screen, test, process, store, label, package, or distribute human 
cellular and tissue-based products as ``manufacturers.'' The term 
``product'' is a term of art coined under Section 351 of the PHS Act, 
i.e., ``biological product,'' while the term ``manufacturer'' is used 
in FDA's current regulations that affect biological products, drugs, 
and devices. However, Section 361 of the PHS Act, which gives FDA the 
authority to make and enforce regulations to prevent the spread of 
communicable disease, does not require use of the term ``product'' to 
define its scope. The agency has received comments to the first two 
proposed rules to implement the proposed approach objecting to the use 
of the terms ``product'' and ``manufacturer'' as applied to human cells 
and tissues. In finalizing these rules, the agency will consider 
whether alternative terminology to describe the scope of the 
regulations should be used.
    FDA anticipates that determining the regulatory process for certain 
cellular and tissue-based products may be complicated. To help answer 
questions about how a particular cellular or tissue-based product will 
be regulated, the agency developed the Tissue Reference Group (TRG). 
The TRG is composed of: (1) Three representatives from the Center for 
Biologics Evaluation and Research (CBER); (2) three representatives 
from the Center for Devices and Radiological Health (CDRH); (3) the 
product jurisdictional officer from each Center; and (4) a liaison from 
the agency's Office of the Chief Mediator and Ombudsman (OCMO), a 
nonvoting member. Other FDA staff attend the TRG meetings as needed to 
discuss issues related to products in their area of expertise. The TRG 
provides a single reference point and makes recommendations to the 
center directors regarding product jurisdiction of specific tissue.
    In addition, FDA recognizes that further public discussion of how 
the proposed tissue regulations would be applied to certain categories 
of human cells and tissues may be warranted due to the complexity or 
sensitivity of the issues. For example, the agency held a public 
meeting to discuss how proposed definitions for ``minimally 
manipulated'' and ``homologous use'' should be applied to human bone 
allograft products on August 2, 2000. FDA intends to provide further 
opportunities for public discussion of how the regulatory approach 
should be applied to reproductive cells and tissue. FDA anticipates 
that there may be additional needs for discussion through public 
meetings, public hearings, or guidance as the agency implements the new 
regulations. The regulatory categories applicable to human cellular and 
tissue-based products are discussed in greater detail in the 
registration and donor-suitability proposed rules (63 FR 26744 at 
26746; 64 FR 52696 at 52698).
    Under the regulatory scheme being proposed at part 1271, all human 
cellular and tissue-based products, regardless of the regulatory 
category in which they belong, would be subject to certain core 
requirements designed to address concerns common to all such products. 
(These core requirements will cover registration procedures, donor 
testing and screening, and CGTP, and will be in subparts B, C, and D of 
part 1271.) Because of their nature as derivatives of the human body, 
all human cellular and tissue-based products pose a potential risk of 
transmitting communicable diseases. Thus, the donor-suitability 
proposed rule would require that most cell and tissue donors be tested 
and screened for evidence of relevant communicable-disease infection. 
Similarly, the CGTP regulations now being proposed are designed to 
prevent the introduction, transmission, and spread of communicable 
diseases. For example, compliance with CGTP would require such 
precautions as cleaning of facilities and equipment, storage procedures 
designed to prevent product mix-ups, and controls over processing to 
prevent product contamination and impairment to function or integrity.
    Those human cellular or tissue-based products regulated solely 
under the authority of section 361 of the PHS Act would be subject only 
to the requirements contained in part 1271. In contrast, human cellular 
or tissue-based products regulated as devices or biological drugs would 
be subject not only to the core requirements contained in subparts B, 
C, and D of part 1271, but also to other applicable statutory and 
regulatory requirements.

C. Legal Authority

    FDA is proposing to issue these new regulations under the authority 
of section 361 of the PHS Act. Under section 361 of the PHS Act, FDA 
may make and enforce regulations necessary to prevent the introduction, 
transmission, or spread of communicable diseases between the States or 
from foreign countries into the States. (See sec. 1, Reorg. Plan No. 3 
of 1966 at 42 U.S.C. 202 for delegation of section 361of the PHS Act 
authority from the Surgeon General to the Secretary, Health and Human 
Services; see 21 CFR 5.10(a)(4) for delegation from the Secretary to 
FDA.) Intrastate transactions may also be regulated under section 361 
of the PHS Act. (See Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. 
La. 1977).)
    Certain diseases, such as those caused by the human 
immunodeficiency virus (HIV) and the hepatitis B and C viruses, may be 
transmitted through the implantation, transplantation, infusion, or 
transfer of human cellular or tissue-based products derived from 
infected donors. The agency has, in an earlier rulemaking, proposed 
that most cell and tissue donors be screened and tested for these and 
other relevant communicable diseases (donor-suitability proposed rule, 
64 FR 52696 at 52720). However, donor screening and testing, although 
crucial, are not sufficient to prevent the transmission of disease by 
human cellular and tissue-based products. Rather, each step in the 
manufacturing process needs to be controlled. Errors in labeling, mix-
ups of testing records, failure to adequately clean work areas,

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and faulty packaging are all examples of improper practices that could 
lead to a product capable of transmitting disease to its recipient. 
Similarly, as noted in the proposed approach document, improper 
handling of a human cellular or tissue-based product can lead to 
bacterial contamination of the product or to cross-contamination 
between products.
    In addition to the direct transmission of communicable disease 
agents by human cellular and tissue-based products to their recipients, 
the agency is also concerned about the spread of communicable disease 
through the use of products whose function or integrity have been 
impaired. When a product does not work in a patient because it has not 
been manufactured properly, the risk of introducing, transmitting, or 
spreading a communicable disease is increased each time a procedure is 
repeated for at least two reasons: (1) Despite the best controls, there 
is a risk, albeit smaller than without controls, of communicable 
disease transmission, and (2) a procedure for transfer or transplant 
can carry an independent risk of communicable disease transmission. For 
example, use of a product whose function or integrity may have been 
compromised could create a circumstance that increases a patient's need 
for an additional transfer or transplant attempt. A repeat surgical 
procedure necessitated by the damaged product would further expose the 
patient to the additional communicable disease risks inherent in any 
such procedure. Moreover, a patient in a weakened state from the first 
unsuccessful procedure is at greater risk of contracting a communicable 
disease by experiencing a repeat procedure. Therefore, the agency 
considers that requirements aimed at maintaining product function and 
integrity are necessary, and thus may be issued under section 361 of 
the PHS Act.
    The proposed CGTP regulations would govern the methods used in, and 
the facilities and controls used for, the manufacture of human cellular 
and tissue-based products. CGTP requirements are a fundamental 
component of FDA's risk-based approach to regulating human cellular and 
tissue-based products. Products that the agency is proposing to 
regulate solely under section 361 of the PHS Act and proposed part 
1271, would be subject to less rigorous agency oversight than products 
also regulated under the act and/or section 351 of the PHS Act. By 
requiring that 361 products be manufactured in compliance with CGTP, in 
combination with the other proposed requirements in part 1271, the 
agency can be assured that 361 products are subject to sufficient 
regulatory controls to protect the public health.
    FDA is proposing that the CGTP regulations would supplement, but 
not supersede, the current good manufacturing practice (CGMP) and 
quality system (QS) regulations applicable to drugs and devices in 
parts 210, 211, and 820 (21 CFR parts 210, 211, and 820). Under the 
proposed rule, human cellular and tissue-based products regulated as 
biological drugs under the act and section 351 of the PHS Act, or as 
devices under the act, would have to be manufactured in accordance with 
CGTP, in addition to existing requirements. Thus, in keeping with the 
plan outlined in the proposed approach document, those products 
regulated as biological drugs or devices would be subject to more 
comprehensive regulation of manufacturing than the 361 products.
    In the donor-suitability proposed rule, the agency proposed to 
amend the existing CGMP regulations for drugs and the QS requirements 
for devices to incorporate the testing and screening provisions of 
proposed part 1271, subpart C. At that time, in order to obviate the 
need for further revisions, the agency also proposed to amend those 
sections to incorporate the current good tissue practice procedures of 
proposed part 1271 subpart D. In amending the CGMP and QS regulations, 
FDA is relying both on the authority provided by section 361 of the PHS 
Act to make regulations to prevent the spread of communicable disease, 
and on its authority under the act to issue CGMP regulations (section 
301(a)(2)(B) and (h) of the act) (21 U.S.C. 351(a)(2)(B) and (h)), 
section 520(f)(1) of the act (360j(f)(1)); section 701 of the act (21 
U.S.C. 371)).
    Under proposed 21 CFR 210.1(c), the manufacturer of a human 
cellular or tissue-based product regulated as a drug or biological drug 
would be required to comply with the CGTP procedures in part 1271, 
subpart D (donor suitability proposed rule, (64 FR 52696 at 52699 and 
52719)). Likewise, under proposed 21 CFR 820.1, the manufacturer of a 
human cellular or tissue-based product regulated as a device would be 
required to comply with the same procedures (donor suitability proposed 
rule (64 FR 52696 at 52699 and 52719)). If the manufacturer failed to 
follow the CGMP requirements, including the good tissue practice 
procedures in part 1271, the product would be adulterated under section 
501(a)(2)(B) of the act.
    FDA is also relying on its authority under section 361 of the PHS 
Act to propose several reporting, labeling, inspection, and enforcement 
provisions. Because products regulated under the act and/or section 351 
of the PHS Act, are subject to similar regulation requirements, these 
provisions would apply only to 361 products. Proposed subpart E of part 
1271 contains regulations on reporting and labeling pertaining to 361 
products and is discussed in section III of this document. Proposed 
subpart F of part 1271 contains inspection and enforcement provisions 
also applicable only to 361 products; the relevant discussion appears 
in section IV of this document.

II. Summary of the Proposed CGTP Regulations

    The regulations being proposed would require manufacturers of human 
cellular and tissue-based products to follow CGTP, which includes 
proper handling, processing, storage, and labeling of human cellular 
and tissue-based products, recordkeeping, and the establishment of a 
quality program. The proposed CGTP regulations are designed to address 
issues common to all human cellular and tissue-based products, and so 
are intentionally broad in scope. The agency anticipates that, as it 
implements the new regulations, there may be additional need for 
discussion, through public meetings, public hearings, or guidance, of 
how these general regulations would apply to specific types of 
products. In addition, there may be specific elements of these proposed 
requirements that some readers may not consider appropriate to general 
application. The agency welcomes comments that will assist it in 
achieving the proper balance between generality and specificity in 
these regulations.

A. General Provisions (Proposed Secs. 1271.150 and 1271.155)

    Proposed Sec. 1271.150 contains general provisions intended to aid 
in the interpretation of the requirements contained in subparts C and D 
of part 1271. Proposed Sec. 1271.155 sets out the procedures for 
obtaining an exemption or variance from one or more of these 
requirements.
    1. Current Good Tissue Practice (Proposed Sec. 1271.150(a))
    Proposed Sec. 1271.150(a) states that CGTP requirements govern the 
methods used in, and the facilities and controls used for, the 
manufacture of human cellular and tissue-based products. CGTP 
requirements are intended to prevent the introduction, transmission, 
and spread of communicable disease through the use of human cellular 
and tissue-based products by helping to

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ensure that: (1) The products do not contain relevant communicable 
disease agents; (2) they are not contaminated during the manufacturing 
process; and (3) the function and integrity of the products are not 
impaired through improper manufacturing, all of which could lead to 
circumstances that increase the risk of communicable disease 
transmission. ``Manufacture'' as defined in the registration proposed 
rule, includes, but is not limited to, any or all steps in the 
recovery, processing, storage, labeling, packaging, or distribution of 
any human cellular or tissue-based product, and the screening and 
testing of a cell or tissue donor (proposed Sec. 1271.3(f), 63 FR 26744 
at 26754.) The definition of ``human cellular or tissue-based product'' 
as revised in the donor suitability proposed rule, is intended to cover 
such products at all stages of their manufacture, from recovery through 
distribution (see proposed Sec. 1271.3(e) (64 FR 52696 at 52719). For a 
human cellular or tissue-based product to be manufactured properly, 
CGTP must be followed in each step of the manufacturing process.
    The word ``current'' is included in the term ``current good tissue 
practice'' because the agency recognizes that appropriate practices may 
change over time, as research is conducted and new manufacturing 
methods are developed. These regulations are not intended to require 
that practices considered current at the time of issuance of the final 
regulations be maintained indefinitely; instead, the obligation on an 
establishment is to maintain up-to-date practices over time. 
Recognizing that improved manufacturing techniques may be developed, 
the agency has generally refrained in these proposed regulations from 
requiring specific procedures, such as particular processing methods or 
storage temperatures. Instead, the proposed regulations set out general 
objectives. This approach not only allows for new developments, but 
also affords establishments flexibility in developing procedures that 
are both appropriate to their particular operations and that comply 
with the regulations.
    The proposed requirements are based on current good industry 
practice and are intended to address what the agency considers 
important minimum criteria for the manufacture of these products. In 
developing these regulations, the agency has reviewed several sets of 
industry standards, including those issued by the American Association 
of Tissue Banks (AATB) and by the Eye Bank Association of America 
(EBAA). The agency expects that some establishments will need to make 
only small changes in their operations to achieve compliance. Other 
establishments may find that complying with the new requirements 
entails revising certain procedures and recordkeeping practices, but 
few operational changes. Another group of establishments--for example, 
those that have not previously been subject to regulation and that do 
not belong to any standard-setting or accrediting organization--may 
need to revise their procedures more completely, in order to bring them 
into compliance with these regulations and industry practice.
    Proposed Sec. 1271.150(a) states that CGTP requirements are set 
forth in subparts C and D of part 1271. The CGTP provisions 
specifically governing donor suitability, including donor testing and 
screening, are set out separately in subpart C of part 1271. The agency 
notes that Sec. 1271.90 contains exceptions from required testing and 
screening for two types of human cellular and tissue-based product: 
Banked cells and tissues for autologous use, and reproductive cells or 
tissue donated by a sexually-intimate partner of the recipient for 
reproductive use (64 FR 52696 at 52723). (Donor testing and screening 
are recommended, however.) The agency specifically notes that the 
exceptions in Sec. 1271.90 apply only to subpart C of part 1271 and do 
not extend to the provisions of subpart D of part 1271. Because the 
safety concerns addressed by the proposed CGTP requirements apply to 
all human cellular and tissue-based products, no exceptions are being 
proposed for any particular category of product. Thus, banked cells and 
tissues for autologous use, and reproductive cells or tissue donated by 
a sexually-intimate partner of the recipient for reproductive use, 
would be subject to the CGTP requirements in subpart D of part 1271.
    2. Compliance With Applicable Requirements (Proposed 
Sec. 1271.150(b))
    FDA recognizes that several establishments may be involved in the 
manufacture of a single human cellular or tissue-based product. For 
example, one establishment may recover tissue from a cadaver, another 
establishment may make the donor-suitability determination, a third may 
process the tissue, and a fourth may distribute the product. The agency 
has taken care, in designing these proposed regulations, to reflect the 
fact that manufacturing roles might be divided up in a variety of 
possible ways. Thus, under proposed Sec. 1271.150(b), an establishment 
that engages in only some operations subject to the regulations in 
subparts C and D of part 1271 need only comply with those requirements 
applicable to the operations in which it engages. Under 
Sec. 1271.150(b), an establishment that does not process cells or 
tissue would not be obligated to establish and maintain process 
controls under proposed Sec. 1271.220. However, an establishment that 
engages another establishment, under a contract, agreement, or other 
arrangement, to perform any step in the manufacturing process, would be 
responsible for ensuring that the work is performed in compliance with 
the requirements in subparts C and D of part 1271. One method of 
accomplishing this might be by performing periodic audits.
    Given that the steps in manufacturing a single human cellular or 
tissue-based product may be carried out by several establishments, FDA 
considers it essential that additional safeguards be established to 
ensure compliance with regulatory requirements throughout the 
manufacturing process. The agency has considered various ways of 
allocating regulatory responsibilities among the establishments 
involved in manufacturing a human cellular or tissue-based product. The 
agency seeks to permit establishments to maintain flexibility in 
sharing manufacturing responsibilities, while ensuring that products 
made available for release maintain their function and integrity, are 
not contaminated, and do not contain communicable disease agents.
    The agency first considered assigning overall responsibility for 
ensuring that a human cellular and tissue-based product is manufactured 
in compliance with all applicable regulations to the establishment that 
determines donor suitability. However, the agency recognized that the 
role this establishment plays in the manufacture of a human cellular or 
tissue-based product occurs early in the sequence of manufacturing 
events. As a practical matter, the establishment that determines donor 
suitability might not be able to ensure that later manufacturing steps, 
such as processing and labeling, are performed in compliance with the 
regulations. A more pragmatic approach would be to assign 
responsibility to the establishment that makes a product available for 
distribution.
    Another option would be to permit the establishments engaged in the 
manufacturing process to decide among themselves which party bears 
ultimate responsibility for the product. However, the agency is 
concerned that, under this approach, there would be occasions when no 
establishment would step forward as the one ultimately responsible, and 
that as a consequence

[[Page 1512]]

compliance with certain requirements might not be accomplished. As a 
result, products might be released that pose a risk of transmitting 
communicable disease or otherwise increasing the risk of disease 
transmission. For the same reasons, FDA has rejected the idea that 
designating a responsible establishment is unnecessary.
    The agency has also considered a ``cascading'' set of 
responsibilities. Under this approach, an establishment would be 
responsible for ensuring that its own operations comply with applicable 
requirements, and also would bear the burden of proof that operations 
performed by other establishments prior to its receipt of the cells or 
tissue were performed in compliance with applicable requirements.
    After considering the unique nature of the cell and tissue 
industry, and each of the above options, the agency has tentatively 
concluded that the best approach is to assign ultimate responsibility 
for the product to the establishment that is responsible for making the 
product available for distribution. This is consistent with the 
proposed approach document, which stated that ``[t]he establishment or 
person responsible for determining suitability of release of cells or 
tissues would be responsible for ensuring that required screening and 
testing had been performed prior to final release of the material.'' 
Thus, proposed Sec. 1271.150(b) states that the establishment that 
determines that a product meets release criteria and makes the product 
available for distribution, whether or not that establishment is the 
actual distributor, is responsible for ensuring that the product has 
been manufactured in compliance with the requirements of subpart C and 
D of part 1271 and any other applicable requirements.
    The agency specifically requests comments on the allocation of 
overall manufacturing responsibility. Examples of industry arrangements 
currently in existence would be particularly useful to the agency in 
evaluating the comments on these proposed regulations.
    3. Compliance With Parts 210, 211, and 820
    The proposed CGTP regulations are similar to the CGMP requirements 
applicable to drugs and the QS requirements for devices. However, the 
CGMP and QS regulations do not contain provisions specifically intended 
to prevent the spread of communicable disease. In contrast, the purpose 
of the proposed CGTP regulations is limited to preventing circumstances 
that increase the risk of introduction, transmission, and spread of 
communicable disease; the proposed regulations are therefore less 
extensive in scope than the CGMP and QS regulations.
    Proposed Sec. 1271.150(c) states that, with respect to human 
cellular and tissue-based products regulated as biological drugs or as 
devices, the proposed CGTP procedures will supplement, not supersede, 
the CGMP and QS requirements. Proposed Sec. 1271.150(c) states that, in 
the event that it is impossible to comply with all applicable 
regulations, the regulations specifically applicable to the biological 
drug or device in question shall supersede the more general.
    4. ``Where Appropriate''
    Several of the requirements contained in part 1271, subpart D, are 
qualified by the term ``where appropriate,'' which as explained in 
proposed Sec. 1271.150(d), are considered to be appropriate, and must 
be followed, unless an establishment can justify otherwise, and 
maintains documentation of that justification. Under proposed 
Sec. 1271.150(d), a requirement is ``appropriate'' if nonimplementation 
could reasonably be expected to result in the: (1) Product's not 
meeting its specified requirements related to preventing the 
introduction, transmission, and spread of communicable disease agents 
and diseases; or (2) manufacturer's inability to carry out any 
necessary corrective action.
    5. Exemptions and Alternatives (Proposed Sec. 1271.155)
    FDA recognizes the possibility that, as technology and scientific 
knowledge advance, new methods may be developed that could be used in 
the manufacture of human cellular and tissue-based products, or other 
unanticipated circumstances may arise that warrant a departure from an 
approach detailed in the regulations. Some of these technical 
developments may not be consistent with the terms of the donor-
suitability and CGTP regulations, although the purpose of those 
regulations might be satisfied. In order to provide establishments with 
flexibility, and to ensure that the agency may respond appropriately to 
improved technologies and increased scientific knowledge, the agency 
proposes that establishments may apply for exemptions or alternatives 
from the regulatory requirements contained in subparts C and D of part 
1271.
    Proposed Sec. 1271.155 sets out the procedures for obtaining an 
exemption or alternative from a requirement in subpart C of part 1271, 
pertaining to donor suitability, or in subpart D of part 1271, 
pertaining to CGTP. Under proposed Sec. 1271.155, an establishment 
could demonstrate to the agency that it should be exempted from an 
otherwise applicable regulatory requirement or permitted to satisfy the 
purpose of the requirement in an alternative manner. A request for an 
exemption or alternative would need to be accompanied by supporting 
documentation, including all relevant valid scientific data. Requests 
would be made in writing or electronically, except that in limited 
circumstances (e.g., emergencies) a request might be made and granted 
orally, with a written request and acknowledgment of approval to 
follow.
    Under proposed Sec. 1271.155(c), the Director of the Center for 
Biologics Evaluation and Research (CBER) could grant an exemption or 
alternative if he or she found that doing so would be consistent with 
the goals of preventing circumstances that increase the risk of the 
introduction, transmission, and spread of communicable disease. In 
addition, an exemption or alternative would be conditioned on a finding 
by the Director that the information submitted justified an exemption 
or that the proposed alternative satisfied the purpose of the 
requirement. An establishment that requested an exemption or 
alternative could not begin operating under its terms until the 
exemption or alternative had been granted. Some exemptions or 
alternatives might have expiration dates, in which case an extension 
could be requested. An establishment operating under the terms of an 
exemption or alternative would be required to maintain documentation 
that the exemption or alternative had been granted, and of the date on 
which the establishment began operating under the terms of the 
exemption or alternative.

B. Definitions (Proposed Sec. 1271.3)

    Definitions pertinent to part 1271 will be contained in subpart A, 
in Sec. 1271.3. In the registration proposed rule, FDA set out defined 
terms in paragraphs (a) through (h) of Sec. 1271.3. In the donor-
suitability proposed rule, further definitions were proposed, to be 
contained in Sec. 1271.3(i) through (ee), and the proposed definition 
of human cellular or tissue-based product in paragraph (e) was revised.
    Now, the agency is proposing new paragraphs (ff) through (tt) in 
Sec. 1271.3. These new definitions are discussed below, when the 
requirements to which the defined terms relate are discussed.

C. Quality Program (Proposed Sec. 1271.160)

    Any establishment that manufactures human cellular or tissue-based 
products

[[Page 1513]]

needs to have in place a method of ensuring that its manufacturing 
processes are performed properly and in compliance with applicable 
regulations. For devices, such a program is called a ``quality system'' 
(Sec. 820.1 et seq.). In these regulations, FDA is proposing to use 
``quality program'' to refer to the set of activities, including 
management review, training, audits, and corrective and preventive 
actions, that represent a commitment on the part of an establishment's 
management to the quality of its products. FDA proposes to define 
``quality program'' in Sec. 1271.3(oo) as ``an organization's 
comprehensive system for manufacturing and tracking human cellular and 
tissue-based products. This program includes preventing, detecting, and 
correcting deficiencies that may lead to circumstances that increase 
the risk of the introduction, transmission, or spread of communicable 
disease.''
    Proposed Sec. 1271.160 would require an establishment that performs 
any step in the manufacture of human cellular and tissue-based products 
to establish and maintain a quality program that is appropriate for the 
specific human cellular and tissue-based products manufactured and the 
manufacturing steps performed and that meets the requirements of this 
part. With proposed Sec. 1271.160, FDA intends to require that a 
quality program perform certain basic functions, but also intends to 
provide each establishment with flexibility to devise a program 
appropriate to its particular activities and characteristics. Thus, FDA 
expects that quality programs may differ from establishment to 
establishment, depending on the size of the establishment and the type 
of manufacturing performed, among other factors. A smaller company that 
performs limited manufacturing steps might have a less complex quality 
program than a larger establishment that processes a variety of 
products.
    Some establishments may currently have in place quality programs 
that would meet the requirements of proposed Sec. 1271.160. An 
establishment that manufactures human cellular and tissue-based 
products regulated as devices would likely find it unnecessary to make 
major changes to its quality system established in compliance with 
Sec. 820.5 in order to comply with proposed Sec. 1271.160. Such an 
establishment would not need to maintain both a QS and a separate 
quality program.
    The functions of a quality program, as listed in proposed 
Sec. 1271.160(b), include but are not limited to: (1) Ensuring that 
required procedures are established and maintained; (2) ensuring the 
appropriate analysis and sharing of information that could affect the 
integrity and function of a human cellular or tissue-based product, 
possible contamination of the product, or the potential transmission of 
communicable disease by the product; (3) ensuring that appropriate 
corrective actions are taken and documented; (4) ensuring the proper 
training and education of personnel; (5) establishing and maintaining 
appropriate monitoring systems; (6) establishing and maintaining a 
system for maintaining records; (7) investigating and documenting 
product deviations and making certain required reports; and (8) 
conducting evaluations, investigations, audits, and other actions 
necessary to ensure compliance with the regulations.
    Proposed Sec. 1271.160(b)(2) would specifically require procedures 
to be established for sharing and receiving information that could 
affect the integrity and function of a human cellular or tissue-based 
product, the possible contamination of the product, or the potential 
transmission of communicable disease by the product. This would include 
information on testing or screening results that could make a donor 
unsuitable; such information would need to be shared with other 
establishments that are known to have recovered cells or tissue from 
the same donor. An establishment would also need procedures in place in 
order to respond appropriately (through investigation, evaluation, 
possible recall, reporting, etc.) if it received any such information 
from another establishment.
    Proposed Sec. 1271.160(b)(7) would require establishments to 
investigate and document all product deviations in manufacturing. The 
term ``product deviation'' is defined in proposed Sec. 1271.3(kk) as 
``an event that represents a deviation from current good tissue 
practice, applicable standards, or established specifications; or an 
unexpected or unforeseeable event that may relate to the transmission 
or potential transmission of a communicable disease agent or disease 
from a human cellular or tissue-based product to a recipient, may lead 
to product contamination, or may adversely affect the function or 
integrity of the product.'' Investigation would be required to include 
a review and evaluation of the product deviation in manufacturing, the 
efforts made to determine the cause, and the implementation of 
corrective action designed to address the event and prevent its 
recurrence.
    Certain product deviations in manufacturing would be required to be 
reported. The proposed requirement, applicable to distributed 361 
products, for reporting product deviations in manufacturing that could 
lead to adverse reactions is discussed below in section III of this 
document. Certain product variations, referred to currently as errors 
and accidents, involving human cellular and tissue-based products 
regulated as biological drugs are required to be reported under 21 CFR 
600.14 (currently undergoing revisions; see 62 FR 49642, September 23, 
1997). In addition, each establishment would be required to perform a 
periodic review and analysis of all investigations of product 
deviations in manufacturing, at least once each year, for the purpose 
of identifying trends and adopting appropriate corrective and 
preventive measures. Section 1271.160(b)(7) specifies that this 
analysis shall be available for review upon inspection and for 
submission to FDA upon request.
    Under proposed Sec. 1271.160(c), one or more designated persons 
shall have authority over the quality program, and this person shall 
report to management at least once a year on the performance of the 
quality program. However, more frequent reports may be necessary in 
order to keep management informed of the status of the program.
    Audits are an important component of a quality program. Under 
proposed Sec. 1271.160(d), a comprehensive quality audit of all 
activities would be required at least once a year. FDA proposes to 
define ``quality audit'' in proposed Sec. 1271.3(nn), as ``a 
documented, independent inspection and review of an establishment's 
activities, including manufacturing and tracking, performed according 
to procedures, to verify, by examination and evaluation of objective 
evidence, the degree of compliance with those aspects of the quality 
program under review.'' In addition to the annual quality audit, 
special audits would be performed as necessary to ensure that quality 
program objectives are achieved.
    Proposed Sec. 1271.160(e) covers the use of computers or automated 
data processing systems used as part of the quality program, as part of 
manufacturing, or for maintaining manufacturing data or records. An 
establishment using such a computer or automated system would be 
required to validate the computer software for its intended use 
according to an established protocol, as well as all software changes. 
Validation and results would be required to be documented. The agency 
proposes to define

[[Page 1514]]

``validation'' in proposed Sec. 1271.3(rr) as ``confirmation by 
examination and provision of objective evidence that particular 
requirements can consistently be fulfilled * * *''.

D. Organization and Personnel (Proposed Sec. 1271.170)

    Proposed Sec. 1271.170 sets out general requirements for the 
organization and personnel of establishments that manufacture human 
cellular and tissue-based products. Under this section, each 
establishment would be required to maintain an adequate organizational 
structure and sufficient personnel to ensure that the requirements of 
part 1271 are met. Moreover, an establishment would need to have 
sufficient personnel with the necessary education and experience, or 
combination thereof, to assure competent performance of their assigned 
functions.
    Under proposed Sec. 1271.170, personnel would only be permitted to 
perform those activities for which they are qualified. Training of 
personnel to perform their assigned responsibilities adequately would 
be required, as would any necessary retraining. Because of the 
particular risks addressed by the requirements of part 1271, the agency 
is proposing to require that personnel be educated about possible 
consequences of improperly performing their duties; e.g., the risk that 
an improperly handled product could cause harm to the product's 
recipient, by transmitting a communicable disease or by failing to 
function adequately. A record of the education, experience, training, 
and retraining would need to be maintained for all personnel.

E. Procedures (Proposed Sec. 1271.180)

    Under proposed Sec. 1271.180, each establishment would be required 
to establish and maintain procedures for all significant steps that it 
performs in the manufacture of human cellular and tissue-based 
products. The agency is proposing to define ``establish and maintain'' 
in Sec. 1271.3(ll) as ``define, document (in writing or 
electronically), and implement, then follow, review, and as needed, 
revise on an ongoing basis.'' FDA intends, by using the phrase 
``establish and maintain'' in these regulations, to indicate that, once 
established, procedures must be followed on an ongoing basis. Because 
established procedures would, by definition, be documented in writing 
or electronically, the agency is proposing to use the term 
``procedures'' as opposed to ``written procedures.''
    Procedures required under proposed Sec. 1271.180, and those 
specifically required elsewhere in subpart D of part 1271, would be 
required to be designed to prevent circumstances that increase the risk 
of the introduction, transmission, and spread of communicable diseases 
through the use of human cellular and tissue-based products by ensuring 
that: (1) The products do not contain relevant communicable disease 
agents; (2) the products do not become contaminated during 
manufacturing; and (3) the function and integrity of the products are 
not impaired through improper manufacturing. Procedures must be 
designed to ensure compliance with the requirements of part 1271.
    The recovery of cells or tissue is an example of an especially 
significant step in the manufacture of a human cellular or tissue-based 
product, for which procedures would have to be established. Under the 
terms of proposed Sec. 1271.180, such procedures would need to include 
the use of procurement techniques designed to prevent the transmission 
of communicable disease agents and diseases by the product. In 
addition, procedures for recovery would have to be designed to ensure 
that the function and integrity of the procured cells or tissue are 
maintained during and after procurement.
    All procedures shall be reviewed and approved by a responsible 
person prior to implementation. At least once in a 12-month period, all 
procedures would be required to be reviewed and, if necessary, revised; 
such review would need to be documented. Procedures must be readily 
available to personnel in the area where relevant operations are 
performed, unless this would be impractical. Any deviation from a 
procedure must be authorized by a responsible person, recorded, and 
justified.
    FDA is not prescribing the contents of particular procedures, but 
is allowing establishments to develop procedures that suit their 
particular operations. Alternatively, under proposed Sec. 1271.180, an 
establishment could adopt current standard procedures, e.g., those in a 
technical manual prepared by another organization, so long as the 
procedures are consistent with the requirements of part 1271, at least 
as stringent as those requirements, and appropriate for the 
establishment's operations.
    Any procedure that becomes obsolete would be required to be 
archived for at least 10 years. Since some tissues have long expiration 
dates, they can be transplanted many years after they were recovered or 
processed. Should an adverse reaction occur after transplantation, it 
would be important to know the procedures under which the tissue was 
recovered or processed, especially if those procedures differ from the 
ones currently in place.

F. Facilities, Environmental Control and Monitoring, Equipment, and 
Supplies and Reagents

1. Facilities (Proposed Sec. 1271.190)
    Under proposed Sec. 1271.190, any facility used in the manufacture 
of human cellular or tissue-based products must be of suitable size, 
construction, and location to facilitate cleaning, relevant 
maintenance, and proper operations. A facility that, for whatever 
reason, cannot be adequately cleaned is not appropriate for use in the 
manufacture of human cellular and tissue-based products, because of the 
potential risk of product contamination. ``Relevant maintenance'' 
refers to those actions that, if not taken, could lead to potentially 
adverse effects on product integrity or function, or to the accidental 
exposure of human cellular and tissue-based products to communicable 
disease agents, or to contamination or cross-contamination with such 
agents. Finally, any operation undertaken by a manufacturing 
establishment needs to be performed in a facility in which the 
operation can be performed correctly. For example, although not 
specifically required to do so by these regulations, an establishment 
may need to establish gowning procedures for its employees, in order 
that their functions be performed properly. Such an establishment would 
need to provide employees with a dressing room and gowning area.
    Proposed Sec. 1271.190 would also require that a facility be 
maintained in a good state of repair. Broken windows, peeling paint, 
uneven flooring, and improper electrical wiring are all examples of 
maintenance problems that could lead to product contamination or 
impairment of product function or integrity. In addition, adequate 
lighting, ventilation, plumbing, drainage, and washing and toilet 
facilities would all be required.
    Proposed Sec. 1271.190(b) sets out requirements for the location of 
operations within a facility used in the manufacture of human cellular 
or tissue-based products. Such a facility would need to be divided into 
separate or defined areas of adequate size for each operation that 
takes place in the facility. As an alternative, however, other control 
systems could be established and maintained to prevent improper 
labeling, mix-ups, contamination, cross-contamination,

[[Page 1515]]

and accidental exposure of human cellular and tissue-based products to 
communicable disease agents. Examples of different types of operations 
that an establishment might perform, and which would need to be 
conducted either in separate locations or subject to other controls, 
include: (1) Receipt, identification, and storage of containers, 
labels, supplies, and reagents; (2) processing, including laboratory 
functions; (3) storage of human cellular and tissue-based products, 
both before and after release from quarantine; (4) product labeling; 
(5) storage and disposal of biohazards and/or medical waste; (6) 
irradiation; and (7) sterilization and aseptic processing.
    Proposed Sec. 1271.190(c) contains basic requirements for facility 
cleaning and sanitation. Facilities must be maintained in a clean, 
sanitary, and orderly manner. Sewage, trash, and other refuse must be 
disposed of in a timely, safe, and sanitary manner. Procedures for 
facility cleaning and sanitation would be required to be established 
and maintained. These procedures would need to include an assignment of 
responsibility for sanitation, cleaning methods to be used, and a 
cleaning schedule. Finally, all significant cleaning and sanitation 
activities that are done to prevent contamination would need to be 
documented, and records maintained.
2. Environmental Control and Monitoring (Proposed Sec. 1271.195)
    Proposed Sec. 1271.195 would require monitoring and control over 
environmental conditions where such conditions (e.g., temperature, air 
quality) could reasonably be expected to have an adverse effect on the 
function or integrity of human cellular and tissue-based products, to 
cause contamination or cross-contamination of products or equipment, or 
to lead to accidental exposure of products to communicable disease 
agents. In these situations, an establishment would be required to 
establish and maintain procedures to adequately control and monitor 
environmental conditions and to provide proper conditions for 
operations.
    Depending on the particular environmental factors at a facility, 
and the type of operations that take place there, environmental 
controls and monitoring could include one or more of the following: 
Temperature and humidity controls; ventilation and air filtration; 
cleaning and disinfecting of rooms and equipment to ensure aseptic 
processing operations; maintenance of equipment used to control 
conditions necessary for aseptic processing operations; and 
environmental monitoring for organisms. Proposed Sec. 1271.195(a) would 
require these elements to be adopted, where appropriate. Thus, under 
proposed Sec. 1271.195, an establishment would be required first to 
identify any environmental conditions that require monitoring and 
control, and then to respond appropriately.
    Periodic inspections of environmental controls systems would be 
required. In addition, environmental controls and monitoring activities 
would have to be documented, and records maintained.
3. Equipment (Proposed Sec. 1271.200)
    CGTP requirements for equipment are set out in proposed 
Sec. 1271.200. For human cellular and tissue-based products to be 
manufactured properly, the equipment used in their manufacture must be 
appropriate. Thus, Sec. 1271.200(a) contains the general requirement 
that equipment used in the manufacture of human cellular and tissue-
based product be of appropriate design for its use. Equipment must be 
suitably located and installed to facilitate operations, including 
cleaning and maintenance. In addition, equipment must not have any 
adverse effect on the products being manufactured.
    Equipment used for inspection, measuring, and testing must be 
capable of producing valid results; such equipment could include 
automated, mechanical, electronic, computer, or other kinds of 
equipment. Section 1271.200(c) would require regularly scheduled 
calibration of equipment used for inspection, measuring, and testing. 
Thus, for example, a thermometer used in a storage area would be 
required to produce valid results and would also be subject to 
regularly scheduled calibration procedures. ``Equipment used for 
inspection'' would include any equipment used to inspect a human 
cellular or tissue-based product during its manufacture or prior to 
making it available for distribution.
    Under Sec. 1271.200(b), an establishment would be required to 
establish and maintain procedures for cleaning, sanitizing, and 
maintaining equipment. The purpose of these procedures is to prevent 
equipment malfunctions, contamination or cross-contamination, 
accidental exposure of human cellular and tissue-based products to 
communicable disease agents, and other events that could reasonably be 
expected to have an adverse effect on product function or integrity. 
Cleaning, sanitizing, and maintenance of equipment would be required to 
be performed according to established schedules.
    Section 1271.200(d) sets out a requirement for routine inspections 
of equipment for cleanliness, sanitation, and calibration, and to 
ensure compliance with maintenance schedules.
    Section 1271.200(e) contains specific requirements for records, to 
be maintained in accordance with the general records provisions in 
Sec. 1271.270. All maintenance, cleaning, sanitizing, calibration, and 
other activities performed in accordance with Sec. 1271.200 would be 
required to be documented. Records of recent maintenance, cleaning, 
sanitizing, calibration, and other activities must be available at each 
piece of equipment; this requirement promotes both accurate 
recordkeeping and ease of reference. In addition, the use of each piece 
of equipment must be documented, and this record of use must identify 
each human cellular or tissue-based product manufactured using the 
equipment. This requirement is necessary to ensure that those products 
manufactured with a particular piece of equipment may be traced for 
follow-up and appropriate corrective action, in the event that a 
problem (e.g., contamination or malfunction) is discovered after the 
equipment is used.
4. Supplies and Reagents (Proposed Sec. 1271.210)
    Use of a contaminated or otherwise defective supply or reagent in 
the manufacture of a human cellular or tissue-based product could 
adversely affect the product; e.g., by introducing a disease agent or 
by failing to properly preserve the product. For this reason, 
compliance with CGTP requires that care be taken in receiving supplies 
and reagents into an establishment, in determining their 
appropriateness for use, and in keeping track of the products in whose 
manufacture they are used. By ``supplies and reagents,'' the agency 
refers to all of the products that might be used during the 
manufacturing process but excludes any material that might be 
considered to become a component of a human cellular or tissue-based 
product. Supplies and reagents would include, but not be limited to, 
``processing material,'' which the agency is proposing to define at 
Sec. 1271.3(hh) as ``any material or substance that is used in, or to 
facilitate, processing, but which is not intended by the manufacturer 
to be included in the human cellular or tissue-based product when it is 
made available for distribution.''

[[Page 1516]]

    Proposed Sec. 1271.210 contains several requirements with respect 
to supplies and reagents used in the manufacture of human cellular and 
tissue-based products. An establishment would be required to establish 
and maintain procedures for receiving supplies and reagents. Before 
using a supply or reagent, the establishment must verify that the 
supply or reagent meets specifications that are designed to prevent 
circumstances that increase the risk of the introduction, transmission, 
and spread of communicable disease through product contamination or the 
impairment of product function or integrity. An establishment could 
verify on its own that the supplies and reagents that it uses meet 
specifications; e.g., by testing the product. Alternatively, 
verification could be accomplished by the vendor of the supply or 
reagent. ``Verification'' is defined in proposed Sec. 1271.3(ss) as 
``confirmation by examination and provision of objective evidence that 
specified requirements have been fulfilled.''
    Section 1271.210(b) would require that reagents used in processing 
and preservation of human cellular and tissue-based products be of 
appropriate grade for their intended use and, if appropriate, sterile. 
Some establishments may produce their own in-house reagents. These 
establishments would be required to validate and/or verify the 
procedures for producing such reagents.
    Section 1271.210(c) would require that specific records relating to 
the receipt, verification, and use of each supply and reagent be 
maintained.

G. Processing

    Three sections of the proposed CGTP regulations address the 
processing of human cellular and tissue-based products. Proposed 
Sec. 1271.220 would require controls to be established over processing. 
Requirements for making changes to processes are contained in proposed 
Sec. 1271.225. Proposed Sec. 1271.230 would require process validation 
in place of verification in some situations and sets out certain 
specific requirements related to process validation.
    ``Processing'' is defined in proposed Sec. 1271.3(mm) as ``any 
activity other than recovery, donor screening, donor testing, storage, 
labeling, packaging, or distribution performed on a human cellular or 
tissue-based product, including, but not limited to, preparation, 
sterilization, steps to inactivate and remove adventitious agents, 
preservation for storage, and removal from storage.''
    1. Process Controls (Proposed Sec. 1271.220)
    Under proposed Sec. 1271.220(a), any establishment engaged in the 
processing of human cellular and tissue-based products would be 
required to develop, conduct, control, and monitor its manufacturing 
processes to ensure that each product: (1) Conforms to its 
specifications, (2) is not contaminated, (3) maintains its function and 
integrity, and (4) is manufactured so as to prevent transmission of 
communicable disease by the product. By ``specifications,'' the agency 
refers to those criteria established by a manufacturer for a human 
cellular or tissue-based product that must be met at defined stages in 
the manufacturing process and before the product is made available for 
distribution.
    Sections 1271.220(b) governs the removal of processing materials. 
In accordance with the definition proposed in Sec. 1271.3(hh), 
processing materials would not be intended by the manufacturer to be 
included in a human cellular or tissue-based product when it is made 
available for distribution. Under Sec. 1271.220(b), where a processing 
material could reasonably be expected to have an adverse effect on a 
human cellular or tissue-based product's function or integrity, the 
establishment would be required to establish and maintain procedures 
for the use and removal of the processing material to ensure that it is 
removed or limited to an amount that does not adversely affect the 
product's function or integrity. Any such removal or reduction would be 
required to be documented.
    Section 1271.220(c) would prohibit the pooling of human cells or 
tissue from two or more donors during manufacturing. Pooling refers to 
placing products in physical contact with each other or mixing them in 
a single receptacle. Such commingling of cells or tissues from a single 
infected donor with cells or tissues from other donors can contaminate 
the entire pooled quantity, greatly increasing the risk to recipients 
of the pooled materials of exposure to infectious agents. The proposed 
regulation is consistent with recommendations made by FDA's 
Transmissible Spongiform Encephalopathy Advisory Committee, at their 
meeting on October 6, 1997, with respect to the pooling of dura mater.
    Section 1271.220(d) would require procedures to be established for 
in-process monitoring, or monitoring of the product during processing, 
for compliance with specified requirements. This requirement is 
modified by the phrase ``where appropriate.'' In other words, as 
discussed in section II.A.4. of this document, in-process monitoring 
would be required unless the establishment can justify, and document, 
that it would be unnecessary under the terms of Sec. 1271.150(d). The 
in-process product would have to be controlled until the completion of 
any required inspection, tests, or other verification activities, or 
until any necessary approvals are received and documented. Any sampling 
taken of the in-process product for the purpose of testing or 
inspection would be required to be representative of the material being 
evaluated.
2. Process Changes (Proposed Sec. 1271.225)
    Proposed Sec. 1271.225 would require an establishment to establish 
procedures for making changes to a process. Any such change would have 
to be verified or validated, to ensure that the change does not create 
an adverse impact elsewhere in the operation. Any change would also 
have to be approved by a responsible person with appropriate knowledge 
and background before being implemented. Proposed Sec. 1271.225(b) 
would require that records be kept of all such changes, and sets out 
the required elements of such records (e.g., the rationale for the 
change).
3. Process Validation (Proposed Sec. 1271.230)
    Proposed Sec. 1271.230 contains requirements related to the 
validation of processes. Process validation, under proposed 
Sec. 1271.3(rr), means ``establishing by objective evidence that a 
process consistently produces a result or product meeting its 
predetermined specifications.''
    Proposed Sec. 1271.230(a) would require establishments to validate 
their processes where verification is not feasible; e.g., where 
verification cannot be performed on each and every finished product. 
Thus, Sec. 1271.230(a) states that, where the results of a process 
cannot be fully verified by subsequent inspection and tests, the 
process must be validated and approved according to established 
procedures, and the validation activities must be documented.
    Under Sec. 1271.230(b), any claim made in labeling or promotional 
materials that is related to the process used to manufacture a human 
cellular or tissue-based product must be based on a process that has 
been validated. Validation must be documented, and evidence of the 
validation must be maintained at the establishment and made available 
for review on inspection. Examples of such process-related claims

[[Page 1517]]

include the claim that a product is sterile or that it has undergone 
viral inactivation.
    The agency is proposing in Sec. 1271.230(c) a requirement that 
would apply specifically to establishments that process dura mater. 
Donor screening and testing requirements for donors of dura mater have 
been proposed in the donor-suitability proposed rule, but additional 
processing safeguards are necessary to prevent the transmission of 
Creutzfeldt-Jakob disease (CJD) (64 FR 52696 at 52706). Proposed 
Sec. 1271.230(c) would require that dura mater be processed using a 
validated procedure to reduce CJD infectivity, while preserving the 
clinical utility of the product. Currently, an example of such a 
procedure would be a sodium hydroxide (NaOH) protocol that has been 
validated to reduce CJD infectivity (in an animal model) while 
preserving the tissue's clinical utility. In the future, other methods 
that more effectively reduce CJD infectivity may be developed.
    If processes are validated, in place of verification, then 
procedures must be established and maintained to ensure that the 
specified requirements continue to be met; this requirement appears in 
proposed Sec. 1271.230(d). Under Sec. 1271.230(e), any change or 
deviation from a validated process would require a review and 
evaluation of the process and, where appropriate, revalidation.

H. Labeling Controls (Proposed Sec. 1271.250)

    Under proposed Sec. 1271.250, an establishment would be required to 
establish and maintain procedures to control the labeling of human 
cellular and tissue-based products. These control procedures would be 
designed to ensure that products are identified properly and to prevent 
mix-ups. The agency is not specifying how such controls should be 
designed, but notes that they would likely need to include such 
elements as proper storage methods to prevent deterioration of 
adhesives, among other problems. In addition, Sec. 1271.250 would 
require procedures to include verification of label accuracy, 
legibility, and integrity. Thus, for example, a labeled product would 
be checked under such verification procedures to ensure that its label 
was affixed securely to the container, could be read with ease, and 
accurately identified the product by identifier and product type.
    Proposed Sec. 1271.250 would also require that procedures be 
established and maintained to ensure that products are labeled in 
accordance with all applicable labeling requirements. ``Applicable 
labeling requirements'' for human cellular and tissue-based products 
regulated as biological drugs include the labeling regulations in parts 
201 and 610 (21 CFR parts 201 and 610); for products regulated as 
devices, they include those in part 801 (21 CFR part 801). Other 
labeling requirements appear in several sections of proposed part 1271, 
and these are listed in proposed Sec. 1271.250. For example, 
Sec. 1271.90 is cross-referenced in Sec. 1271.250; it would require 
that banked cells and tissues for autologous use be labeled ``FOR 
AUTOLOGOUS USE ONLY'' (donor-suitability proposed rule (64 FR 52723)). 
Procedures established in compliance with proposed Sec. 1271.250 would 
need to ensure that banked cells and tissues for autologous use were 
labeled with this statement.

I. Storage (Proposed Sec. 1271.260)

    Proposed Sec. 1271.260 sets out storage requirements. The proposed 
regulation addresses three general areas of concern: Control of storage 
areas; storage temperature; and expiration date.
    Under proposed Sec. 1271.260, each establishment would be required 
to establish and maintain procedures for the control of storage areas 
and stock rooms in order to prevent mix-ups, commingling, 
deterioration, contamination, and cross-contamination of human cellular 
and tissue-based products and supplies, as well as any other condition 
that might adversely affect product function or integrity. In addition, 
controls would be required to prevent improper release for 
distribution.
    Storage at a proper temperature, in order to preserve a product's 
function and integrity and prevent deterioration, is an important 
aspect of CGTP. FDA recognizes that appropriate temperatures may differ 
for various types of products. Thus, Sec. 1271.260(b) would require an 
establishment to establish acceptable temperature limits for the 
storage of human cellular and tissue-based products at each step of the 
manufacturing process. Monitoring of storage temperatures would be 
required. Temperatures would have to be documented, and recorded 
temperatures reviewed periodically to assure that temperatures remained 
in the permissible range.
    Different products may be stored for differing lengths of time 
before use. The maximum storage period depends on such factors as 
product type, processing procedures and method of preservation, storage 
conditions, and type of packaging. Section 1271.260(c) would require, 
where appropriate, that an expiration date be assigned for each human 
cellular or tissue-based product.
    Under Sec. 1271.260(d), corrective action must be taken and 
documented whenever proper storage conditions are not met.

J. Receipt and Distribution (Proposed Sec. 1271.265)

    Proposed Sec. 1271.265 covers the receipt and distribution of human 
cellular and tissue-based products. Section 1271.265(a) contains 
general requirements for procedures and recordkeeping. Section 
1271.265(b) governs receiving activities. Requirements that must be met 
prior to making a product available for distribution are contained in 
Sec. 1271.265(c). The remaining paragraphs deal with packaging, 
shipping conditions, and the return of products to inventory.
    Under Sec. 1271.265(a), procedures would be required for receiving, 
accepting or rejecting, and distributing human cellular and tissue-
based products, as well as for the destruction or other disposition of 
such products. Each of these activities, when performed, must be 
documented. Required documentation would include the identification of 
the human cellular or tissue-based product, the activities performed 
and the results of such activities, the date or dates of the activity, 
the quantity of product subject to the activity, and the disposition of 
the product. The disposition of the product would include, for example, 
the identity of the consignee. Complete and accurate identification of 
a consignee would include not only the consignee's name, but its 
address and telephone number.
    Section 1271.265(b) contains specific requirements with respect to 
the receipt of human cellular and tissue-based products for processing, 
distribution, or any other step in the manufacturing process. As part 
of its receiving activities, an establishment would be required to 
inspect incoming human cellular and tissue-based products, according to 
established procedures, for damage, contamination, deterioration, or 
any other indication that the integrity of the product had been 
impaired. The establishment would then determine whether to accept or 
reject the product. Acceptance or rejection of the incoming product 
would need to be documented.
    An establishment receiving a human cellular or tissue-based product 
would also be required to ascertain its status and handle the product 
appropriately. For example, a product that is shipped under quarantine, 
pending completion of the donor-suitability determination required 
under subpart C of part 1271,

[[Page 1518]]

would be required to be maintained in quarantine after its receipt 
until the determination was complete. Other issues of product status 
(e.g., stage in processing, results of donor screening and testing) 
would dictate other appropriate action with respect to the product.
    Proposed Sec. 1271.265(c) deals with an establishment's 
determination that a product is ``available for distribution,'' a term 
that the agency is proposing to define in proposed Sec. 1271.3(ff). 
Under that definition, a human cellular or tissue-based product is 
``available for distribution'' if it has been determined to meet all 
release specifications and to be suitable for distribution. Under 
Sec. 1271.265(c), an establishment would be required to establish and 
maintain procedures for making products available for distribution, 
including developing release criteria. These procedures would be 
designed to prevent the release of products that are in quarantine, 
have deteriorated, or otherwise have been manufactured in violation of 
CGTP. They must also prevent the release of products from donors who 
have not been determined to be suitable, except as provided under 
proposed Secs. 1271.65 and 1271.90.
    Prior to making a human cellular or tissue-based product available 
for distribution, an establishment would be required to review all 
records pertaining to the product and to verify and document that 
release criteria have been met. The determination that a product is 
available for distribution must be documented and dated by a 
responsible person.
    Under Sec. 1271.265(d), all packaging and shipping containers would 
be required to be designed, validated, and constructed so as to ensure 
product function and integrity and to protect the product from damage, 
deterioration, contamination, or other adverse effects during customary 
conditions of processing, storage, handling, and distribution. Section 
1271.265(e) would require that appropriate shipping conditions, to be 
maintained during transit, be defined for each type of product. And 
Sec. 1271.265(f) would require that an establishment develop procedures 
for determining whether a product that is returned to the establishment 
may be returned to inventory.

K. Records (Proposed Sec. 1271.270)

    Proposed Sec. 1271.270 contains general requirements for 
recordkeeping under part 1271. Section 1271.270(a) would require 
establishments to maintain records concurrently with the performance of 
each significant step required in subparts C and D of part 1271. Many, 
but not necessarily all, of the requirements for documenting a 
manufacturing activity are specifically noted elsewhere in the 
regulations. For example, an establishment's receipt of tissue for 
processing would be a significant step that needs to be documented; 
proposed Sec. 1271.265(a) lists the specific documentation that would 
be required. As noted in proposed Sec. 1271.270(a), any requirement in 
part 1271 that an activity be documented involves the creation of a 
record, and that record would be subject to the requirements of 
Sec. 1271.270.
    Section 1271.270(a) would require records to be accurate, 
indelible, and legible. Entries must be dated and the person performing 
the work in question must be identified. Records would have to be 
sufficiently detailed to provide a complete history of the work 
performed and to relate the records to the particular human cellular or 
tissue-based product involved. In order to protect the privacy of both 
donors and recipients, adequate record security systems would be 
required.
    Under Sec. 1271.270(b), establishments would have the flexibility 
to develop individualized systems of maintaining and organizing their 
records, so long as certain objectives were achieved. Records could be 
maintained in more than one location, provided that the records 
management system was designed to ensure prompt identification, 
location, and retrieval of all records. Further, the records management 
system would need to facilitate the review of a particular human 
cellular or tissue-based product's history both prior to its release 
for distribution and, if necessary, at a later date as part of a 
follow-up evaluation or investigation. In addition to records 
pertaining to individual products, records for product types would be 
required to be maintained and organized. Thus, for example, a 
manufacturer of several different types of human cellular and tissue-
based products would be required to maintain, for each product type, 
records of pertinent procedures, product specifications, labeling and 
packaging procedures, and equipment logs. A records management system 
could be as simple as keeping all information pertaining to the 
manufacture of one product in one file folder, and keeping all file 
folders for one product type, e.g., tendons, in one drawer of the file 
cabinet. This drawer, labeled ``Tendons'', would also contain a folder 
for ``generic'' procedures common to all tendons. A more elaborate 
records management system could utilize a computer to generate files 
and subfiles.
    Section 1271.270(d) and (e) deal with methods and time frames for 
retaining records. Under Sec. 1271.270(d), records could be maintained 
electronically, as original paper records, or as true copies. Examples 
of true copies include photocopies, microfiche, and microfilm. Suitable 
equipment would be required to be available for reading and 
photocopying any records maintained on microfiche or microfilm. Records 
stored in automated data processing systems must be backed up to 
prevent their loss. Any electronic record or electronic signature would 
be subject to the requirements in 21 CFR part 11.
    Under Sec. 1271.270(e), all records would be required to be kept 
for 10 years after their creation. However, consistent with proposed 
Sec. 1271.55(b) on records of donor-suitability determinations, records 
pertaining to a particular human cellular or tissue-based product must 
be retained at least 10 years after the date of implantation, 
transplantation, infusion, or transfer of the product. See donor-
suitability proposed rule (64 FR 52721). If the date of implantation, 
transplantation, infusion, or transfer is not known, then the records 
must be retained at least 10 years after the date of the product's 
distribution, disposition, or expiration, whichever is latest. The 
establishment must make provisions for all records to be maintained for 
the required period in the event that the establishment ceases 
operation. FDA requests comment on whether there are specific types of 
records for which a retention period shorter than 10 years would be 
appropriate and would not compromise the agency's ability to prevent 
the introduction, transmission and spread of communicable disease.
    Section 1271.270(c) cross-references records requirements proposed 
in subpart C of part 1271 that relate to donor testing and screening, 
in order to make clear that records required under subpart C of part 
1271 are subject to the recordkeeping requirements in Sec. 1271.270. 
Section 1271.270(f) would require an establishment to maintain records 
of contracts, agreements, and other arrangements with other 
establishments under which any step in the manufacturing process is 
performed by the other establishment. These records would need to 
contain not only the name and address of the other establishment, but 
also a description of each party's responsibilities.

L. Tracking (Proposed Sec. 1271.290)

    FDA considers product tracking to be an essential component of its 
proposed

[[Page 1519]]

regulatory system for human cellular and tissue-based products. Should 
the recipient of such a product contract a communicable disease, 
tracking would permit appropriate follow-up, such as an investigation 
to determine whether the human cellular or tissue-based product 
transmitted the disease agent and, if so, would permit steps to be 
taken to prevent the distribution of other similarly infected products. 
Similarly, if a donor is discovered, post-donation, to have had a 
communicable disease, tracking would permit an establishment to locate 
products from that donor. Thus, a tracking system is closely linked to 
the agency's regulatory objective of preventing the spread of 
communicable disease.
    As with other components of these CGTP regulations, FDA is 
proposing certain basic requirements, but is allowing establishments 
flexibility in designing tracking programs that suit their particular 
activities. Auditing of an establishment's tracking method to ensure 
its effectiveness would be required under the quality program (proposed 
Sec. 1271.160(b)(8) and (d)). FDA recognizes that some establishments 
have already developed and implemented tracking systems and requests 
comments from those establishments on the success or failure of 
particular tracking methods.
    Part 821 (21 CFR part 821) of FDA's regulations contains the 
medical device tracking requirements. Except for dura mater, human 
cellular and tissue-based products regulated as devices generally have 
not been subject to tracking under part 821; thus, there will be little 
or no duplication of tracking requirements. When a human cellular or 
tissue-based product is designated as a ``tracked device,'' and subject 
to the device tracking regulations, the manufacturer would be required 
to satisfy both sets of tracking requirements. However, given the 
variety of methods that could be devised to satisfy the tracking 
requirements proposed in Sec. 1271.290, it is foreseeable that a single 
tracking method could be adopted that conforms with the requirements of 
both Sec. 1271.290 and part 821.
    Proposed Sec. 1271.290 would require each human cellular or tissue-
based product to be tracked. Section 1271.290(a) would place the 
tracking obligation on each establishment that performs any step in the 
manufacture of a human cellular or tissue-based product.
    Proposed Sec. 1271.290(b) would require the establishment to 
establish and maintain a method of product tracking that enables the 
tracking of all human cellular and tissue-based products from the donor 
to the recipient or final disposition and conversely from the recipient 
or final disposition to the donor. FDA recognizes, however, that some 
establishments may be better equipped than others to establish an 
effective tracking system. For this reason, the agency proposes to 
permit an establishment that performs some, but not all, of the steps 
in the manufacturing process to participate in a method of product 
tracking that has been established by another establishment responsible 
for other steps in the manufacturing process, provided that the 
tracking method meets all the requirements of Sec. 1271.290. One 
possible method of tracking would be to collect information about 
recipients on cards that are returned to the tracking establishment.
    Section 1271.290(c) would require that each human cellular or 
tissue-based product be assigned and labeled with a distinct 
identification code (e.g., alphanumeric) that relates the product to 
the donor and to all records pertaining to the product. Except in the 
case of autologous or directed donations, such a code must be created 
specifically for tracking and may not include an individual's name, 
social security or medical record number. An establishment that 
receives a human cellular or tissue-based product for further 
manufacturing might use the code already assigned or might assign a new 
identifier to the product. The regulation specifies, however, that an 
establishment that assigns a new identifier to a product shall 
establish and maintain procedures for relating the new identifier to 
the old identifier.
    Section 1271.290(d) would require establishments to ensure, through 
agreements with consignees or through other measures, that the code and 
type of each human cellular or tissue-base product that is implanted, 
transplanted, infused, or transferred into a recipient be recorded in 
the recipient's medical records, or in other pertinent records, to 
enable tracking from the recipient to the donor. Section 1271.290(e) 
would require an establishment to document and maintain records of the 
disposition of each of its human cellular or tissue-based products to 
enable tracking from the donor to the recipient or final disposition. 
The information to be maintained must permit the prompt identification 
of the recipient of the product.
    Under Sec. 1271.290(f), an establishment would be required to 
inform its consignees in writing of the requirements in Sec. 1271.290 
and of the tracking method that the establishment is using to comply 
with those requirements. For example, a statement might be included in 
the materials accompanying the consigned human cellular or tissue-based 
product that would describe applicable regulations and the 
establishment's tracking method. The establishment would be required to 
document that the consignee agreed to participate in its tracking 
method and to take all necessary steps to ensure compliance with the 
requirements of Sec. 1271.290; this agreement would need to be obtained 
and documented upon initial distribution of human cellular or tissue-
based products to a consignee and would not need to be obtained for 
each subsequent consignment.
    Proposed Sec. 1271.290(g) contains a requirement specific to donors 
of dura mater, intended to address the particular communicable-disease 
concerns associated with that type of product. Appropriate specimens 
from the dura mater donor would be required to be archived, under 
appropriate storage conditions, and for the appropriate duration, to 
enable future testing of the archived material for evidence of 
transmissible spongiform encephalopathy (TSE) and appropriate 
disposition of any affected dura mater tissue, if necessary. Although 
archiving samples may not immediately increase the assurance of safety 
for a dura mater graft, it would permit later testing for TSE-induced 
changes using improved or new methods as they become available. In the 
event that a dura graft recipient became ill with CJD, such testing of 
archival donor material would be needed to confirm whether the dura 
graft was the source of infection, so that no additional grafts from 
the affected lot would be distributed. At this time, based on currently 
available information, FDA recommends that samples of donor brain and 
dura mater tissues be archived at a temperature equal to or less than 
minus 70 \1/2\C for 16 years beyond the product's expiration date.
    Ideally, archived samples should be retained for the lifetime of 
the graft recipient, because the maximum incubation period is not 
certain. To date, the longest known incubation period is 16 years (Ref. 
1). FDA believes that it may be unrealistic to expect a manufacturer to 
maintain an archive for such a long time. FDA suggests that 
establishment of a nationally supported archive be considered for 
prolonged storage of these materials, in order to further the study of 
iatrogenic transmission of spongiform encephalopathies.

[[Page 1520]]

M. Complaint Files (Proposed Sec. 1271.320)

    Proposed Sec. 1271.320 would require establishments to maintain 
records of, and review, all complaints. ``Complaint'' is defined in 
proposed Sec. 1271.3(ii) as:

    any written, oral, or electronic communication that alleges: (1) 
that a human cellular or tissue-based product has transmitted or may 
have transmitted a communicable disease to the recipient of the 
product; (2) that the function or integrity of a human cellular or 
tissue-based product may have been impaired; or (3) any other problem 
with a human cellular or tissue-based product that could result from 
the failure to comply with current good tissue practice.

A communication from a physician expressing concern about possible 
product contamination would be a ``complaint.''
    The proposed regulation would require establishments to establish 
and maintain procedures for the prompt review, evaluation, and 
documentation of all complaints. Records of each complaint that the 
establishment receives would be required to be maintained in a file 
designated for complaints. The complaint file would be required to 
contain sufficient information about each complaint for proper review 
and evaluation of the complaint, including the identifier of the human 
cellular or tissue-based product that is the subject of the complaint. 
For example, the complaint file should include the date of each report, 
the unique product identifier, and the name of the person or 
establishment that submitted the complaint. Proposed Sec. 1271.320 
would require that the complaint file be made available for review and 
copying upon request from an authorized employee of FDA. Section 
1271.320(c) sets out requirements for the review and evaluation of 
complaints.

III. Additional Requirements With Respect to 361 Products

    Proposed subpart E of part 1271 contains reporting and labeling 
requirements that would apply only to those establishments that 
manufacture human cellular and tissue-based products as described in 
proposed Sec. 1271.10 (registration proposed rule (63 FR 26754)). Such 
products would be products that: (1) Are minimally manipulated, (2) are 
not promoted or labeled for any use other than a homologous use, (3) 
are not combined with or modified by the addition of any nontissue or 
noncellular component that is a drug or a device, and (4) do not have a 
systemic effect. The agency proposes to regulate such products solely 
under the authority of section 361 of the PHS Act and not as biological 
drugs or devices. Thus the heading of subpart E of part 1271 is 
``Additional Requirements for Establishments Described in 
Sec. 1271.10.'' Human cellular and tissue-based products regulated as 
biological drugs or as medical devices will continue to be subject to 
reporting and labeling requirements that are currently in place.
    Although the title of proposed subpart E of part 1271 refers to 
``additional'' requirements for establishments described in 
Sec. 1271.10, the proposed reporting and labeling requirements are 
designed to be less extensive and burdensome than the current 
requirements applicable to products regulated as biological drugs or as 
devices. This approach is in keeping with the agency's expressed plans 
to put in place a tiered regulatory scheme, under which human cellular 
and tissue-based products would be subject to an appropriate level of 
regulation based on the degree of risk. At the same time, the proposed 
reporting and labeling requirements for 361 products have been drafted 
to be generally consistent with existing biological drug and device 
regulations.

A. Reporting Requirements (Proposed Sec. 1271.350)

    In order to stay informed of potential problems with human cellular 
and tissue-based products related to communicable-disease transmission, 
and to be able to take appropriate steps in response, FDA needs to 
receive information from establishments on adverse reactions and 
certain product deviations that could result in adverse reactions. For 
this reason, FDA is proposing to require two different kinds of reports 
from establishments that manufacture human cellular and tissue-based 
products regulated solely under section 361 of the PHS Act: the 
reporting of adverse reactions, and the reporting of product 
deviations.
1. Adverse Reactions
    Under proposed Sec. 1271.350(a), establishments would be required 
to report adverse reactions to CBER. The agency is engaged in an 
ongoing effort to enhance agency-wide consistency in the collection of 
safety data and, where possible, consistency with the definitions, 
reporting periods, formats, and standards recommended by the 
International Conference on Harmonisation of Technical Requirements of 
Registration of Pharmaceuticals for Human Use (ICH). See ``Expedited 
Safety Reporting Requirements for Human Drug and Biological Products,'' 
final rule (62 FR 52237, October 7, 1997). In order to achieve a degree 
of uniformity throughout the agency and to simplify reporting 
requirements for firms, FDA has modeled the procedures in 
Sec. 1271.350(a) on the reporting requirements for other regulated 
products (i.e., drugs, devices, and biological products) and is 
proposing to require use of the same standard reporting form that is 
already in use (FDA Form-3500A).
    Proposed Sec. 1271.3(gg) would define an adverse reaction as ``a 
noxious and unintended response to any human cellular or tissue-based 
product for which there is a reasonable possibility that the response 
may have been caused by the product (i.e., the relationship cannot be 
ruled out).'' This definition reflects the agency's intention to shift 
from adverse experience reporting to adverse reaction reporting, 
consistent with ICH guidelines (62 FR 52237 at 52238), and is 
consistent with the ICH E2A guideline's definitions of ``adverse drug 
reaction,'' International Conference on Harmonisation; Guideline on 
Clinical Safety Data Management; Definitions and Standards for 
Expedited Reporting, availability (60 FR 11284 at 11285, March 1, 
1995). Under the proposed definition, not all unsuccessful outcomes 
would be considered ``adverse reactions.'' For example, the agency 
recognizes that a recipient may reject a human cellular or tissue-based 
product, or that there may be a failure to engraft (e.g., of 
hematopoietic stem cells), for reasons that are unrelated to the 
product itself. Or a procedure may fail for reasons that, whether or 
not specifically identified, are known not to be product-related. On 
the other hand, if the relationship between the product and the noxious 
and unintended response cannot be ruled out, the response would be 
considered an adverse reaction under the proposed definition.
    The phrase ``the relationship cannot be ruled out'' is included in 
the proposed definition to clarify which individual cases should be 
reported to FDA. Instances of probable, possible, remote, or unlikely 
relationships would all be considered adverse reactions, because there 
would be at least a reasonable possibility that the noxious and 
unintended response may have been caused by the human cellular or 
tissue-based product, even though causality has not been established.
    Under proposed Sec. 1271.350(a), only those adverse reactions that 
involved the transmission of a communicable

[[Page 1521]]

disease, product contamination, or the failure of a human cellular or 
tissue-based product's function or integrity would be required to be 
reported. Moreover, reporting would be limited to those adverse 
reactions that are fatal or life-threatening, that result in permanent 
impairment of a body function or permanent damage to body structure, or 
that necessitate medical or surgical intervention.
    In order to determine which adverse reactions are required to be 
reported, each establishment would be required to review all adverse 
reaction reports. The source of the information is not relevant; all 
reports, regardless of source, would have to be considered.
    The procedures proposed for reporting adverse reactions are modeled 
on those used for other products regulated by the agency. Reports to 
the agency would be required within 15 calendar days of initial receipt 
of the information, with a possible follow-up report. Reports would be 
submitted to CBER. The proposed regulation provides addresses and 
information on obtaining forms.
    With respect to human cellular and tissue-based products regulated 
as biological drugs, the reporting requirements in 21 CFR 600.80 
continue to apply. For those products regulated as devices, the medical 
device reporting requirements in 21 CFR part 803 apply. The agency 
notes that the transmission of a serious communicable disease would 
constitute an event that is required to be reported under current 
regulations.
2. Product Deviations
    FDA is proposing to require, in Sec. 1271.350(b), that those 
product deviations that could reasonably be expected to lead to a 
reportable adverse reaction be reported to CBER, along with information 
on corrective actions. A definition of the term ``product deviation'' 
is proposed in Sec. 1271.3(kk) and has been discussed at section II.C 
of this document.
    In the proposed approach document, FDA indicated that 
establishments would be required to maintain records of errors and 
accidents, a term that is incorporated in this proposal within the 
meaning of ``product deviation'' (see proposed Sec. 1271.3(kk)), and to 
make them available for inspection, but that no reports to the agency 
would be required. The General Accounting Office, in its report on 
human tissue banks, criticized the agency for not requiring that such 
records be reported (Ref. 2).
    The agency is now proposing to require the reporting of certain 
product deviations: those that are of the type that could reasonably be 
expected to lead to a reportable adverse reaction. In addition, 
required reporting would be limited to product deviations involving 
human cellular or tissue-based products that have been distributed. The 
agency considers that these limitations on the reporting obligation 
will lessen the burden on establishments and on the agency, making it 
possible for the agency to receive meaningful information and respond 
appropriately (e.g., by monitoring recalls and assisting in their 
implementation as necessary and appropriate).
    Proposed Sec. 1271.350(b) sets out the requirements for reporting 
product deviations that could give rise to an adverse reaction and 
provides the address to be used. Reports of such product deviations 
would be expected as soon as possible. Although no particular reporting 
form would be required, Sec. 1271.350(b)(2) states that each report 
shall contain a description of the product deviation and information on 
all corrective actions that have been or will be taken in response to 
the product deviation, such as recalls.

B. Labeling and Claims

    Proposed Sec. 1271.370 contains requirements for product labeling 
and would govern promotional claims made for human cellular and tissue-
based products regulated solely under the authority of section 361 of 
the PHS Act. Section 1271.370(a) describes the required contents of 
product labels and accompanying materials. The types of claims that may 
be made for human cellular and tissue-based products are addressed in 
Sec. 1271.370(b).
    The agency considers regulation of labeling and promotion to be an 
essential part of its proposed tiered, risk-based regulatory system for 
human cellular and tissue-based products.
    Labeling and promotional materials which contain incomplete, 
unclear, inaccurate, unbalanced, or misleading information can increase 
the risk of the introduction, transmission, or spread of communicable 
disease by misleading the public into inappropriate or unsafe practices 
regarding these products (e.g., storing a product at an incorrect 
temperature) or by hindering corrective action which might become 
necessary (e.g., by delaying identification of the establishment 
distributing an unsafe product).
    For these reasons, the agency considers that section 361 of the PHS 
Act provides the agency with sufficient authority to issue these 
requirements.
1. Labeling Information
    Proposed Sec. 1271.370(a) would require each human cellular or 
tissue-based product made available for distribution to be labeled 
clearly and accurately. In addition, certain basic information would be 
required to appear on the product label: (1) The name and address of 
the establishment that determined that the product met release criteria 
and made the product available for distribution, (2) a description of 
the type of product, and (3) the product's expiration date, if any. The 
agency considers each of these items to be of sufficient importance 
that they warrant placement on the product label itself instead of in 
materials that accompany the product. The first two items are crucial 
for accurately identifying the product and responsible establishment in 
the event of any necessary follow-up action (e.g., adverse reaction 
reports). Requiring products to be labeled with their expiration dates 
helps to ensure that they maintain their function and integrity at the 
time of use.
    Recognizing that space on the product label may be limited, the 
agency proposes to require that the following information appear either 
on the product label or in a package insert: (1) Storage temperature, 
(2) warnings, where appropriate, and (3) instructions for use. 
Information on storage temperature will help prevent errors in handling 
and help ensure that the product maintains its integrity and functions 
properly in the recipient. Warnings and instructions for use will 
inform the physician of the proper use of the product and would 
increase the probability of a successful procedure.
2. Claims
    Section 1271.370(b) deals with claims for human cellular and 
tissue-based products in labeling, advertising, and promotional 
materials. Consistent with the agency's plans outlined in the proposed 
approach document, this provision would require that any such claim be 
clear, truthful, balanced, and not misleading. A ``balanced'' claim for 
a product would, for example, reflect an objective, unbiased view of 
the product, including not only claims for the product's benefits but 
also explanations of any hazards. A claim may be considered to be 
misleading if it omits important information.
    Proposed Sec. 1271.370(b)(2) is intended to clarify one of the four 
criteria that must be met for a human cellular or tissue-based product 
to be regulated solely under the authority of section 361 of the PHS 
Act. Under proposed Sec. 1271.10, a 361 product is one that, in

[[Page 1522]]

addition to meeting other criteria, is not promoted or labeled for any 
use other than a homologous use (registration proposed rule (63 FR 
26744 at 26754)). Section 1271.370(b)(2) explains that a labeling claim 
or promotional materials regarding the therapeutic or clinical outcome 
of a human cellular or tissue-based product (other than for 
reconstruction, replacement, repair, or supplementation of cells or 
tissue) would be considered a claim for a use other than a homologous 
use. A product for which such a claim was made would be subject, along 
with its labeling, to regulation under the act and/or section 351 of 
the PHS Act.
3. Labeling of Biological Drugs and Devices
    Proposed Sec. 1271.370 applies only to 361 products; human cellular 
and tissue-based products regulated as biological drugs or as devices 
will continue to be subject to labeling requirements currently in 
place. Parts 201 and 610 (21 CFR parts 201 and 610) will apply to human 
cellular or tissue-based products regulated as biological drugs, as 
will relevant statutory provisions and any conditions of product 
licensure. Human cellular and tissue-based products regulated as 
devices will be subject to the labeling requirements in part 801, in 
addition to the provisions of the act and any applicable conditions of 
approval or clearance.
    In order to ensure that all human cellular and tissue-based 
products, regardless of regulatory category, bear certain basic 
relevant information, FDA proposes to interpret several current 
regulations as encompassing the information set out in proposed 
Sec. 1271.370(a). The agency would expect the information listed in 
proposed Sec. 1271.370(a) to appear on the label or package insert of 
those products regulated as biological drugs or devices.
    The paragraphs below set out each item listed in proposed 
Sec. 1271.370(a), along with the parallel regulation applicable to 
biological drugs or devices. The agency expects that few if any changes 
will need to be made to current labeling to ensure that the information 
listed in proposed Sec. 1271.370(a) is provided. Where there is a 
difference in required placement of the information (e.g., on the label 
or in a package insert), the placement required in the biological drug 
or device regulation will apply.
    a. Name and address of the establishment that determines that the 
product meets release criteria and makes the product available for 
distribution. For biological drugs, Secs. 610.60(a)(2), 610.61(b), and 
610.63 require the name, address, and license number of the 
manufacturer or, in the case of divided manufacturing responsibilities, 
all manufacturers. Section 610.64 permits the name of the distributor 
to appear. For human cellular and tissue-based products, FDA considers 
the establishment that determines that the product meets release 
criteria and makes the product available for distribution to be a 
manufacturer and will expect that manufacturer's name and address to 
appear on the product label.
    Section 801.1(a) requires the label of a device to specify the name 
and place of business of the manufacturer, packer, or distributor. FDA 
proposes to interpret this requirement, with respect to human cellular 
and tissue-based products regulated as devices, as requiring the name 
of the establishment that determines that the product meets release 
criteria and makes the product available for distribution.
    b. Description of the type of product. For biological drugs, 
Secs. 610.60(a)(1) and 610.61(a) require the proper name of the product 
to appear on the container and package label. The product's proper name 
will serve as an adequate description of the type of product. For 
devices, section 502(e)(2) and (e)(4) of the act (21 U.S.C. 352(e)(2) 
and (e)(4)) requires products to be labeled with their established 
name, or if there is no established name, then with the common or usual 
name of the device; either will suffice, so long as it adequately 
describes the type of product.
    c. Expiration date. For biological drugs, Secs. 610.60(a)(4) and 
610.61(d) require products to be labeled with their expiration dates. 
For devices, Sec. 801.109(c) requires products to be labeled with 
information on ``any relevant * * * precautions''; FDA proposes to 
interpret this provision as requiring a product's expiration date, if 
the product has one, because the expiration date is effectively a 
precaution against use of an out-of-date product.
    d. Storage temperature. For biological drugs, Sec. 610.61(h) 
requires the recommended storage temperature to appear on the package 
label. For devices, FDA proposes to interpret Sec. 801.109(c), which 
requires information for use, including precautions, to include the 
proper storage temperature.
    e. Warnings, where appropriate. For biological drugs, 
Sec. 210.57(e) requires warnings. For devices, Sec. 801.109(c) requires 
information on hazards, contraindications, side effects, and 
precautions, which FDA proposes to interpret as including any 
appropriate warnings.
    f. Instructions for use. For biological drugs, Sec. 610.61(i), (j), 
and (k), as well as Sec. 201.57(c), requires instructions for use. For 
devices, instructions for use are required in Sec. 801.109(b)(2) and 
(c).

IV. Inspection and Enforcement Provisions

    Proposed subpart F of part 1271 contains provisions on inspections; 
human cellular and tissue-based products offered for import; and orders 
of retention, recall, destruction, and cessation of manufacturing. 
Subpart F of part 1271 would apply only to those establishments 
described in proposed Sec. 1271.10; i.e., those establishments that 
manufacture human cellular and tissue-based products regulated under 
the authority of section 361 of the PHS Act and proposed part 1271, but 
not as biological drugs or as devices. Products that the agency is 
regulating as devices or biological drugs will be subject to the 
enforcement provisions of the act and applicable regulations.
    The proposed inspection and enforcement provisions are based on 
those contained in part 1270, subpart D, which are currently applicable 
to human tissue intended for transplantation. These provisions were 
fully discussed in the rulemaking on part 1270 (``Human Tissue Intended 
for Transplantation,'' interim rule (58 FR 65514 and 65517 to 65518, 
December 14, 1993); ``Human Tissue Intended for Transplantation,'' 
final rule (62 FR 40429 and 40439 to 40440, July 29, 1997).
    Authority for the enforcement of section 361 of the PHS Act is 
provided for in part under section 368 of the PHS Act (42 U.S.C. 271). 
Under section 368(a) of the PHS Act, any person who violates a 
regulation prescribed under section 361 of the PHS Act may be punished 
by imprisonment for up to 1 year (42 U.S.C. 271(a)). Individuals may 
also be punished for violating such a regulation by a fine of up to 
$100,000 if death has not resulted from the violation or up to $250,000 
if death has resulted (18 U.S.C. 3559, 3571(b)). Organizations may be 
fined up to $200,000 per violation not resulting in death and $500,000 
per violation resulting in death (18 U.S.C. 3559, 3571(c)). In 
addition, Federal District Courts have jurisdiction to enjoin 
individuals and organizations from violating regulations implementing 
section 361 of the PHS Act.

A. Inspections (Proposed Sec. 1271.400)

    Proposed Sec. 1271.400 addresses the inspectional process. In large 
part,

[[Page 1523]]

inspections of establishments that manufacture human cellular and 
tissue-based products would be conducted in the same manner as 
inspections of firms dealing in other FDA-regulated commodities.
    Establishments subject to inspection include those that perform any 
step in the manufacture of human cellular and tissue-based products, 
including recovery, donor screening, donor testing, processing, 
storage, labeling, packaging, and distribution. All of these 
establishments, including any location performing contract services, 
would be required to permit inspections by an authorized FDA 
representative at any reasonable time and in a reasonable manner. The 
FDA representative would determine which areas of the establishment to 
inspect in order to determine compliance with the provisions of part 
1271; these might include, but would not necessarily be limited to, the 
establishment's facilities, equipment, processes, products, procedures, 
labeling, and records.
    Inspections would be made with or without prior notification and 
would ordinarily occur during regular business hours. The frequency of 
inspection would be at the agency's discretion.
    The FDA representative would call upon the most responsible person 
available at the time of inspection of the establishment and could 
question the personnel of the establishment as the representative deems 
necessary. The FDA representative could review and copy any records 
required to be kept under part 1271, and could take photographs or make 
video tapes. The agency notes that, under the policy expressed in 
Compliance Policy Guide 7151.02, ``FDA Access to Results of Quality 
Assurance Program Audits and Inspections,'' the FDA representative 
would not ordinarily review or copy an establishment's records and 
reports that result from audits of the establishment's quality program 
established under proposed Sec. 1271.160, when such audits are 
conducted according to the establishment's written quality program. 
This policy is intended to encourage the establishment to conduct 
quality program audits that are candid and meaningful. The agency would 
continue to have access to all information required to be maintained 
under proposed part 1271, such as complaint files, information on 
product deviations, and information on corrective actions.
    At the end of the inspection, if possible violations of the 
regulations are found, the FDA representative would issue to the most 
responsible person at the establishment a list of ``Inspectional 
Observations'' (Form FDA-483), describing the observations of the 
representative that represent an observed or potential problem with the 
facility or with the human cellular and tissue-based products. After 
the report of the FDA representative is reviewed, FDA may issue 
additional correspondence to the establishment describing the 
violations to the regulations and requesting appropriate follow-up 
action.
    The public disclosure of records containing the name or other 
positive identification of donors or recipients of human cellular or 
tissue-based products would be handled in accordance with FDA's 
procedures on disclosure of information as set forth in 21 CFR part 20. 
Under these procedures, FDA takes necessary precautions to protect the 
privacy of names of donors and recipients prior to public disclosure of 
records containing identifiers of the donor and recipients. FDA 
recognizes the sensitive nature of information that would identify a 
human tissue donor or recipient. FDA may copy records containing 
identification of the donors or recipients if such records are needed; 
for example, to document the distribution of potentially infectious 
human cellular and tissue-based products.
    The agency invites additional comments on possible alternative 
inspection and enforcement provisions that would leverage agency 
resources, be cost-effective, and achieve the public health goals of 
the proposed rule. The agency welcomes comments on the advantages and 
disadvantages of various types of programs, such as joint agency-third 
party inspectional programs and joint Federal-State inspectional and 
enforcement programs, as well as any other alternative approach that 
would help ensure compliance with the proposed rule.

B. Imports (Proposed Sec. 1271.420)

    Proposed Sec. 1271.420, which is derived from Sec. 1270.42, is 
intended to clarify the administrative steps for the importation of 
human cellular and tissue-based products into the United States. Human 
cellular and tissue-based products that have been recovered from 
sources outside the United States can enter the country, and products 
that have been recovered from sources in the United States and then 
sent outside the United States for processing can reenter the country, 
consistent with the provisions of part 1271. All imported human 
cellular and tissue-based products would be required to be accompanied 
by appropriate records identifying the donor and the status of donor 
testing and screening in accordance with the records requirements 
proposed in the donor-suitability proposed rule.
    As with other imports, when a human cellular or tissue-based 
product is offered for entry, the importer of record must notify the 
director of the FDA district having jurisdiction over the port of entry 
through which the product is imported or offered for import. ``Importer 
of record'' is defined in proposed Sec. 1271.3(tt). The human cellular 
or tissue-based product offered for import must be held intact, under 
conditions necessary to maintain product function and integrity, 
prevent contamination, and prevent transmission of communicable 
disease, until it is released by FDA.
    Human cellular and tissue-based products that are offered for 
import and found to be in violation of part 1271 would be subject to 
recall and destruction in accordance with Sec. 1271.440.

C. Orders of Retention, Recall, Destruction, and Cessation of 
Manufacturing (Proposed Sec. 1271.440)

    Proposed Sec. 1271.440 describes the procedures for the retention, 
recall, and destruction of human cellular and tissue-based products and 
for the cessation of manufacturing operations, and is derived in large 
part from Sec. 1270.43. Section 1271.440(a) states that, upon a finding 
that a human cellular or tissue-based product or an establishment is in 
violation of the regulations in this part (and thus poses a risk of 
spreading a communicable disease), the agency may issue an order that 
the product be recalled and/or destroyed, as appropriate, or that it be 
retained until it is recalled by the distributor, destroyed, or 
disposed of as agreed by FDA, or until the safety of the product is 
confirmed. Alternatively, the agency may take possession of and/or 
destroy the violative product.
    Section 1271.440(c) describes in further detail the order of 
retention, recall, or destruction, and describes possible alternatives 
to destruction. Section 1271.440(e) provides an opportunity for a 
hearing under 21 CFR part 16 and states that, if such a hearing is 
requested, any possible destruction of human cellular and tissue-based 
products would be held in abeyance pending resolution of the hearing 
request.
    Proposed Sec. 1271.440(a)(3) contains a provision not found in 
Sec. 1270.43: an ``order to cease manufacturing until compliance with 
the regulations of this part has been achieved.'' This type of order 
would bar an establishment from continuing its manufacturing operations

[[Page 1524]]

until the agency has determined that compliance has been achieved. The 
order will specify the regulations at issue, and will ordinarily 
specify the particular operations covered by the order (e.g., 
distribution, labeling, etc.). Operations may not resume without prior 
authorization of FDA.
    Authority for this new provision derives from section 361 of the 
PHS Act, which states that, ``[f]or purposes of carrying out and 
enforcing such regulations, the Surgeon General may provide for such 
inspection, * * * destruction * * *, and other measures, as in his 
judgment may be necessary.'' The agency considers these new measures to 
be a necessary component of its new comprehensive approach to cell and 
tissue regulation, which includes the proposed establishment 
registration and product listing and the proposed CGTP requirements.
    The agency recognizes that an order to retain particular human 
cellular and tissue-based products suspected of being in violation of 
the regulations may be appropriate in some instances, and intends to 
continue to issue such orders as necessary. However, such a limited 
action against a product or products may be an inadequate enforcement 
tool in some instances; e.g., when an establishment fails to comply 
with CGTP. In that situation, it may be more appropriate to take action 
directly against the establishment, rather than against the products of 
the establishment.
    For example, an order to cease operations would be appropriate in 
the case of an establishment that failed to establish and maintain 
proper procedures under proposed Sec. 1271.260(a) for storage of human 
cellular and tissue-based products in such a way as to prevent their 
cross-contamination. Such a failure to comply with CGTP would cause 
potential serious communicable-disease risk from all of the 
establishment's products. An order to retain or destroy particular 
products would not prevent the establishment from continuing its faulty 
practices and could therefore be inadequate.
    The agency expects that, typically, an order of cessation may be 
directed only at the distribution of human cellular or tissue-based 
products and would not affect the rest of an establishment's 
operations. However, in some cases, the order might cover a particular 
step in the manufacturing process. And in egregious cases involving 
serious CGTP deficiencies, the order might cover all of a firm's 
operations.

V. Proposed Revocation of Part 1270

    Part 1270 contains regulations governing infectious disease 
testing, donor screening, recordkeeping, and enforcement for human 
tissue intended for transplantation. Products currently subject to the 
provisions in part 1270 would be considered human cellular and tissue-
based products under the definition in Sec. 1271.3(e) and would be 
regulated under proposed part 1271. The agency has previously announced 
its intention that proposed part 1271 would supersede the regulations 
in part 1270 (donor suitability proposed rule (64 FR 52696)). After the 
regulations in part 1271 go into effect, the regulations in part 1270 
will be unnecessary, confusing, and duplicative. For these reasons, the 
agency now proposes to revoke part 1270.

VI. Proposed Effective Date

    FDA proposes that any final rule that may issue based on this 
proposal become effective 180 days after the date of its publication in 
the Federal Register.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VIII. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
under the Unfunded Mandates Reform Act (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The Regulatory 
Flexibility Act requires agencies to analyze whether a rule may have a 
significant impact on a substantial number of small entities and, if it 
does, to analyze regulatory options that would minimize the impact. The 
Unfunded Mandates Reform Act requires that agencies prepare a written 
statement under section 202 (a) of anticipated costs and benefits 
before proposing any rule that may result in an annual expenditure by 
State, local and tribal governments, in the aggregate, or by the 
private sector, of $100 million in any one year (adjusted annually for 
inflation).
    The agency believes that this final rule is consistent with the 
principles identified in Executive Order 12866. The Office of 
Management and Budget (OMB) has determined that the final rule is a 
significant regulatory action as defined by the Executive Order and so 
is subject to review. Because the rule does not impose mandates on 
State, local, or tribal governments, or the private sector, that will 
result in an expenditure in any one year of $100 million or more, FDA 
is not required to perform a cost-benefit analysis according to the 
Unfunded Mandates Reform Act. Many of the establishments within the 
tissue industry would be classified as small business entities, and a 
number of these facilities will incur new costs. Because of the limits 
of information to characterize the current quality management practices 
at many of these facilities, and thus the increased effort required to 
meet the standards of CGTP, the cost impact on small business entities 
is uncertain. The FDA has therefore prepared an Initial Regulatory 
Flexibility Analysis.

A. Estimated Cost Impact

    With the proposed CGTP rule, the FDA is furthering completion of 
the set of proposals that represent a comprehensive new system of 
regulating human cellular and tissue-based products. Manufacturers of 
tissue products may need to make certain changes to their operations to 
comply with the rule, such as creating new procedures and providing 
additional documentation. The proposed rule affects several industries 
involved in the manufacture of human cellular and tissue-based 
products. These include: Eye banks, conventional tissue banks, 
hematopoietic stem cell facilities, and reproductive tissue facilities.
    FDA estimates are based on available administrative data on the 
number of facilities within each industry sector and the number 
accredited by various industry associations. Where good statistical 
data are not available, FDA's cost impact estimates have incorporated 
the quantified judgments of individual experts identified through 
contacts with the industry associations. Because of the lack of 
comprehensive data to characterize patterns of current practice within 
each affected industry sector, and the importance of this data in 
development of an accurate assessment of cost impact, FDA requests 
detailed industry comment on the number of facilities involved in the 
manufacture of cellular and tissue products, and the net change in 
quality assurance efforts

[[Page 1525]]

needed for those facilities to comply with the proposed rule.
    1. The Number and Type of Entities Affected
    The economic impact of the proposed rule is organized around four 
subgroups: eye banks, conventional tissue banks, stem cell facilities, 
and reproductive tissue facilities. The number of facilities and the 
percent of facilities that follow current industry standards are 
summarized in table 1 of this document. In estimating net new costs for 
facilities, it is critical to account for facility adherence to current 
industry standards. In a number of tissue manufacturing sectors the 
industry standards for many manufacturing operations meet or exceed the 
specifications in the proposed rule. Facilities following those 
standards should experience very little impact in complying with FDA-
proposed standards.
    As presented in table 1 of this document, FDA estimates that there 
are 114 eye banks currently operating in the United States, although 
the EBAA believes that the number of banks is declining and may 
currently be closer to 100. According to EBAA, virtually all operating 
eye banks currently comply with the industry (EBAA) medical and 
procedural standards for quality control. For eye banks, the costs 
associated with following the proposed rule result from additional 
quality assurance steps and process documentation as specified under 
the CGTP.
    FDA estimates that 110 tissue banks are involved in the manufacture 
of other conventional tissue, e.g., pericardium, dura mater, heart 
valves, skin allografts, bone allografts, fascia, tendon, and ligaments 
(hereafter referred to as ``conventional tissue banks''). Industry 
sources report that approximately 75 to 80 percent of these facilities 
currently follow the standards for tissue banking established by the 
AATB. For these facilities, there will be some additional cost 
associated with review of the proposed FDA rule and with alignment of 
their current procedures to FDA's requirements. There may also be some 
additional recurring cost, where documentation and quality control 
required under the proposed rule extend beyond current practice. For 
the remaining 20 to 25 percent of facilities not following the industry 
standard, the cost of compliance would be somewhat higher. These 
facilities may need to establish more formal procedures and quality 
control steps, and may need to devote added staff hours to performing 
these procedures and processing controls.
    Facilities that produce stem cell products from peripheral blood or 
from umbilical cord blood would also be affected by the proposed rule. 
FDA finds that available data to estimate the number of peripheral 
blood stem cell (PBSC) facilities and current practices are quite 
limited. The actual number of PBSC facilities may range from 200 to 
400. Of the estimated total involved in peripheral blood stem cell 
production, approximately 150 are currently accredited by the AABB and 
an estimated 130 have applied for accreditation by the Foundation for 
the Accreditation of Hematopoietic Cell Therapy (FAHCT). Industry 
sources estimate that approximately 80 of these facilities are seeking 
dual AABB/ FAHCT accreditation, indicating an unduplicated count of 
approximately 200 PBSC facilities assumed to be accredited by AABB and/
or FAHCT. However, the manufacturing practices of non-accredited 
facilities are unknown. The International Bone Marrow Transplant 
Registry/Autologous Blood and Marrow Transplant Registry (IBMTR/ABMTR) 
estimates that the total number of peripheral blood or bone marrow 
facilities may be as high as 400\1\ (i.e., 200 more than the number 
estimated to be accredited by AABB or FAHCT), but the number of IBMTR/
ABMTR-estimated facilities that actually process peripheral blood (as 
opposed to bone marrow) is uncertain.
---------------------------------------------------------------------------

    \1\Based on the National Inpatient Sample of hospital discharge 
data collected by the Agency for Health Care Policy Research (AHCPR) 
in the Health Care Utilization Project (HCUP), a total of 7,300 stem 
cell transplants were performed in 1994, the most recent year 
reported. With the number of stem cell facilities ranging from 400 
to 200, this would translate to a range of 18 to 37 transplants per 
facility per year. Based on the implied volume of product per 
facility per year, a total of as many as 400 facilities would seem 
unlikely if the number of transplants in 1994 were representative of 
the current volume of demand for stem cell products.
---------------------------------------------------------------------------

    In addition, the proposed rule would apply to facilities involved 
with reproductive tissue, primarily sperm banks and Assisted 
Reproduction Technology (ART) facilities. For purposes of this 
discussion, references to ART facilities include infertility clinics, 
and andrology and embryology laboratories. The American Society of 
Reproductive Medicine (ASRM) has a membership of approximately 330 ART 
facilities. The ASRM also has a 1996 list of approximately 110 sperm 
banks operating in the United States. Based on conversations with 
consultants, most commercial sperm banking and most ART facilities 
currently adhere to industry standards similar to those in the proposed 
rule. The 20 largest sperm banks are estimated to handle 95 percent of 
the total volume of product for the industry, and these facilities are 
believed to follow industry standards that are comparable to the CGTP. 
According to industry consultants, approximately one-third of the 20 
largest sperm banks are accredited by the AATB, and the remaining two-
thirds are licensed by State health agencies, including the California 
Department of Health and the New York Department of Health. Sperm banks 
are also regulated under the Clinical Laboratory Improvement Amendment 
(CLIA) of 1988.
    Andrology laboratories at ART facilities are also subject to CLIA 
1988. The Committee on Laboratory Accreditation (COLA) and the Joint 
Commission on Accreditation of Health Care Organization (JCAHO), also 
inspect embryo laboratories for accreditation. The requirements for 
accreditation by the College of American Pathologists (CAP), which also 
accredits ART facilities, closely resemble those in the proposed CGTP 
rule, with a few exceptions. Consultants estimate that as many as 80 
percent of ART facilities may currently comply with the CAP 
requirements.

 Table 1.--Estimated Number of Facilities That Follow Industry Standards
------------------------------------------------------------------------
                                                    Percent of  Firms
  Affected  Industry       Relevant  Industry      Following  Industry
                               Standards                Standards
------------------------------------------------------------------------
Eye Tissue: 100-114     EBAA\1\                  100% facilities
 facilities                                       estimated compliant
------------------------------------------------------------------------
Conventional Tissue:    AATB\2\                  75-80% facilities
 (e.g., pericardium,                              estimated compliant
 dura mater, heart
 valves, skin
 allograft, bone
 allograft) 110
 facilities
------------------------------------------------------------------------
Stem Cells Peripheral   AABB or FAHCT\3\         85% accredited
 Blood (PB): 400                                  facilities estimated
 facilities             FAHCT                     compliant
 [uncertain]
Cord Blood (CB): 25                                100% CB facilities
 facilities                                       compliant
------------------------------------------------------------------------

[[Page 1526]]

 
Reproductive Tissue     AATB; CAP\4\             20% facilities
 Sperm Banks: 110        accreditation; State     estimated compliant
 facilities              Licensed (e.g.,          (accounting for 95% of
                         NY,CA); CLIA\5\-         all production)
                         certified
------------------------------------------------------------------------
Reproductive Tissue     CAP accreditation;       approximately 80%
 ART\6\ Facilities:      State licensed (e.g.,    facilities estimated
 330 facilities          NY,CA); ASRM\7\          compliant
                         guidelines
------------------------------------------------------------------------
\1\Eye Bank Association of America
\2\American Association of Tissue Banks
\3\Foundation for the Accreditation of Hematopoietic Cell Therapy
\4\College of American Pathologists
\5\Clinical Laboratory Improvement Amendments of 1988
\6\Assisted Reproductive Technology
\7\American Society for Reproductive Medicine

    2. Estimated Impact on Industry Facilities
    In the sections that follow, the agency considers each of the 
provisions of the proposed rule its estimated impact on facilities in 
the identified sectors of the tissue industry. The impact analysis 
distinguishes expected cost impacts based on both facility size and 
estimated current adherence with industry standards. As defined by the 
U.S. Small Business Administration, a small facility has revenues less 
that $5.0 million.

 Table 2.--Estimated Cost per Facility and Estimated Percentage of Facilities That Would Be Affected by Proposed
                                        Current Good Tissue Practices\1\
----------------------------------------------------------------------------------------------------------------
                                                                     Stem Cell
                                                Conventional        Facilities                       ART \2\
   Section          Title        Eye Banks     Tissue (Small/       (Compliant/     Sperm Banks     Facilities
                                                   Large)          noncompliant)                  (Small/Large)
----------------------------------------------------------------------------------------------------------------
1271.150       Current good      - -          - -                - -                 - -          - -
                tissue
                practice:
                general
----------------------------------------------------------------------------------------------------------------
1271.155       Exemptions and    - -          - -                - -                 - -          - -
                alternatives
----------------------------------------------------------------------------------------------------------------
1271.160       Establishment
                and
                maintenance of
                a quality
                program
(b)(2)         Functions--Proc  $349 (95%)   $698/ $2,004       $0/ $698 (0%/ 80%)  $698 (5%)    $698/ $0 (5%/
                edures for                    (23%)                                               0%)
                sharing
                information
(b)(3)         Functions--Corr  $414 (95%)   $828 (23%)         $0/ $828 (0%/ 80%)  $828 (5%)    $828/ $0 (5%/
                ective actions                                                                    0%)
(b)(7)         Functions--Inve  $2,022       $2,022 (23%)       $0/ $2,022 (0%/     $2,022 (5%)  $2,022 /$0 (5%/
                stigations       (95%)                           80%)                             0%)
(d)(1)         Audits--Annual   $414 (95%)   $828/ $1,656       $0/ $828 (0%/ 80%)  $828 (5%)    $828/ $1,656
                                              (23%)                                               (50%)
(d)(3)         Audits--Report   $138 (95%)   $276 /$552 (23%)   $207 (95%)          $207 (5%)    $207/ $414
                                                                                                  (50%)
(e)            Computers--Vali  $2,040       $2,040 (10%)       $2,040 (10%)        $2,040 (5%)  $2,040 (5%)
                date             (10%)
                customized
                software
(f)            Procedures--Qua
                lity program
               --Facility with  $449 (95%)   $449/ $1,159       $449 (80%)          $449 (80%)   $449/ $1,159
                minor                         (23%)                                               (80%)
                deficiencies
               --Facility with  $2,191 (5%)  $2,191/ $4,359     $0/ $2191 (0%/ 5%)  $2,191 (5%)  $2,191/$4,359
                major                         (5%)                                                (5%)
                deficiencies
               --Cost for       $1,236       $1,236 (23%)       $1,236 (80%)        $1,236       $1,236 (80%)
                additional       (95%)                                               (80%)
                quality
                control work
----------------------------------------------------------------------------------------------------------------
1271.170       Organization
                and personnel
(b)            Competent        - -          $15,560 (23%)      $0/ $15,560 (0%/    $15,560      $15,560 (5%)
                performance of                                   95%)                (5%)
                functions--Suf
                ficient
                personnel
(c)            Training         - -          $2,348/ $3,104     $0/ $2,348 (0%/     $2,348 (5%)  $2,348/ $0 (5%/
                                              (23%)              95%)                             0%))
(d)            Records--Person   - -          - --               - -                 - -          - -
                nel
----------------------------------------------------------------------------------------------------------------
1271.180       Procedures--Gen  $8,280 (5%)  $8,280 (23%)       $0/ $8,280 (0%/     $8,280       $8,280 (50%)
                eral                                             95%)                (50%)
                requirements
----------------------------------------------------------------------------------------------------------------
1271.190       Facilities
(a)            General           - -          - -                - -                $14,000      $14,000/$28,000
                                                                                     (5%)         (5%/ 5%)
(b)            Operation-        - -          - -               $0/$14,000 (0%/     14,000 (5%)  $14,000/$28,000
                Separation                                       95%)                             (5%/ 15%)
                 of Operations
(b)            General-          - -          - -               ..................
                Separation

[[Page 1527]]

 
(c)(3)         Facility         $299 (5%)    $299/ $471 (23%)   $299 (95%)          $299 (5%)    $299/ $471 (5%)
                cleaning and
                sanitation--Pr
                ocedures
(c)(4)         Facility         - -          - -                - -                 - -          - -
                cleaning and
                sanitation--Re
                cords
----------------------------------------------------------------------------------------------------------------
1271.195       Environmental
                control and
                monitoring
(a)            General--Proced   - -         $299/ $471 (23%)   $299 (95%)          $299 (80%)   $299/ $471
                ures for                                                                          (80%)
                ventilation
                and air
                filtration
(b)            Inspections--En  $1,000 (5%)   - -                $1,000 ( 50%/      $1,000       $1,000/$2,000
                vironmental                                      95%)                (20%)        (20%)
                control
                systems
(c)            Records--Enviro  $162 (95%)   $162/ $324 (23%)   $162 ( 95%)         $162 (80%)   $162/ $324
                nmental                                                                           (80%)
                control and
                monitoring
                activities
----------------------------------------------------------------------------------------------------------------
1271.200       Equipment
(b)            Procedures and    - -         $1,254/ $2,638     $0/ $1,254 (0%/     $1,343       $1,343/$2,261
                schedules--Cle                (23%)              95%)                (90%)        (90%)
                aning,
                sanitizing,
                and
                maintenance
(c)            Calibration of    - -         $1,254/ $2,638     $1,254 (95%)        $1,343 (5%)  $1,343/
                equipment                     (23%)                                               $2,261(50%)
(d)            Inspections--Ro  $204 (95%)   $408/ $816 (23%)   $204 (95%)          $204 (5%)    $204/ $408 (5%)
                utine
(e)            Records--Mainte
                nance,
                cleaning,
                sanitizing,
                and
                calibrating
                activities
               --Keeping        $162 (95%)   $324/ $648 (23%)   $162 (95%)          $162 (5%)    $162/ $324 (5%)
                records of
                cleaning and
                calibration
                activities
               --Keeping        $648 (95%)   $1,296/ $2,592     $1,296 (95%)        $1,296       $1,296/$2,592
                records of the                (23%)                                  (100%)       (100%)
                use of each
                piece of
                equipment
----------------------------------------------------------------------------------------------------------------
1271.210       Supplies and
                reagents
(a)            Receipt and      $100 (95%)   $299/ $471 (23%)   $100/ $299 (95%/    $299 (5%)    $299/ $471
                verification--                                   95%)                             (80%)
                Procedures
(b)            Reagents--Proce   - -         $299/ $471 (23%)   $299 (95%)
                dures in-house
(c)(1)         Records--Receip  $162 (95%)   $162 / $324 (23%)  $0 / $162 (0%/      $162 (5%)    $162 / $324
                t of supply or                                   95%)                             (5%)
                reagent
----------------------------------------------------------------------------------------------------------------
1271.220       Process
                Controls
(b)            Processing       $299 (95%)   $299/ $471 (23%)   $299 (95%)          $299 (90%)   $299/ $471
                material--Proc                                                                    (90%)
                edures for the
                use and
                removal of
                damaging
                processing
                materials
(d)            In-process       $349 (95%)   $349/ $1,002       $698 (95%)          $349 (5%)    $349/ $1,002
                monitoring--Pr                (23%)                                               (5%)
                ocedures
----------------------------------------------------------------------------------------------------------------
1271.225       Process changes
(a)            Procedures--Pro  $698 (95%)   $698/ $2,004       $0 /$698 (0%/ 95%)  $698 (5%)    $698/ $2,004
                cess changes                  (23%)                                               (90%)
(b)            Change records   $414 (95%)   $414/ $828 (95%)   $414 (95%)          $414 (90%)   $414/ $828
                                                                                                  (90%)
----------------------------------------------------------------------------------------------------------------
1271.230       Process
                validation
(a)            General          $1,570       $1,570 (95%)       $1,570 (95%)         - -          - -
                                 (95%)
(d)            Procedures       $1,396       $698 / $2004       $698/ $1,396 (95%/
                                 (95%)        (95%)              95%)
(e)            Changes and      $785 (95%)   $1,570 (95%)       $1,055 (95%)
                deviations--Re
                validation
----------------------------------------------------------------------------------------------------------------
1271.250       Labeling         $349 (5%)    $349 / $1,002      $349 (5%)           $349 (5%)    $349 / $1,002
                Controls--Proc                (5%)                                                (5%)
                edures
----------------------------------------------------------------------------------------------------------------
1271.260       Storage           - -          - -                - -                 - -          - -
----------------------------------------------------------------------------------------------------------------
1271.265       Receipt and
                distribution
(a)(1)         General--Docume  $816 (5%)    $1,632/ $3,264     $1,632/ $3,264      $1,632 (5%)  $1,632/ $3,264
                nt                            (5%)               (5%)                             (5%)
                identification
                of product

[[Page 1528]]

 
(b)            Receiving         - -         $349/ $1,002       $698 (95%)          $698 (5%)    $698/ $2,004
                activities--Pr                (23%)                                               (5%)
                ocedures
(c)            Availability      - -         $349/ $1,002       $349/ $698 (95%)    $698 (5%)    $698/ $2,004
                for                           (23%)                                               (5%)
                distribution--
                Procedures
(d)            Packaging--Vali  $1,296       $1,296 (95%)       $544 (95%)          $544 (100%)  $544 (100%)
                dation           (95%)
(f)            Return to         - -         $299/ $471 (23%)   $0/$399 (0%/95%)    $299 (5%)    $299/$471
                inventory--Pro                                                                    (100%)
                cedures
----------------------------------------------------------------------------------------------------------------
1271.270       Records
(a)            General          $648 (95%)   $0/ $648 (0%/      $648 (95%)           - -          - -
                                              95%)
(b)            Records          $2,760       $0/ $2,760 (0%/    $2,760 (95%)        $2,760 (5%)  $2,760/$5,520
                management       (95%)        95%)                                                (50%)
                systems
(e)            Length of        $18 (5%)     $18 (50%/ 95%)     $18 (95%)           $18 (5%)     $18/$36 (5%)
                retention
----------------------------------------------------------------------------------------------------------------
1271.290       Tracking
(b)(1)         Method of        $698 (5%)    $0/ $349 (0%/      $349 (95%)          $349 (80%)   $349/ $1,002
                product                       95%)                                                (80%)
                tracking-
                General method
(e)            Recipient        $1,632 (5%)  $0/ $3,264 (0%/    $3,264 (95%)         - -          - -
                information                   95%)
(f)            Consignees       $1,380 (5%)  $1,380 (23%)       $1,380 (95%)        $1,380       $1,380 (80%)
                                                                                     (80%)
----------------------------------------------------------------------------------------------------------------
1271.320       Complaint file
(a)            Procedures       $100 (95%)   $299/ $471 (23%)   $299 (95%)          $299 (5%)    $299/ $471 (5%)
(b)            Complaint file    - -          - -                - -                 - -          - -
(c)            Review and       $552 (95%)   $552 / $1,104      $552 (95%)          $552 (5%)    $552 / $1,104
                evaluation of                 (23%)                                               (5%)
                complaints
                       E--Additional Requirements for Establishments Described in 1271.10
----------------------------------------------------------------------------------------------------------------
1271.350       Reporting         - -          - -                - -                 - -          - -
----------------------------------------------------------------------------------------------------------------
1271.370       Labeling and      - -          - -                - -                 - -          - -
                claims
----------------------------------------------------------------------------------------------------------------
                      F--Inspection and Enforcement of Establishments Described in 1271.10
----------------------------------------------------------------------------------------------------------------
1271.400       Inspections
(a)            Inspections--Ge  $708 (100%)  $708 (100%)        $708 (100%)         $708 (100%)  $708 (100%)
                neral
----------------------------------------------------------------------------------------------------------------
1271.420       Human cellular    - -          - -                - -                 - -          - -
                and tissue-
                based products
                offered for
                import
----------------------------------------------------------------------------------------------------------------
1271.440       Orders of         - -          - -                - -                 - -          - -
                retention,
                recall,
                destruction,
                and cessation
                of
                manufacturing
----------------------------------------------------------------------------------------------------------------
\1\Only sections estimated to have compliance costs for these industries are shown. No cost is estimated for a
  section (indicated by a double dash``--'') if the background analysis (see a detailed presentation of cost
  assumptions provided in FDA's Cost Impacts of the Proposed Current Good Tissue Practices Rule on Eye Banks,
  Conventional Tissue Banks and Stem Cell Facilities: Background Paper, April 1999, and in Cost Impacts of the
  Proposed Current Good Tissue Practice Rule on Sperm Banks and ART Facilities, February 1999, prepared by
  Eastern Research Group, Inc. ) shows that the requirements: (1) Do not apply, (2) have no new cost impact, or
  (3) are met by another section of the proposed rule.
\2\Assisted Reproductive Technology

    As indicated by the information in table 2, the impact of the 
proposed rule varies, depending upon the sector of the tissue industry 
and the particular provisions of the proposed rule. For many of the 
proposed provisions, the facility level impact will entail development 
of new procedures, or revision of existing procedures. The scope and 
degree of complexity may vary. FDA expects that the staff typically 
involved in the development and finalization of facility procedures 
will include technicians, clerical staff, lab supervisors, and the lab 
director. For purposes of industry-wide estimation, the agency's 
analysis relies on standardized estimates of the level of effort and 
cost for establishing procedures. Table 3 summarizes the agency's 
assumptions, based on input from industry consultants.\2\
---------------------------------------------------------------------------

    \2\A detailed presentation of level of effort and cost 
assumptions are provided in FDA's ``Cost Impacts of the Proposed 
Current Good Tissue Practices Rule on Eye Banks, Conventional Tissue 
Banks and Stem Cell Facilities: Background Paper,'' April 1999, and 
in ``Cost Impacts of the Proposed Current Good Tissue Practice Rule 
on Sperm Banks and ART Facilities,'' February 1999, prepared by 
Eastern Research Group, Inc. These documents will be available on 
the CBER website.

[[Page 1529]]



   Table 3.--Estimated Level of Effort and Cost per Procedure Revised or Prepared to Comply with the Proposed
                                         Current Good Tissue Practice\1\
 
 
----------------------------------------------------------------------------------------------------------------
Size Category                        Minor Procedures
                                     Major Procedures
----------------------------------------------------------------------------------------------------------------
Small Facility         Revise Existing        Prepare New            Revise Existing        Prepare New
  Staff level of       2.0 hrs.               6.0 hrs.               8.0 hrs.               16.0 hrs.
 effort
  Cost                 $99.50                 $298.50                $349.0                 $698.00
Large Facility
  Staff level of       4.0 hrs.               12.0 hrs.              27.0 hrs.              54.0 hrs.
 effort
  Cost                 $157.00                $471.00                $1,002.00              $2,004.00
----------------------------------------------------------------------------------------------------------------
\1\Small facilities are those with revenues less than $5.0 million. The distinction between major and minor
  procedures is described in the report by Eastern Research Group, Inc.

The analysis of impact is summarized below through a discussion of the 
proposed rule provisions and expected type and extent of industry 
impact. The pertinent section of the proposed rule is noted to 
facilitate reference to the related estimates in table 2.
    a. Section 1271.150--current good tissue practice: general. The 
proposed rule would require manufacturers of human cellular and tissue-
based products to follow CGTP. Section 1271.150(a) gives an overview of 
CGTP but does not present specific compliance requirements. The 
specific requirements are addressed in subsequent sections. Section 
1271.150(b) would require that manufacturers ensure compliance on the 
part of contractors and proposes the establishment that should be 
responsible for compliance. FDA expects that facilities would use 
accredited referral laboratories to ensure compliance with the CGTP 
rule, and therefore new costs would be associated with 
Sec. 1271.150(b). Section1271.150(c) explains the relationship of the 
proposed rule to regulations specifically applicable to biological 
drugs or devices and paragraph (d) defines the term ``where 
appropriate'' in relation to the rule. Neither Sec. 1271.150(c) nor (d) 
would generate any costs for this industry because no compliance 
requirements are specified.
    b. Section 1271.155--exemptions and alternatives. The proposed rule 
would allow establishments to request an exemption or alternative from 
FDA for any of the requirements of the rule. There is currently no 
basis for predicting industry requests for exemptions or alternatives, 
or for predicting the effect of these actions on compliance costs. FDA 
anticipates that very few facilities will consider it appropriate to be 
exempted from the quality standards specified in the proposed rule.
    c. Section 1271.160--establishment and maintenance of a quality 
program. The proposed rule would require that facilities establish and 
maintain a quality program. The quality program would include: 
Procedures for each step in the manufacturing process, procedures for 
exchanging information with other establishments known to have 
recovered cells from the same donor, corrective action and 
documentation, training and education of personnel, appropriate 
monitoring systems, maintenance of records, investigation and 
documentation of all product deviations, other actions necessary to 
assure compliance with the quality program; assignment of authority 
over the quality control program, audits, computer software validation, 
and other procedures specific to the quality program. A number of these 
functions are further specified in subsequent provisions of the rule, 
and the impact is estimated in the context of those provisions.
    In general, FDA anticipates that almost all of the establishments 
in the affected industries have the appropriate facilities, equipment, 
and systems to support comprehensive quality management, but only those 
already estimated to be following industry standards are expected to 
have comprehensive quality programs in place. Some facilities may need 
to upgrade their quality program for several of the proposed 
requirements. These include: Procedures for sharing information, 
corrective actions, and investigations. Further, some facilities may 
need to take additional steps to administer corrective actions and 
conduct investigations, if they currently do so only when major 
deviations arise.
    Although sharing of information is an industry-wide practice, some 
small facilities, particularly those not following current industry 
standards, may not have written procedures and reporting forms for this 
task. FDA estimates that 95 percent of industry eye banks would need to 
revise a major procedure; 23 percent of other conventional tissue 
banks, not following the current AATB standard, would need to write a 
major procedure to comply with this requirement; 80 percent of the 
peripheral blood stem cell facilities not following the FAHCT or AABB 
standards would need to prepare a major procedure; and 5 percent of 
sperm banks and 5 percent of ART facilities would need to prepare a 
major procedure to address this requirement.
    Although FDA anticipates that most industry facilities take steps 
to administer corrective actions and conduct investigations, some may 
currently do so only when major deviations arise.
    FDA estimates that 95 percent of eye banks, 23 percent of 
conventional tissue banks, 80 percent of stem cell facilities, and 5 
percent of sperm banks and ART facilities, would need to invest 
additional time. The incremental time for the laboratory director to 
administer corrective actions and document these activities is 
estimated to be an additional half-hour per month of laboratory 
director time at eye banks that already perform this activity to a 
lesser extent, and an additional hour per month at all other facilities 
that will be newly affected by this provision. As shown in table 2 in 
Sec. 1271.160(b)(7) of the background papers prepared by FDA and 
Eastern Research Group Inc., (ERG) for newly required investigations in 
tissue facilities, FDA estimates an additional cost per year of $2,022 
for an additional 2 hours per month for the laboratory director to 
investigate and document deviations, and an additional half hour each 
for the laboratory supervisor and technician to participate in the 
investigations.
    A number of facilities would also institute other requirements of 
the quality program, including audits, computer software validation, 
and procedures specific to the quality program. Audits are part of the 
industry standards published by the AATB, the EBAA, by FAHCT and the 
AABB. However, some facilities following these standards may need to do 
some additional recordkeeping, and facilities not following standards 
would begin to conduct audits. Referring to table 2, FDA assumes that 
up to 95 percent of eye banks would increase their audit efforts, 
including additional lab director time to perform the audit and 
additional

[[Page 1530]]

hours of preparation for the annual audit. An estimated 23 percent of 
conventional tissue banks, and an estimated 50 percent of ART 
facilities, would allocate additional resources for annual audits, with 
a higher allocation of hours at larger facilities, to prepare for, and 
to conduct the audit. For stem cell facilities, FDA estimates that 
there would be no additional auditing required at facilities following 
FAHCT or AABB standards, but an estimated 80 percent of facilities not 
following industry standards would need to spend additional time to 
prepare for and to conduct an audit each year. It is also assumed that 
approximately 5 percent of sperm banks would allocate additional staff 
hours for these audit-related activities.
    In addition to performing the annual audit, the proposed rule would 
require preparation of an annual audit report. Facilities following 
current industry standards may need to increase the time for reporting.
    FDA estimates that 95 percent of industry eye banks will experience 
an increase of approximately 2 hours per year of lab director time for 
preparing the audit report. The 23 percent of conventional tissue 
facilities not following AATB standards are estimated to devote 4 hours 
of lab director time, in the case of small facilities, and 8 additional 
hours of lab director time at large facilities for the preparation of 
an annual audit report. Laboratory directors of 95 percent of the stem 
cell facilities, 5 percent of sperm banks, and 33 percent of ART 
facilities, would spend an estimated additional 3 hours to prepare the 
annual audit report. Approximately 17 percent of ART facilities would 
also be affected, with an increase of approximately 6 hours per year of 
staff time for audit report preparation.
    Section 1271.160 of the proposed rule further stipulates that 
facilities would be required to validate the computer software used in 
their operations. The FDA assumes that off-the-shelf commercial 
software packages for particular applications are already validated by 
the software vendor, but that a facility's custom software would 
require complete software validation. FDA assumes that none of the 
affected facilities currently validate their custom software and that 
approximately 10 percent of eye, conventional tissue and stem cell 
facilities, and approximately 5 percent of reproductive tissue 
facilities have developed custom software that would require full 
software validation under the proposed rule. While the scope of such 
work can vary, FDA estimates that the custom software in use has a 
limited scope of application, and an average of 60 hours of work by the 
laboratory supervisor would be required to validate custom software at 
a facility. Detailed presentations of these assumptions are provided in 
section 2.4.3 of the background reports by FDA and ERG.
    The last requirement for the quality control program is for 
procedures that stipulate how the quality program should be operated. 
Industry consultants indicate that facilities have quality systems in 
place, but that most facilities are not aware of some minor elements 
that should be included in the procedures. Consequently, inspectors for 
accreditation groups often find a few deficiencies during initial 
visits. FDA estimates that about 95 percent of eye banks, 23 percent of 
conventional tissue, and up to 80 percent of stem cell facilities, 
sperm banks and ART facilities will have minor deficiencies that would 
require them to revise one minor and one major procedure. In addition, 
FDA estimates that 5 percent of all eye banks, conventional tissue, 
reproductive tissue facilities, and industry non-compliant stem cell 
facilities, may identify major deficiencies, and would need to prepare 
five minor procedures and one major procedure to address those 
problems.
    The agency further assumes that facilities may generally need to do 
some additional quality control work to comply with the quality control 
program requirements in the CGTP rule. Although some tasks would not 
take any additional time to perform, FDA estimates that one additional 
hour per month each for the laboratory director and supervisor may be 
needed. FDA estimates that 95 percent of all eye banks, 23 percent of 
conventional tissue banks and approximately 80 percent of stem cell 
facilities and reproductive tissue facilities would allocate this 
additional staff time.
    d. Section 1271.170--organization and personnel. The proposed rule 
would require facilities to employ sufficient personnel with the 
necessary education and experience to complete their tasks. Personnel 
would be trained to perform their work adequately. The EBAA, AATB, 
FAHCT, and AABB standards for quality assurance all include provisions 
for appropriate personnel qualifications and training, and 
recordkeeping related to this requirement. It is expected that most 
facilities for eye banking, conventional tissue banking, and stem cell 
production already follow these practices as proposed. The fraction of 
facilities in conventional tissue and stem cell manufacturing that do 
not follow industry standards would incur new costs. Similarly, 5 
percent of the facilities in the reproductive tissue industries would 
incur some new costs associated with hiring staff that meet formal 
training requirements. The cost of this staffing effort is estimated to 
be approximately $15,560 per affected facility.
    FDA anticipates that the 23 percent of conventional tissue 
facilities, 95 percent of industry-noncompliant stem cell facilities, 5 
percent of sperm banks, and 5 percent of small ART facilities would 
incur new training costs in complying with the proposed rule. For a 
small tissue establishment, these costs are estimated to average 
$2,348. The proposed CGTP would also require that records of personnel 
qualifications and training be maintained, but because the incremental 
record keeping is minimal, FDA assumes that the cost to comply with 
this requirement would be negligible. Detailed presentations of these 
assumptions are provided in section 2.4.4 of the background reports by 
FDA and ERG.
    e. Section 1271.180--procedures: general requirements. The proposed 
rule would require establishments to keep written procedures for all 
steps performed during manufacturing of human cellular or tissue-based 
products, and to perform an annual review. FDA anticipates a negligible 
incremental cost for most facilities following industry standards, and 
an additional 120 hours by the laboratory director for facilities not 
following the current industry standards. FDA estimates that 5 percent 
of eye banks would need to expand their current review efforts, and 
that 23 percent of conventional tissue banks, 95 percent of stem cell 
facilities, and 50 percent of reproductive tissue facilities would 
incur new costs for an annual review.
    f. Section 1271.190--facilities. The proposed rule stipulates a 
number of requirements regarding the construction of facilities, 
covering size, location, lighting, ventilation, plumbing, drainage, and 
toilet and washing facilities. The facility would also be required to 
have properly divided areas for appropriate quality control. Cleaning 
requirements are also outlined, including requirements for written 
procedures and schedules for cleaning and documentation of cleaning 
activities. Based on discussions with industry experts, FDA estimates 
that nearly all facilities that follow industry standards would not 
incur new costs under the proposed CGTP rule. However, some 
establishments that generally adhere to cleaning standards do not have 
written procedures. FDA

[[Page 1531]]

estimates that 5 percent of all eye banks, in addition to 23 percent of 
the conventional tissue banks, 95 percent of all stem cell facilities, 
and 5 percent of reproductive tissue facilities would incur the cost of 
writing a minor procedure for cleaning. The facilities provision of the 
CGTP also would require that records of cleaning be maintained. This 
proposed requirement is currently practiced by most facilities, and is 
expected to have a negligible impact on facilities not following 
industry standards.
    g. Section 1271.195--environmental control and monitoring. The 
proposed rule would require that procedures be written for 
environmental control and monitoring activities or systems where an 
environmental condition could have an adverse effect on the human 
cellular or tissue-based product. The rule also would require that 
environmental control systems be regularly inspected and that control 
and monitoring activities be documented. The impact of this provision 
of the CGTP varies by industry sector. For eye banking, the EBAA 
standards already contain relevant provisions, however, some additional 
costs may be incurred for annual inspection of the environmental 
control systems and for keeping records of environmental control and 
monitoring activities. It is estimated that 5 percent of eye banks may 
incur new costs for inspection and certification of equipment. FDA 
anticipates that the conventional tissue facilities following AATB 
standards would experience no new costs, but that the remaining 23 
percent of facilities would need to prepare a minor procedure to 
control and monitor ventilation and air filtration.
    The current FAHCT and AABB standards do not provide for written 
procedures for environmental control and monitoring. FDA therefore 
estimates that 95 percent of all stem cell facilities would need to 
develop a minor procedure to control and monitor ventilation and air 
filtration to comply with the CGTP. However, because the industry 
standards provides for appropriate environmental controls, FDA assumes 
that some facilities are currently performing control activities. The 
agency estimates that as many as half of the facilities currently 
following standards may already be conducting routine inspections of 
their environmental control equipment. It is assumed that the remaining 
50 percent of those facilities, and 95 percent of facilities assumed 
not to be following industry standards, would incur additional costs to 
inspect equipment and perform recordkeeping related to environmental 
control.
    The agency also assumes that most reproductive tissue facilities 
would need to prepare written procedures, and do additional 
recordkeeping in compliance with the CGTP. FDA estimates that 80 
percent of all sperm banks and ART facilities would incur costs to 
comply with this provision of the proposed rule. FDA also estimates 
that 20 percent of ART facilities would increase ventilation systems 
inspection activities. Table 2 provides estimates of cost per facility 
associated with these efforts.
    h. Section 1271.200--equipment. The proposed rule stipulates that 
appropriate equipment be used and any equipment used be validated. 
Cleaning, maintenance, and calibration of equipment would be performed 
according to established schedules and procedures; equipment would be 
regularly inspected for adherence to applicable procedures and 
schedules; and all such activities would be documented. In addition, 
facilities would be required to keep records of each use of each piece 
of equipment, including the identification of each human cellular or 
tissue-based product manufactured with that piece of equipment.
    The standards related to equipment, as specified by AATB, EBAA, 
FAHCT, and AABB generally address maintenance procedures, and 
recordkeeping related to maintenance. However, the proposed rule 
extends beyond the industry standard for EBAA, FAHCT and AABB in the 
areas of equipment inspection and recordkeeping. FDA therefore 
estimates that 95 percent of all eye banks would allocate an additional 
half-hour per month for the laboratory supervisor to inspect equipment, 
an additional half hour per month of technician time to documenting 
equipment cleaning and calibration, and two additional hours of 
technician time per month in recording each use of the equipment.
    The estimated 23 percent of conventional tissue facilities that 
currently do not follow AATB standards would also incur new costs 
related to equipment quality control. FDA estimates that small 
facilities would prepare one minor procedure for calibration, and for 
cleaning and other maintenance for each of six pieces of equipment. In 
addition, small facilities will allocate an additional hour per month 
of lab supervisor time for routine inspection of equipment, an 
additional hour per month of technician time for documentation of 
cleaning and calibration, and 4 hours per month recording each use of 
the equipment. FDA estimates large facilities would write minor 
procedures for each of eight pieces of equipment, and would allocate an 
additional 2 hours per month of lab supervisor time for routine 
inspection of equipment, an additional 2 hours per month of technician 
time to record cleaning and calibration activities, and an additional 8 
hours of technician time per month to record each use of each piece of 
equipment. It is anticipated that the facilities simultaneously 
preparing multiple procedures related to equipment would realize some 
economies of scale because of similarities across procedures. This is 
expected to result in a savings of 30 percent in the total amount of 
staff time to prepare six to eight equipment maintenance procedures at 
one time.
    Stem cell facilities also would be expected to perform some 
additional work to align current practice with the proposed CGTP 
requirements. Current FAHCT procedures provide for routine maintenance 
and calibration of equipment. In addition, the AABB standards recommend 
that standard operating procedures (SOP's) be established for proper 
equipment maintenance and monitoring. To further develop procedures to 
address routine maintenance and recordkeeping under the proposed CGTP, 
FDA estimates that 95 percent of all stem cell facilities would prepare 
a minor procedure for calibration of each of six pieces of equipment. 
In addition to the preparation of procedures, lab personnel would carry 
out the maintenance work, estimated to require an additional half hour 
of supervisor time per month in routine inspection of equipment, an 
additional half hour per month for technicians to document cleaning and 
calibration work, and an added 4 hours per month of technician time to 
record each use of equipment. In addition, most stem cell facilities 
that do not currently follow FAHCT or AABB standards would incur the 
cost of preparing a minor procedure for cleaning, for sanitizing and 
for routine maintenance of six pieces of equipment.
    In the reproductive tissue industry, the agency estimates that all 
facilities have the appropriate equipment to process the tissue 
products, but that only a small percentage currently conduct 
recordkeeping and have written procedures related to maintenance, 
calibration and other activities as specified under the proposed CGTP. 
The agency estimates that 90 percent of sperm banks and ART facilities 
would develop additional procedures, and that 100 percent of these 
facilities would need to perform additional

[[Page 1532]]

recordkeeping related to equipment use. In addition, an estimated 5 
percent of sperm banks, and 50 percent of ART facilities would devote 
additional resources to routine calibration of equipment. An estimated 
5 percent of facilities would need to also increase efforts in routine 
inspection, and record keeping related to equipment cleaning and 
maintenance. The costs per facility associated with each of these areas 
of activity are presented in table 2. Section 2.4.8 of the ERG 
background paper provides a detailed presentation of these assumptions.
    i. Section 1271.210--supplies and reagents. The proposed rule would 
require that procedures be established for receipt of supplies and 
reagents used in the manufacture of human cellular and tissue-based 
products. In particular, manufacturers would be required to verify that 
supplies and reagents meet specifications designed to prevent 
transmission of communicable disease and impairment of product function 
and integrity. Verification of supply or reagent quality could be 
accomplished with a certificate of analysis. The proposed rule would 
also require documentation of receipt, verification, and each use of a 
supply or reagent in product processing.
    The existing industry standards address some or all of these 
activities, and the estimated impact per facility varies accordingly. 
EBAA standards specify that sterilized supplies and reagents should 
contain sterilization dates, method or appropriate expiration dates. 
However, the agency estimates that up to 95 percent of eye banks would 
be required to develop additional procedures related to receipt and 
verification, and would devote additional staff time to recording the 
receipt of supplies and reagents. Similarly, FAHCT and AABB standards 
contain provisions for quality control in the storage, handling and use 
of supplies and reagents, including maintenance of records. However, 
FDA expects that approximately 95 percent of stem cell facilities may 
be required to expand on their current SOP's and recordkeeping in order 
to comply with the CGTP provisions.
    The current AATB standards address most of the requirements for 
supplies and reagents included in the proposed rule. FDA assumes that 
the estimated 23 percent of facilities that follow these standards 
would be required to prepare additional procedures for in-house reagent 
verification, for receipt and verification, and would devote additional 
staff time to keeping records of the receipt of supplies and reagents.
    Based on consultant estimates that 95 percent of commercial sperm 
banks follow AATB guidelines, the agency estimates that only 5 percent 
of sperm banks and 80 percent of ART facilities would need to take new 
steps to comply with this proposed CGTP provision. For these 
facilities, the agency anticipates that each facility would need to 
prepare new procedures for receipt and verification of supplies and 
reagents, and each will devote additional staff time to recording the 
receipt of these materials. The estimated costs per facility are 
presented in table 2.
    j. Section 1271.220--process controls. The proposed rule would 
require facilities to monitor manufacturing processes to ensure that 
specified requirements for the product are met. This includes having 
written procedures for the use and removal of processing material that 
can damage products, and procedures for in-process monitoring. The 
standards for tissue banking specified by the AATB include activities 
to address these process controls, but the EBAA, FAHCT, and AABB 
standards do not include specific requirements for monitoring and 
removal of processing material that may damage the product. FDA 
estimates that 95 percent of eye banks, 23 percent of conventional 
tissue banks, 95 percent of stem cell facilities, and 90 percent of 
sperm banks and ART facilities would need to prepare a minor procedure 
related to monitoring and removal of damaging processing material. 
Consultants estimate that most reproductive tissue facilities have 
procedures for in-process monitoring, and in these industries, an 
estimated 5 percent of reproductive tissue facilities would need to 
prepare procedures to address this activity.
    k. Section 1271.225--process changes. The proposed regulation would 
require establishments to institute process change procedures that will 
govern modifications to established operations. Changes to processes 
would be documented with the date of the change, the date of 
implementation, the rationale for the change, and appropriate approval 
signatures. The current standards for AATB, FAHCT and the AABB provide 
for SOP's for process changes, although recordkeeping procedures are 
not specified. Current EBAA standards do not provide for SOP's for 
process changes. FDA therefore estimates that nearly all eye banks 
would be required to prepare a major procedure for process changes, and 
would allocate an additional half hour of lab director time to document 
process changes.
    FDA anticipates that conventional tissue banks not following the 
AATB standard would need to prepare a major procedure related to 
process changes, and nearly all tissue banks would increase related 
recordkeeping. The agency estimates that small conventional tissue 
banks would spend an additional half hour per month of lab director 
time to document process changes, and large facilities would allocate 
an additional hour of lab director time for this. FDA anticipates that 
almost all stem cell facilities that do not follow FAHCT or AABB 
standards would need to prepare a major procedure to address process 
changes. In addition, FDA estimates that 95 percent of all stem cell 
facilities would allocate an additional half hour of laboratory 
director time to document process changes.
    According to industry contacts, most sperm banks already have 
established written procedures for process changes, and would therefore 
be in compliance with this proposed provision. FDA is also informed 
that ART facilities follow standards for process changes, but the 
procedures may not be in writing. In addition, industry consultants 
estimate that many reproductive tissue facilities may not keep written 
records of their process changes. Based on these characterizations, FDA 
estimates that approximately 5 percent of sperm banks and 90 percent of 
ART facilities would need to develop a written procedure for process 
changes. In addition, the agency estimates that 90 percent of sperm 
banks and ART facilities would need to allocate additional staff time 
(an estimated one half-hour per month at small facilities and one hour 
per month at large facilities) to record changes. The associated costs 
per facility are presented in table 2.
    l. Section 1271.230--process validation. The proposed rule would 
require facilities to validate processes that cannot be verified 
through subsequent inspection and testing. Current EBAA standards do 
not require process validation. Although current AATB, FAHCT, and AABB 
standards include provisions for process validation and related 
recordkeeping, industry experts indicate that additional validation 
work would be required at nearly all facilities under the proposed 
rule. FDA therefore estimates that 95 percent of all eye banks, of all 
conventional tissue banks and all stem cell facilities, not compliant 
with AABB or FAHCT, would need to prepare two major procedures related 
to process validation, and 95 percent of conventional tissue banks and 
AABB/FAHCT-compliant stem cell facilities

[[Page 1533]]

would need to revise two major procedures. FDA estimates that 95 
percent of all facilities in the tissue industry would devote 
additional staff time for process validation.
    In addition to the initial validation work, CGTP would require 
revalidation of procedures. The agency estimates that 95 percent of eye 
banks, conventional tissue banks and stem cell facilities would need to 
allocate an additional amount (on the order of 20 to 40 hours) of 
laboratory staff time for annual revalidation.
    Reproductive tissue industry consultants considered that the 
process validation requirement would have limited application to this 
industry because the tissues involved in laboratory processes (e.g., 
sperm and ova) are not uniform in quality. However, quality control 
through in-process monitoring (under Sec. 1271.220) would be applicable 
to these tissues.
    m. Section 1271.250--labeling controls: procedures. The proposed 
rule would require facilities to establish and maintain written 
procedures for controlling the labeling of products. The procedures 
would ensure proper identification of products and include various 
checks and verifications. Each product would also be accompanied by 
donor suitability information, if applicable. Other labeling 
requirements would also be met, such as labeling products appropriately 
with the required information.
    According to consultants and industry contacts, labeling controls 
are usual and customary practice in the industry. FDA anticipates that 
only about 5 percent of all facilities in eye banking, in conventional 
tissue banking, in stem cell processing and in the reproductive tissue 
industries would need to do additional work to comply with the proposed 
labeling controls. FDA estimates that such facility would need to 
revise a major procedure for proper identification of products.
    n. Section 1271.260--storage. The proposed rule would require that 
storage areas be controlled to prevent mix-ups and contamination. 
Temperature should be monitored and limits established, including 
expiration dating where appropriate. Each of the relevant industry 
standards contains provisions regarding storage practices. Based on 
agency review of current industry standards, and conversations with 
experts about current practices at facilities, FDA anticipates that 
virtually all facilities follow industry standards that would comply 
with this provision of the proposed CGTP. These provisions of the 
proposed rule are therefore expected to produce no new cost impact for 
facilities in eye banking, conventional tissue banking, stem cell 
processing, and reproductive tissue.
    o. Section 1271.265--receipt and distribution. The proposed rule 
would require that procedures be established and maintained for 
receiving, rejecting, distributing, and disposing of human cellular or 
tissue-based products. Documentation of each of those activities, when 
performed, would also be required. Packaging and shipping containers 
would be validated and appropriate shipping conditions must be defined. 
Procedures would also be established to determine whether products 
returned to an establishment are suitable to be returned to inventory. 
Agency review of current industry standards indicates that provisions 
related to this area of quality control, except for package validation, 
are included in each of the relevant standards.
    The primary impact of the proposed CGTP provisions for product 
receipt and distribution thus involves packaging validation for most 
facilities, and procedures development for facilities that do not 
currently follow industry standards. FDA estimates that 95 percent of 
eye banks, conventional tissue banks and stem cell facilities would 
allocate approximately 4 extra hours per month for a laboratory 
technician to validate packaging, particularly packaging changes. In 
addition, an estimated 5 percent of eye banks, conventional tissue 
banks, and stem cell facilities would increase lab supervisor time to 
document receipt of products.
    The agency estimates that conventional tissue banks not following 
AATB standards would need to revise one major procedure for receiving 
products, revise one major procedure related to distribution of 
products, and prepare a minor procedure for return of products to 
inventory. FDA estimates that 95 percent of stem cell facilities would 
need to write one major procedure addressing receiving activities. 
Facilities following FAHCT or AABB standards would also need to revise 
a major procedure for product distribution, while all other facilities 
would need to prepare a new major procedure for product distribution as 
well as a minor procedure for handling of products returned to 
inventory.
    According to industry contacts, most sperm banks and ART facilities 
have a protocol for receiving and distributing reproductive tissue 
products, however, an estimated 5 percent of facilities would need to 
write a major procedure for receiving activities and one for 
distribution. Similarly, an estimated 5 percent of facilities do not 
currently follow industry standards for product documentation. The 
agency estimates that an additional 4 to 8 hours of staff time per 
month would be required by those facilities, for documentation 
activities. Industry consultants indicate that although most 
reproductive tissue facilities utilize ``dry shippers'' for shipped 
products, most do not perform formal packaging validation. FDA 
therefore estimates that all facilities would be required to perform 
packaging validation, in compliance with the proposed CGTP. Experts in 
the reproductive tissue industry also consider it unusual for a product 
to be returned to inventory; given the potential risk of product 
deterioration or damage. It is expected that most sperm banks already 
have a formal procedure for handling returned product, and that ART 
facilities generally have an established protocol, but not a written 
procedure. The agency estimates that approximately 5 percent of sperm 
banks and 100 percent of ART facilities therefore would be required to 
write a minor procedure to comply with this proposed CGTP requirement. 
The costs per facility for these activities are presented in table 2.
    p. Section 1271.270--records. The proposed rule would require that 
records be maintained for any significant step in the manufacturing 
process. A records management system would need to be in place and 
procedures would need to be established for keeping records associated 
with donor suitability record keeping requirements. Records would be 
maintained for at least 10 years. The proposed rule would also require 
that records be kept of any contracts or agreements. Although many 
components of the required recordkeeping system are addressed under 
separate provisions of the proposed CGTP, there may be a few minor gaps 
in the records system of a facility that would be addressed under this 
general provision. FDA therefore estimates that approximately 95 
percent of all eye banks, conventional tissue banks, and stem cell 
facilities that follow FAHCT or AABB standards, would be required to 
write at least one minor procedure, and revise one major procedure 
related to recordkeeping.
    The agency also estimates that additional lab director time would 
be allocated (estimated 40 hours at small facilities and 80 at large 
facilities) to set up enhanced recordkeeping where a system is already 
in place. System enhancement would be performed at an estimated 95 
percent of eye banks, 23 percent of conventional tissue facilities,

[[Page 1534]]

95 percent of stem cell facilities, 5 percent of sperm banks, and 50 
percent of the ART facilities.
    Various industry standards specify record retention, although the 
time periods vary somewhat. Of those facilities following industry 
standards, approximately 95 percent of eye banks and the 77 percent of 
conventional tissue banks retain records for at least 10 years, and the 
remainder retain records for a minimum of 5 years. For these 
facilities, and the stem cell facilities that do not currently follow 
industry standards, FDA estimates increased record retention costs 
based on the cost of storing an additional 5 boxes (2.4 cubic feet 
each) of records per year for 5 years. The retention standards of FAHCT 
and AABB for records related to products are different from those 
concerned with facility and equipment maintenance and personnel 
training. All records related to the product should be retained 
indefinitely and records related to facility and equipment maintenance 
and personnel training should be retained for only 5 years.
    FDA estimates that a half of the records at stem cell facilities 
following industry standards would need to be retained for an 
additional 5 years, and the annual cost will be comparable to that of 
other small tissue facilities. The agency also estimates that nearly 
all stem cell facilities that are not following industry standards will 
increase record retention. Almost all stem cell facilities that do not 
follow industry standards would be required to prepare at least one 
minor procedure and to revise a major procedure related to record 
keeping. The laboratory director at these facilities would be expected 
to allocate 40 hours of time to improving the facility's current 
recordkeeping system.
    Consultants estimate that within the reproductive tissue industries 
all facilities have some record management system, and many facilities 
have systems that meet the requirements of the proposed rule. 
Consultants estimate that most sperm banks and the currently accredited 
ART facilities have adequate records management systems in place, but 
that approximately 5 percent of sperm banks, and about 50 percent of 
the ART facilities would need to allocate additional laboratory staff 
time (i.e., 40 hours at small facilities and 80 hours at larger 
facilities) to enhance their current recordkeeping system in compliance 
with the proposed rule.
    In addition, FDA is informed that the usual and customary practice 
in most ART facilities is to retain donor records for an indefinite 
period. Usual and customary practice in sperm banks is to retain 
records for at least 15 years, thus more than the 10-year period 
specified in the proposed rule. It is estimated that only 5 percent of 
sperm banks and ART facilities would need to extend record retention by 
an estimated 5 years. The additional cost of storing these files is 
based on an assumption of 5 boxes (each approximately 2 cubic feet) 
accumulated per year at small facilities, and 10 boxes per year at 
large facilities, for an additional 5 years, at a cost of 30 cents per 
cubic foot per year. The estimated costs per affected facility are 
summarized in table 2.
    q. Section 1271.290--tracking. The proposed rule stipulates the 
steps needed to properly track a product from donor to recipient and 
vice versa. The proposed CGTP would require that facilities maintain a 
method for product tracking and that each product be assigned and 
labeled with a unique identifier. If a new identifier is assigned 
during the manufacturing process, procedures would be required for 
relating the new identifier to the old identifier. Records of product 
transfers would be kept in the recipient's medical records. The 
facility that manufactured the product would also keep track of the 
disposition of each product, so that the recipient of the product can 
be easily identified. Facilities would be required to inform consignees 
of the established tracking method and would be required to document 
that consignees agreed to participate in their tracking method.
    Product ``traceability'' is a familiar concept and common practice 
in eye banking, in conventional tissue banking, and in the stem cell 
processing industry. Eye banks following EBAA standards maintain 
records with information that permits tracing of product from the donor 
source to the patient recipient, working through the surgeon who 
performed the procedure. FDA anticipates that only 5 percent of eye 
facilities would need to enhance current tracking, and would be 
required to prepare one major procedure related to product tracking, 
spend additional staff time each month to identify and document 
recipient information, and would allocate additional laboratory 
director time to institute agreements for information sharing with the 
consignees who will receive products.
    Conventional tissue facilities following AATB standards are able to 
trace all products from donation source to product recipient. 
Conventional tissue facilities not following AATB requirements would be 
required to revise a major procedure to address product tracking, 
allocate additional staff time each month to obtain and record 
information about product recipients, and allocate some additional 
laboratory director time (on a one-time basis) to institute formal 
contracts with consignees. The FAHCT and AABB standards for product 
tracking in stem cell facilities recommend that the facility be able to 
trace products to final distribution or disposition, but do not specify 
that formal agreements be established with consignees to assure timely 
tracking of products. FDA therefore estimates that 95 percent of stem 
cell facilities would, on a one-time basis, allocate an additional 20 
hours of laboratory supervisor time to institute agreements for 
information sharing with the consignees who will receive products. In 
addition, FDA estimates that 95 percent of stem cell facilities that 
are not following FAHCT or AABB standards would need to revise a major 
procedure related to product tracking, and would need to allocate 
additional staff hours each month for recipient identification and 
documentation.
    Consultants for the reproductive tissue industry indicate that 
although sperm banks and ART facilities generally perform product 
tracking and adhere to the practice of documenting recipient 
information for products, current practices in assigning and 
documenting products with unique identifiers throughout tissue 
processing may widely vary, and there may be little documentation of 
tracking agreements with consignees. Most reproductive tissue 
facilities therefore would need to review current systems and perform 
some enhancements. It is estimated that 80 percent of reproductive 
tissue facilities would need to revise a major procedure related to 
product tracking, and would allocate additional staff hours each month 
for recipient identification and documentation. In addition, 
approximately 80 percent of facilities would need to allocate lab 
supervisor time to institute agreements for information sharing with 
the consignees who will receive products. The estimated cost per 
facility to perform these activities are presented in table 2.
    Hospitals generally handle all categories of cellular and tissue-
based products. For accreditation by the Joint Commission on 
Accreditation of Healthcare Organizations (JCAHO), organizations that 
store tissue must keep records that permit tracing of any tissue from 
the donor or source facility to all recipients or other final 
dispositions. The records must include documentation of tissue use in 
the patient's clinical record. Most hospitals are accredited and, 
therefore, are presumed to be tracking tissue to recipient. We believe 
that hospitals not accredited tend to be specialized

[[Page 1535]]

facilities not handling cellular and tissue-based products. Because we 
know of no hospital receiving tissues and not currently tracking tissue 
to recipient, we expect hospitals to incur no additional costs as a 
result of this regulation. However, as some of our sources (Ref. 45) 
lack conclusive data on the adequacy of hospital recordkeeping, we 
welcome comment on this matter.
    The proposed rule would also require that specimens of dura mater 
be archived for the appropriate duration under appropriate conditions 
to enable future testing for evidence of TSE. FDA recommends that the 
specimens be archived for 16 years beyond the expiration date. As CDRH 
guidance already recommends that such specimens be archived for 10 
years, this requirement would not impose an additional tracking burden. 
FDA assumes the incremental cost of the longer storage time to be 
extremely small and the overall cost impact to be negligible.
    r. Section 1271.320--complaint file. The proposed rule would 
require facilities to maintain procedures for reviewing and evaluating 
complaints and to maintain a file for these complaints. Facilities 
would be required to review and evaluate complaints and to determine 
whether each complaint represents an event that should be reported to 
FDA. Documentation of the review and evaluation would be required, even 
if no investigation is made. FDA finds that the AATB, FAHCT, and AABB 
standards explicitly address procedures or recordkeeping related to 
complaints. Based on discussions with industry experts, the agency 
assumes that nearly all facilities currently track, albeit informally, 
the complaints received from consignees and recipients. Facilities that 
would be required to prepare written procedures for handling 
complaints, and to review complaints on a yearly basis, would incur 
additional costs. The agency estimates that additional costs for 
facilities to maintain a complaint file would be negligible.
    To fully comply with provisions in the proposed rule, FDA estimates 
that 95 percent of all eye banks would revise a minor procedure to 
include the required handling of complaints, and would allocate some 
additional staff time each year to review complaints. FDA assumes that 
conventional tissue facilities following AATB standards would already 
perform the necessary activities, but the estimated 23 percent of 
facilities not following AATB standards would need to prepare a minor 
procedure for complaint handling, and would allocate additional 
laboratory director time each year to review complaints that are 
received.
    Although the industry standards for stem cell processing provide 
that records be maintained of both donor and recipient complaints, the 
proposed rule requires that facilities also have written procedures for 
complaint review. FDA therefore estimates that 95 percent of all stem 
cell facilities would be required to write a minor procedure to handle 
complaints, and that 95 percent of all facilities would also be 
required to allocate additional time for yearly review and handling of 
complaints.
    Consultants assessing the impact of the proposed rule on the 
reproductive tissue industry estimate that about 95 percent of sperm 
banks and ART facilities already have written procedures for dealing 
with complaints, and that 5 percent of facilities would need to prepare 
a minor procedure for complaint handling, and would allocate additional 
laboratory director time each year to review complaints that are 
received. The estimated costs per affected facility are presented in 
table 2.
    s. Section 1271.350--reporting. The proposed rule would require 
facilities to review adverse reaction reports and report any adverse 
reactions, or product deviations, involving transmission of disease, or 
of the failure of a product that is fatal, life-threatening, results in 
permanent impairment of the body, or requires surgical intervention. 
Based on expert assessments of current industry practices, and the 
inclusion of adverse event reporting in current industry standards, the 
agency expects that this requirement, within the proposed CGTP 
framework for quality management, would impose a negligible cost on 
facilities in the industry.
    t. Section 1271.370--labeling and claims. The proposed rule would 
require that products be labeled clearly and accurately, with 
information including name and address of the manufacturer, a 
description of the product, and product expiration date. The storage 
temperature, warnings, and instructions would be required on the label 
or on a package insert. The rule would also require that any claims on 
labeling be truthful and that any therapeutic claim or claim of a 
clinical outcome of a product would be subject to regulation under 
section 351 of the PHS Act and/or the act.
    Industry consultants inform FDA that such elements are typically 
present on the labels of products manufactured by eye banks, 
conventional tissue banks, stem cell facilities, sperm banks and ART 
facilities. Proper labeling is considered very important to these 
industries, to prevent misuse of the product. In addition, these 
industries generally do not make therapeutic or related claims for 
their products. FDA assumes, therefore, that the industry would be in 
compliance with this provision of the proposed CGTP rule, and estimates 
that the cost impact would be negligible.
    u. Section 1271.400--inspections. FDA could conduct inspections of 
any facility subject to the proposed CGTP rule. FDA would interact 
primarily with one responsible person for each establishment, but other 
personnel may also be involved in the inspection. FDA could inspect 
facilities, equipment, processes, products, procedures, labeling, and 
records, and could review and copy any records required to be kept 
under the proposed rule. The agency estimates that all industry 
facilities would be subject to this provision of the proposed CGTP, and 
that inspections would occur annually. FDA estimates that up to 16 
hours of laboratory technician time could be necessary, to accompany 
the FDA inspector through the facility and to support the inspector's 
information needs, and that up to 4 hours of laboratory director time 
would be needed for activities related to the inspection. This is 
expected to yield a cost of approximately $702 per facility.
    v. Section 1271.420--human cellular and tissue-based products 
offered for import. The proposed rule would require importers of human 
cellular and tissue-based products to notify the FDA district director 
having jurisdiction over the port of entry through which the product is 
imported or offered for import. The product would be held intact until 
it is inspected and released by FDA.
    In the cellular and tissue-based product industries there is 
currently very little use of imported tissue that would trigger 
activities for facility compliance with this provision of the proposed 
CGTP. FDA therefore estimates the current cost for industry compliance 
with this proposed requirement would be negligible.
    w. Section 1271.440--orders of retention, recall, and cessation of 
manufacturing. Industry firms could incur costs to comply with orders 
under this proposed provision. There is little available data on which 
to base estimates of the future frequency and scope of tissue industry 
conditions and practices that would necessitate such actions on the 
part of FDA. The agency anticipates that product orders under this 
provision would be rare. FDA estimates that the yearly costs to

[[Page 1536]]

industry resulting from such orders would therefore be negligible.
    3. Summary of One-Time and Yearly Cost Impacts
    The costs for each subsection of the proposed rule are the product 
of the estimated number of affected establishments in the industry 
(table 1), the establishment noncompliance rate by CGTP provision, by 
industry sector, and the compliance cost per establishment (table 2). 
Total compliance costs, summed by provision of the proposed rule, are 
presented by sector in tables 4 through 8. The aggregate compliance 
costs for all tissue industries are summarized in table 9. The total 
annualized costs presented in these summary tables include the reported 
one-time costs, such as are incurred to prepare new procedures, 
annualized over 10 years using a 7 percent discount rate.

                               Table 4.--Aggregate Compliance Costs for Eye Banks
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment        $122,111                $457,459                $474,845
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and           $0                      $0                      $0
                         personnel
       1271.180         Procedures--Gene           $0                 $47,196                 $47,196
                         ral
                         requirements
       1271.190         Facilities             $1,701                      $0                    $242
       1271.195         Environmental              $0                 $23,245                 $23,245
                         control and
                         monitoring
       1271.200         Equipment                  $0                $109,816                $109,816
       1271.210         Supplies and          $10,776                 $17,545                 $19,079
                         reagents
       1271.220         Process Controls      $70,124                      $0                  $9,984
       1271.225         Process changes       $75,593                 $44,836                 $55,599
       1271.230         Process              $321,218                 $85,016                $130,750
                         validation
       1271.250         Labelling              $1,989                      $0                    $283
                         Controls--Proce
                         dures
       1271.260         Storage                    $0                      $0                      $0
       1271.265         Receipt and                $0                $145,008                $145,008
                         distribution
       1271.270         Records              $369,032                    $103                 $52,644
       1271.290         Tracking              $11,845                  $9,302                 $10,989
       1271.320         Complaint file        $10,776                 $59,782                 $61,316
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labelling and              $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                 $80,712                 $80,712
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                  $995,165              $1,080,020              $1,221,708
----------------------------------------------------------------------------------------------------------------


                     Table 5.--Aggregate Compliance Costs for Conventional Tissue Facilities
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment         $77,800                $137,655                $148,732
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and     $393,668                 $63,751                $119,801
                         personnel
       1271.180         Procedures--Gene           $0                $209,484                $209,484
                         ral
                         requirements
       1271.190         Facilities             $8,544                      $0                  $1,216
       1271.195         Environmental          $8,544                  $5,030                  $6,247
                         control and
                         monitoring
       1271.200         Equipment             $79,352                 $62,969                 $74,267
       1271.210         Supplies and          $17,088                  $5,030                  $7,463
                         reagents
       1271.220         Process Controls      $21,128                      $0                  $3,008
       1271.225         Process changes       $25,169                 $53,096                 $56,679
       1271.230         Process              $268,024                $164,065                $202,226
                         validation
       1271.250         Labelling              $2,736                      $0                    $390
                         Controls--Proce
                         dures
       1271.260         Storage                    $0                      $0                      $0
       1271.265         Receipt and           $33,713                $146,448                $151,248
                         distribution
       1271.270         Records              $172,967                    $455                 $25,082
       1271.290         Tracking              $47,498                $101,347                $108,110
       1271.320         Complaint file         $8,544                 $17,140                 $18,356

[[Page 1537]]

 
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labelling and              $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                 $77,880                 $77,880
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                $1,164,775              $1,044,350              $1,210,189
----------------------------------------------------------------------------------------------------------------


                          Table 6.--Aggregate Compliance Costs for Stem Cell Industries
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment        $188,166                $473,119                $499,909
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and     $739,100                $111,530                $216,761
                         personnel
       1271.180         Procedure--Gener           $0                $393,300                $393,300
                         al requirements
       1271.190         Facilities             77,983                $665,000                $676,103
       1271.195         Environmental         $77,983                $202,323                $213,426
                         control and
                         monitoring
       1271.200         Equipment            $387,080                $434,198                $489,309
       1271.210         Supplies and         $113,430                  $7,695                 $23,845
                         reagents
       1271.220         Process Controls     $260,336                      $0                 $37,066
       1271.225         Process changes       $33,155                $108,158                $112,878
       1271.230         Process              $625,670                $275,619                $364,700
                         validation
       1271.250         Labeling               $4,799                      $0                    $683
                         Controls--Proce
                         dures
       1271.260         Storage                    $0                      $0                      $0
       1271.265         Receipt and          $446,405                 $26,520                 $90,078
                         distribution
       1271.270         Records              $161,856                  $2,880                 $25,925
       1271.290         Tracking             $377,103                $155,040                $208,731
       1271.320         Complaint file        $77,983                $144,210                $155,313
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labeling and               $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                $194,700                $194,700
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                $3,571,049              $3,194,292              $3,702,727
----------------------------------------------------------------------------------------------------------------


                           Table 7.--Aggregate Compliance Costs for ART\1\ Facilities
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment        $272,904                $586,854                $625,709
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and     $256,740                 $25,358                 $61,912
                         personnel
       1271.180         Procedures--Gene           $0              $1,366,200              $1,366,200
                         ral
                         requirements
       1271.190         Facilities             $5,909                $621,600                $622,441
       1271.195         Environmental         $94,536                $146,342                $159,802
                         control and
                         monitoring
       1271.200         Equipment            $767,022                $583,549                $692,756
       1271.210         Supplies and          $94,536                  $3,596                 $17,056
                         reagents
       1271.220         Process Controls     $115,834                      $0                 $16,492
       1271.225         Process changes      $341,302                $165,434                $214,028
       1271.230         Process                    $0                      $0                      $0
                         validation
       1271.250         Labeling               $9,481                      $0                  $1,350
                         Controls-
                         Procedures
       1271.260         Storage                    $0                      $0                      $0

[[Page 1538]]

 
       1271.265         Receipt and          $335,612                 $36,230                 $84,014
                         distribution
       1271.270         Records              $612,720                    $400                 $87,637
       1271.290         Tracking             $516,010                      $0                 $73,468
       1271.320         Complaint file         $5,909                 $12,254                 $13,096
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labeling and               $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                $233,640                $233,640
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                $3,428,515              $3,781,457             $4,269,601
----------------------------------------------------------------------------------------------------------------
\1\Assisted Reproductive Technology


                              Table 8.--Aggregate Compliance Costs for Sperm Banks
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment         $12,105                 $23,661                 $25,384
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and      $15,560                  $2,348                  $4,563
                         personnel
       1271.180         Procedures-                $0                 $82,800                 $82,800
                         General
                         requirements
       1271.190         Facilities               $299                 $28,000                 $28,042
       1271.195         Environmental          $4,776                  $6,592                  $7,272
                         control and
                         monitoring
       1271.200         Equipment             $25,522                 $26,286                 $29,920
       1271.210         Supplies and             $299                    $162                    $204
                         reagents
       1271.220         Process Controls       $5,722                      $0                    $815
       1271.225         Process changes          $698                  $7,452                  $7,551
       1271.230         Process                    $0                      $0                      $0
                         validation
       1271.250         Labeling                 $349                      $0                     $50
                         Controls-
                         Procedures
       1271.260         Storage                    $0                      $0                      $0
       1271.265         Receipt and           $12,575                  $1,632                  $3,422
                         distribution
       1271.270         Records                $2,760                     $18                    $411
       1271.290         Tracking              $27,664                      $0                  $3,939
       1271.320         Complaint file           $299                    $552                    $594
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labeling and               $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                 $14,160                 $14,160
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                  $108,628                $193,663                $209,127
----------------------------------------------------------------------------------------------------------------


                    Table 9.--Summary of Aggregate Compliance Costs for All Tissue Industries
----------------------------------------------------------------------------------------------------------------
        Section               Title           One-Time Costs           Annual Costs       Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
       1271.150         Current good               $0                      $0                      $0
                         tissue
                         practice:
                         general
       1271.155         Exemptions and             $0                      $0                      $0
                         alternatives
       1271.160         Establishment        $673,085              $1,678,748              $1,774,580
                         and maintenance
                         of a quality
                         program
       1271.170         Organization and   $1,405,068                $202,987                $403,038
                         personnel
       1271.180         Procedures--Gene           $0              $2,098,980              $2,098,980
                         ral
                         requirements
       1271.190         Facilities            $94,435              $1,314,600              $1,328,046
       1271.195         Environmental        $185,839                $383,532                $409,991
                         control and
                         monitoring
       1271.200         Equipment          $1,258,976              $1,216,819              $1,396,069
       1271.210         Supplies and         $236,129                 $34,028                 $67,648
                         reagents

[[Page 1539]]

 
       1271.220         Process Controls     $473,145                      $0                 $67,365
       1271.225         Process changes      $475,917                $378,976                $446,735
       1271.230         Process            $1,214,911                $524,700                $697,675
                         validation
       1271.250         Labelling             $19,354                      $0                  $2,756
                         Controls--Proce
                         dures
       1271.260         Storage                    $0                      $0                      $0
       1271.265         Receipt and          $828,305                $355,838                $473,770
                         distribution
       1271.270         Records            $1,319,336                  $3,856                $191,700
       1271.290         Tracking              980,120                 265,690                 405,237
       1271.320         Complaint file       $103,510                $233,937                $248,675
       1271.350         Reporting                  $0                      $0                      $0
       1271.370         Labelling and              $0                      $0                      $0
                         claims
       1271.400         Inspections                $0                $601,092                $601,092
       1271.420         Human cellular             $0                      $0                      $0
                         and tissue-
                         based products
                         offered for
                         import
       1271.440         Orders of                  $0                      $0                      $0
                         retention,
                         recall,
                         destruction,
                         and cessation
                         of
                         manufacturing
      Total                                $9,268,130              $9,293,783             $10,613,357
----------------------------------------------------------------------------------------------------------------

B. Estimated Benefits of the Proposed Rule

    The overall purpose of the CGTP rule is to prevent the 
introduction, transmission, or spread of communicable disease through 
the use of human cellular and tissue-based products. Although industry 
quality standards exist for most of the affected products, not all 
members of the industry follow these standards. FDA finds that public 
safety cannot be assured or effectively protected through reliance on 
this less formal and voluntary mechanism for quality assurance. The 
existing industry standards vary to some extent in their 
comprehensiveness. Moreover, there are variations in the extent to 
which the industry follows these standards.
    For example, most industry consultants for the cost analysis agree 
that quality standards, such as those proposed by the FDA, and similar 
standards recommended by industry, could substantially reduce the risk 
of product contamination and product failure. However, most experts 
also opined that, because additional costs are associated with 
maintaining higher quality standards, and because there is no explicit 
patient demand for higher quality standards to prevent contamination 
risks, some facilities are not currently following adequate quality 
control standards. A regulatory requirement for quality systems would 
provide the incentive needed to bring all facilities to a more uniform 
and appropriately high standard of quality.
    The primary beneficiaries of the proposed CGTP rule would be the 
patients who receive the cellular and tissue-based products. Benefits 
to patients would result from the reduced risk of communicable disease 
by avoiding product contamination or product failure through CGTP. The 
discussion that follows considers the potential benefit of avoided 
problems with tissue products, based on a survey of the clinical 
literature.
    Recent clinical literature indicates that each type of tissue 
product considered in the proposed rule has documented contamination or 
other product problems resulting from processing, or other steps in 
manufacturing. These reported quality problems provide a basis for 
assessing the magnitude of the potential benefit from further reducing 
events that increase the risk of communicable disease transmission. In 
cases involving eye tissue, conventional tissue, or stem cell products, 
problems have required medical intervention to treat infection, or to 
replace an implanted defective product. In some clinical applications, 
product failures have increased the risk of patient mortality. In other 
applications, such as embryo processing, poor product quality is 
associated with lower success rates (i.e., pregnancy rates) among 
treated patients, which results in an increase in transfer attempts. In 
general, FDA anticipates that the risk of communicable disease 
transmission from product quality problems will decline as a result of 
compliance with the proposed CGTP.
    The sections that follow describe product-related problems 
associated with communicable disease transmission that are at least 
partly attributable to a lack of uniform quality standards in 
manufacturing. The costs related to correcting these problems are 
considered, in order to gauge the potential magnitude of the benefits 
associated with improved quality in manufacturing. The discussion is 
organized by types of tissue product.
1. Eye Tissue Products
    Primary corneal graft failure is a key adverse outcome of concern 
following corneal tissue transplant. Such failures result in additional 
graft attempts. Each attempt increases the risk of communicable disease 
transmission by exposing the recipient to another tissue product and to 
another surgical procedure. Although primary corneal graft failure is 
relatively uncommon, its occurrence has been attributed to several 
factors related to tissue collection, processing and product 
distribution. These factors include donor characteristics such as age 
(Ref. 3), donor infectivity (e.g., with Herpes Simplex Virus) (Ref. 4) 
length of product storage, storage medium, and shipping distance from 
the eye bank to the recipient site. In a recent analysis of factors 
contributing to primary corneal graft failure, Wilhelmus et al. found 
that ``[T]he duration of donor corneal preservation may have a 
significant effect on endothelial vitality,'' citing studies that 
demonstrate endothelial cell loss in chondroitin-supplemented storage 
media after 7 to 10 days of storage. The authors suggest that, with 
modern eye bank screening and preservation procedures, a donor corneal 
storage time greater than 1 week increases the risk of primary failure 
by more than twofold.
    Wilhelmus et al. include in their analysis a summary of selected 
findings of studies published between 1971 and

[[Page 1540]]

1994 reporting primary graft failure for corneal transplants using 4 
deg.C preservation, and using a variety of preservation methods. The 
rates of primary graft failure ranged from 0.9 to 3.1 percent, and a 
combined rate of 2.1 percent was estimated across all preservation 
methods. In their analysis of factors associated with corneal graft 
failures reported to the EBAA for 1991 to 1993, the findings of 
Wilhelmus et al. illustrate the importance of documentation of the 
receipt of supplies and reagents used in tissue processing. The authors 
found the identical manufacturer's lot number for the preservation 
medium among 2 media in 34 cases, among 3 media in 36 cases, and among 
4 media in 16 cases. Thus, 86 cases (approximately 59 percent of cases) 
with primary graft failure shared preservation media from the same 
lots. The lot number was unique in 45 cases (31 percent) and was not 
recorded in 16 cases (10 percent of cases) involving product failure. 
These findings also underline the importance of the proposed CGTP-
required verification of quality and documentation of each particular 
lot of processing media used in the manufacture of a uniquely labeled 
and traceable product.
    Primary corneal graft failure typically requires repeat surgery to 
replace the failed graft. According to the Agency for Health Care 
Policy Research (AHCPR)\3\ (Ref. 5), an estimated 7,443 corneal 
transplants were performed in 1994, with a mean hospital length of stay 
(LOS) of 2 days, and a mean total hospital charge equal to $7,530. The 
estimated rate of primary graft failure resulting from one or more 
aspects of product collection, processing, or distribution ranges from 
0.1 percent (the number of cases officially reported to EBAA for the 
period 1991 to 1993) to as much as 2.1 percent (combined failure rate 
reported in the literature, across the range of preservation media 
currently used in eye tissue processing, cited in Wilhelmus et al.). 
Based on the AHCPR-reported 1994 volume of corneal transplants, the 
estimated cases of primary graft failure may range from 7 cases [0.001 
x  7,443] to 156 cases [0.021  x  7,443]. The total cost of replacement 
of a failed corneal graft is estimated to include $454 of physician 
services, including an office visit to diagnose the graft failure prior 
to hospitalization\4\ (Ref. 6), and initial and follow-up physician 
visits during patient hospitalization\5\ (Ref. 6) for the repeated 
corneal transplant. It also includes one follow-up physician office 
visit to assess the outcome of the second transplant. The patient is 
estimated to further incur at least one week of time lost from work for 
the doctor visits, hospitalization and recovery of visual function 
after surgery. The cost of $772 for this patient time loss is estimated 
based on a 40-hour work week and average hourly compensation of 
$19.30.\6\ Thus, the current cost impact of corneal graft failure may 
range from $61,292 [7  x  ($7,530 + $454 + $772)] to $1,365,936 [156 
x  ($7,530 + $454 + $772)].
---------------------------------------------------------------------------

    \3\ These AHCPR estimates are based on data from the Healthcare 
Cost and Utilization Project (HCUP-3) National Inpatient Sample. 
This is a Federal-State-industry partnership to assemble health care 
data, based on a nationwide inpatient sample of hospital discharge 
records for 1994, from 20 percent of U.S. community hospitals from 
17 States. The HCUP-3 estimated hospital charges do not include 
physician payments.
    \4\ An estimated submitted charge of $76 per office visit for 
ophthalmology care is based on HFCA allowed payments for Medicare 
beneficiaries in the Health Care Financing Review 1997 Statistical 
Supplement Table 62, adjusted to estimate submitted charges.
    \5\ An estimated initial hospital visit charge of $214 and 
subsequent visit charge of $88, based on HFCA allowed payments for 
Medicare beneficiaries in the Health Care Financing Review 1997 
Statistical Supplement Table 62, adjusted to estimate submitted 
charges.
    \6\ This estimate is based on the 1994 average total 
compensation of $36,834 adjusted by 2.9 percent annual increase 
between 1994 and 1997, per the U.S. Statistical Abstract. ($36,834 
x  1,0293/2080) = $19.3
---------------------------------------------------------------------------

    These estimates provide an indication of the potential cost savings 
from avoided eye tissue product failures, based on corneal transplants. 
Tissue quality would improve through the institution of multiple good 
quality practices, including the validation of processing methods, the 
verification of processes quality control, and improved documentation. 
Since these events represent only one type of eye tissue product, the 
potential for benefit across all products in the eye tissue industry 
may be greater. The estimated benefits of CGTP applied to eye tissue, 
measured in terms of avoided corneal graft failures, therefore provide 
a lower-bound estimate of the potential benefits of the proposed rule. 
Based on just this one type of eye tissue product, the cost of graft 
failures that may be avoidable through a universal application of good 
tissue practices ranges from $61,292 per year, with the lower estimated 
failure rate, to $1,365,936 per year, based on the higher rate of 
primary graft failure reported in the clinical literature.
2. Conventional Tissue Products
    Conventional tissue includes a wide range of products including 
bone allograft, skin allograft, heart valves, and other products. FDA's 
survey of the clinical literature indicates that bone, skin and heart 
valve allograft each presents a different potential for product failure 
and thus different kinds of benefits from improved quality assurance in 
product manufacture. The discussion that follows considers three 
distinct areas of benefit.
    a. Bone allograft products. An analysis of the incidence, nature, 
and treatment of infection in bone allograft (Ref. 7) by Lord et al. 
demonstrates the importance of quality standards and process 
requirements to prevent tissue contamination. Of the 283 patients in 
their analysis who had received a massive allograft of bone, infection 
developed in 33 cases (11.7 percent). The final outcome for those 33 
patients was poor compared to the 250 uninfected patients. About 82 
percent (27 of the 33) of the infected allograft were considered 
failures of treatment because amputation or resection of the graft was 
required to control the infection. Potential sources of contamination 
cited in the study include donor infection or contamination introduced 
during processing (estimated to occur in as many as 7 percent of the 
grafts), in addition to factors such as the duration of the operation, 
loss of blood, injury to soft tissue, and skin sloughing during the 
operation. These risk factors highlight the critical need for tissue 
products that are both sterile and viable.
    The importance of processing validation is implied by Hardin (Ref. 
8) in a review of banked bone allograft processes. In describing 
methods for sterilization, Hardin lists ethylene oxide as one of the 
most commonly used chemicals, but indicates that its effectiveness may 
nonetheless be questionable, because of reports of graft failures in 
which residues of ethylene oxide have been blamed, and some 
experimental evidence indicating toxicity of ethylene oxide in human 
tissues.
    Based on an average rate of 0.057 for bone allograft failure due to 
contamination (based on an estimated allograft infection rate of 0.07 
and an estimated 0.82 failure rate for infected bone allograft), and 
the assumption that all failures would be treatable through repeat 
surgery to replace the bone graft, the associated costs could be on the 
order of $33 million per year [$33,069,348 = 0.057  x  39,000  x  
($13,538 + $1,338)]. This is based on a national estimate of 39,000 
bone allograft per year\7\ (Ref. 9), and an estimated $13,538 per 
hospitalization

[[Page 1541]]

for repeat surgery (AHCPR HCUP-3 NIS). Physician costs per 
hospitalization are estimated to be $1,338 including $135 for each of 
two specialty physician office visits: one prior to, and one following 
hospitalization\8\ (Ref. 6); and $1,068 for surgeon services while 
hospitalized, based on HCFA-reported average submitted charges per 
person served for orthopedic surgery\9\ (Ref. 6).
---------------------------------------------------------------------------

    \7\ Detailed Diagnoses and Procedures, National Hospital 
Discharge Survey 1995, Series 13: Data from the National Health 
Survey, No. 13, November 1997, table 4, p. 131.
    \8\ An estimated cost of $135 per service based on average 
submitted charges per service for ``All Other Physician'' specialty 
groups is used to estimate specialist office visit charges. This 
cost per service is reported in the Health Care Financing Review 
1997 Statistical Supplement Table 59.
    \9\ See Health Care Financing Review 1997 Statistical Supplement 
Table 59, Submitted Charges, for Orthopedic Surgery.
---------------------------------------------------------------------------

    The reported average length of stay for bone surgery is 
approximately 5 days. The estimated cost of patient time lost assumes 
that repeat surgery would require at least 1 week of time from work, at 
an estimated value of $772, based on a 40-hour work week and average 
hourly compensation of $19.30 (see footnote 6). This yields a total 
estimated patient time cost of $1,716,156 [0.057  x  39,000  x  $772]. 
The total annual cost of bone allograft failure due to contamination is 
therefore estimated to be nearly $35 million [$34,785,504 = $33,069,348 
+ $1,716,156].
    If bone allograft failures result in amputation, the direct and 
indirect costs would be significantly higher. For example, the cost per 
hospitalization for lower extremity amputation is estimated to be 
$24,178, based on the AHCPR HCUP-3 data. Moreover, permanent disability 
following amputation imposes extremely high costs on the patient, and 
on society.
    FDA is uncertain about the extent to which the estimated cost 
impact will be reduced through CGTP for two reasons. First, some tissue 
graft failures may result from the transplant procedures rather than 
the bone allograft manufacture. Second, some facilities may have 
already developed new bone processing methods that may greatly reduce 
infection risk. If as much as 75 to 80 percent of the estimated risk is 
actually attributable to other factors, or has already been addressed 
through better manufacturing procedures at many facilities, the net 
benefit from the proposed CGTP rule applied to the remainder of bone 
tissue processes and facilities would be approximately $8 million 
[$34,785,504  x  0.23] per year.
    b. Skin allograft products. Skin allograft represent another type 
of tissue product that is critically dependent on quality controls to 
prevent the manufacture and distribution of contaminated or defective 
products. The clinical literature reports cases of cytomegalovirus 
(CMV) transmission through skin donor infection (Ref. 10), and HIV 
contamination from infected donor tissue and subsequent skin tissue 
handling (Ref. 11). CMV infections are usually not life-threatening in 
healthy individuals, but present grave risks to the types of patients 
who typically require skin grafts. In general, patients who have 
suffered severe burns and require skin grafts are immunosuppressed as a 
result of their injury and are therefore susceptible to potentially 
life-threatening CMV infections. These include pneumonitis, retinitis, 
gastroenteritis, hepatitis, and neurological complications (Ref. 10). 
Contamination of skin allograft can significantly affect burn patient 
survival. Because the clinical literature does not provide summary 
estimates of the risk of contamination of skin allografts, the agency 
is unable to quantify overall risk. The agency welcomes comment on the 
rate and severity of skin tissue contamination.
    c. Heart valve allograft. Heart valve allograft, another 
conventional tissue product, provide another compelling case for 
process validation and quality control. Valve tissue contaminants not 
effectively removed in tissue processing have resulted in serious 
infections that, at minimum, require valve replacement and that may 
also result in patient death.
    Sources of contamination of a valve allograft include the donor, 
the environment during harvesting and processing, and the operating 
room during implantation. Microbial contamination of valve tissue is 
common at tissue harvesting, with reports of over 50 percent 
contamination among valves retrieved in open mortuary areas. According 
to a study by Kuehnert et al. (Ref. 12) common contaminants found 
before disinfection consist of gastrointestinal and skin flora, 
including coliforms, viridans group streptococci, Staphylococcus 
aureus, Staphylococcus epidermidis, and Bacillus species. In general, 
bacterial contamination can be effectively removed through standard 
disinfection procedures used in most tissue banks. However, tissue that 
remains contaminated with these pathogens, particularly Staphylococcus 
and Streptococcus species, can cause early onset allograft valve 
endocarditis. In contrast to bacterial contamination, reported rates of 
fungal contamination are relatively low. However, Kuehnert et al. 
report that rates vary widely (1.7 percent to 28.0 percent), and that 
the inclusion of anti-fungal drugs in the tissue disinfection regimen 
is not effective in eradicating fungal contamination.
    Fungal endocarditis is a rare but potentially fatal complication of 
allograft valve replacement. According to Kuehnert et al., the 
incidence of fungal endocarditis following surgery for heart valve 
replacement with allograft is estimated to range from 0.3 percent to 
1.4 percent (midpoint estimate of 0.0085). In one reported case, the 
infected patient needed subsequent surgery to replace the valve and 
required intravenous amphotericin B for the following 8 weeks. In many 
cases, treatment is not successful and death results. In one review, 
cited by Kuehnert et al., over 40 percent of the patients who had 
acquired fungal endocarditis after valve allograft implantation died 
within 2 weeks of diagnosis.
    In their study, Kuehnert et al. describe the process controls used 
by AATB-affiliated facilities, including the establishment, validation, 
and documentation of decontamination protocols. Because these regimens 
have not been found effective against fungal contamination, AATB-
affiliated facilities routinely discard tissue with documented fungal 
contamination. However, according to Kuehnert et al., the supplier of 
over 85 percent of all heart valve allograft does not follow AATB 
standards, but instead follows a decontamination protocol that is 
reported to be proprietary. This protocol apparently includes efforts 
to disinfect rather than discard tissue with fungal contamination. 
However, efforts to eradicate fungal contamination identified in 
processing can be unsuccessful, and in this case, a false-negative 
culture following processing resulted in the tissue being distributed 
for patient use.
    The proposed rule would require that all facilities validate the 
effectiveness of each step in processing, and would require that 
contaminated tissue that cannot be effectively disinfected be discarded 
or otherwise removed from processing for distribution. Based on the 
rates of infection and mortality risk reported by Kuehnert et al., and 
a total of 61,000 heart valve allografts reported per year by the 
National Hospital Discharge Survey (Ref. 13), there may be an estimated 
519 cases per year [0.0085  x  61,000] of heart valve contamination 
causing fungal endocarditis. These contaminated valves may further 
cause an estimated 207 deaths per year [0.0085 x 0.40 x 61,000]. 
Changes in processing based on the proposed CGTP requirements would 
help to avoid these deaths. Substantial health care cost

[[Page 1542]]

savings could also be achieved through improved processing controls. 
Based on an average cost of $63,096 per hospitalization for 
implantation of a heart valve allograft (Ref. 5), and estimated 
physician charges of $6,796 per case, including repeat surgery and 
patient care during the average 13-day hospital stay. If the CGTP 
requirements avoided 80 percent of these valve infections, this might 
result in health care cost savings of up to $29 million [0.8 x 519 x 
$63,096 + $6,796)].
3. Stem Cell Products
    According to the National Center for Health Statistics National 
Hospital Discharge Survey, approximately 8,000 stem cell transplant 
procedures were performed in 1994. Based on the AHCPR HCUP-3 NIS data 
for 1994 (Ref. 5), the average length of hospital stay for bone marrow 
transplant procedures was 35 days, with an average cost per stay of 
$168,573.
    Promising outcomes from use of peripheral blood stem cells (PBSC) 
and cord blood-derived stem cells (CBSC) in lieu of bone marrow have 
resulted in increased collection and use of these products in stem cell 
transplants. For example, recent studies have respectively reported use 
of PBSC (rather than bone marrow) in 54 percent (Ref. 14) and 62 
percent (Ref. 15) of cases. However, studies of stem cell products 
indicate that products manufactured by this industry can become 
contaminated during collection and processing. Moreover, the therapy-
induced immunosuppression of the oncology patients who receive these 
products places them at particular risk for serious infection and 
subsequent mortality. Manufacturing methods conforming to good tissue 
practice are necessary to prevent this threat to the safety and 
effectiveness of stem cell therapies. For example, earlier 
investigations of PBSC reported that the large quantity of blood that 
must be processed to obtain adequate numbers of stem cells resulted in 
large volumes of cryopreserved cells received by patients. This process 
posed the risk of increased toxicity, because of the amount of dimethyl 
sulfoxide used for cryopreservation (Ref. 16).
    Another quality concern with PBSC involves the maintenance of 
sterile integrity of the apheresis catheter and component throughout 
the period of leukopheresis, cryopreservation, thawing, and transfusion 
(Espinosa et al., 1996). Webb et al. (Ref. 14) reported a 2.41 percent 
rate of bacterial contamination in PBSC products, and a 13.7 percent 
rate of infection of patients receiving contaminated products.
    Although the bacteremia-induced fever and other clinical sequelae 
are considered reversible, infections present more serious risks in 
stem cell recipients than for the general population. Survival rates 
for hematopoietic stem cell transplantation are significantly reduced 
for patients that become critically ill. In a study of survival rates 
among stem cell recipients admitted to an intensive care unit, Price et 
al. (Ref. 15) found that patients with probable infection had a 
significantly higher death rate (57 percent) compared to patients with 
no probable infection (13 percent). Multiple regression analyses by 
Price et al., to predict probability of death controlling for other 
risk factors such as patient intubation, type of transplant, source of 
stem cells, human leukocyte antigen compatibility, type of malignancy 
and patient age, also found infection to be a significant predictor of 
mortality.
    An estimated 15 patients per year could suffer infection following 
receipt of contaminated PBSC, based on the reported rates of 2.4 
percent of patients receiving contaminated PBSC, 13.7 percent of those 
patients subsequently developing infection, and 8,000 stem cell 
transplants reported for 1994, and assuming that 58 percent of stem 
cell transplants (the average of the two reported rates of PBSC 
transplant cited above) involve PBSC. Costs of treating patients who 
become infected after receiving contaminated stem cell product are 
based on an average AHCPR-reported hospital charge\10\ (Ref. 5) of 
$17,981 per 9-day patient stay for treatment of bacterial infection. 
Estimated health care costs also include physician costs of $918 
assuming one initial hospital visit, and daily follow-up visits during 
the patient stay\11\ (Ref. 6). Patient time loss during the 
hospitalization is valued at $1,387, based on estimated hourly 
compensation of $19.30 (see footnote 4) and a 9-day hospital stay. 
Thus, the total annual cost impact of patient infection following 
transplant of contaminated PBSC products is estimated to be $304,290 
[15  x  ($17,981 + $918 + $1,387)].
---------------------------------------------------------------------------

    \10\ Based on AHCPR HCUP-3 National Inpatient Survey for 1994 
hospital charges by principal diagnosis, ``bacterial infection, 
unspecified site'' ($17,891), http://www.ahcpr.gov/data/94dcchpr.htm. 1998.
    \11\ Physician charges are based on estimates of physician 
submitted charges using data reported in the Health Care Financing 
Review Statistical Supplement, 1997, table 62. Initial inpatient 
visit charge is estimated to be $214, and daily follow-up visits in 
the hospital are estimated to be $88 per visit. Thus total physician 
charges for care during the 9-day hospital stay are estimated to be 
$918.
---------------------------------------------------------------------------

    In addition to avoided health care costs, eliminating the risk of 
contaminated products could yield a potential of seven avoided stem 
cell patient deaths per year, due to infection. This number reflects 
the excess mortality risk reported for stem cell recipients with 
infection versus those without infection. It is based on the following: 
(8,000 transplant procedures per year)  x  (58 percent of procedures 
with PBSC)  x  (2.41 percent PBSC patients receiving contaminated 
product)  x  (13.7 percent patients receiving contaminated product 
develop infection)  x  (57 percent to 13 percent) excess rate of death 
for stem cell recipients given presence of infection.
    As bacterial contamination has also been documented in a study of 
cord blood processing, the proposed CGTP requirements for staff 
training and process validation would support similar risk reduction 
efforts across CBSC facilities. For example, a study by Kogler et al. 
(Ref. 17) found that during the initial 6 months of an unrelated CB 
collection program, the median bacterial contamination rate was 18 
percent. After extensive training in sterile procedures for the staff 
who collect cord blood, the contamination rate was reduced to 1 
percent.
4. Reproductive Tissue Products
    Most aspects of cellular and tissue product manufacturing in the 
reproductive tissue industry would become newly regulated under the 
proposed CGTP rule. The affected establishments within this industry 
include sperm banks and ART facilities. Reports of the sensitivity of 
product quality to variations in tissue collection, technician skill, 
processing methods, environmental conditions, and other factors (Ref. 
22), indicate that the risk of communicable disease transmission would 
be reduced by improving the proposed overall product quality, and 
economic benefits would be seen through improved patient outcomes from 
facility compliance with the proposed CGTP requirements.
    The tissue used in commercial sperm banks is washed, processed, and 
cryopreserved donor sperm used for therapeutic donor insemination 
(TDI). The sperm are obtained generally from paid donors who have been 
screened and tested for infectious disease and certain genetic disease 
risks.
    The tissues used in ART facilities include fresh or cryopreserved 
oocytes, sperm, zygotes, and embryos. The handling of tissues include 
but are not limited to: Retrieval of oocytes from a

[[Page 1543]]

female, collection of sperm from a male, in vitro fertilization (IVF), 
cryopreservation of fertilized oocytes not transferred in the same 
treatment cycle, and thawing of frozen fertilized oocytes. The success 
of in vitro fertilization, measured as the number of deliveries per IVF 
cycle, has gradually increased over the past decade or so, from 11 
percent in 1985 to 18 percent in 1994 (Ref. 18). More recently, the 
Centers for Disease Control and Prevention (CDC) have reported average 
live birth pregnancy rates for ART clinics to be as high as 19.6 
percent per cycle in 1995 and 22.6 percent per cycle in 1996 (Refs. 19 
and 20).
    Despite the increasing effectiveness of infertility treatment 
through ART, problems can occur in tissue processing. Adverse outcomes 
owing to problems with product quality can result from contamination 
that produces infection (e.g., HIV transmission) in the infertility 
patient (Ref. 21). Problems with ART facility processing of sperm or 
oocytes can also lead to reduced rates of fertilization, and 
unsuccessful IVF attempts, which would ultimately increase the number 
of transfer attempts. Each additional transfer attempt increases the 
risk of communicable disease with each attempt.
    Where quality problems in tissue processing result in reduced 
embryo quality and lower probability of pregnancy, the patient, on 
average, needs to undergo more cycles of IVF to achieve a pregnancy 
that produces a live birth. The estimated patient cost per cycle ranges 
from $8,000 to $10,000 (Refs. 24 to 26).
    The number of Americans who would potentially benefit from improved 
reproductive tissue processing is substantial. According to the 1995 
National Survey of Family Growth (NSFG), (Ref. 28) 15.4 percent of 
American women 15 to 44 years of age, approximately 9.3 million women, 
have reported receiving infertility services. Approximately 600,000 
women report receiving ART's, defined in NSFG to include artificial 
insemination and IVF services. The number of ART procedures annually 
has been increasing in recent years. According to the CDC (Ref. 29) a 
total of over 64,000 cycles of ART were performed by U.S. facilities in 
1996, compared to approximately 60,000 cycles in 1995. The proposed 
CGTP rule, therefore, has the potential to benefit thousands of 
infertile couples.
    Processes that affect product quality. Recent clinical literature 
reports a number of factors in the manufacturing process that could 
affect tissue quality. These factors include technician skill, 
equipment accuracy and reliability, methods used in laboratory 
processing, and environmental controls affecting product quality. 
Following process validation and quality controls that would be 
required under the proposed rule is expected to substantially reduce or 
eliminate detrimental variations, and thereby improve product quality.
    Sperm processing occurs in both commercial sperm banks and ART 
facilities. Commercial sperm banks generally screen, wash, and 
cryopreserve donor sperm. ART facilities typically include an andrology 
laboratory that performs semen analysis and conducts IVF. Variations in 
methods and technician skills at various stages of sperm processing 
have been associated with variations in quality. Poor sperm quality 
increases the probability that additional tissue transfer procedures 
will be necessary. For example, in a study conducted to establish 
quality controls in semen analysis, Yeung et al. found that the 
subjective thresholds for judging sperm motility (a key measure of 
sperm function for diagnosis and treatment) differed for each 
technician performing the analysis (Ref. 30). The establishment of 
values for threshold velocities, and standards for technician training 
were identified as methods to improve consistency in technician 
assessments.
    A study by Mahmoud et al. (Ref. 31) compared 10 different methods 
for estimation of sperm concentration (another key indicator of sperm 
quality) and reported substantial differences in the accuracy of 
laboratory assessments, depending upon the type of pipette and the 
method used. They found that although a few devices and methods 
produced accurate, low-variability estimates, others had a tendency to 
overestimate or to underestimate sperm concentration. These findings 
strongly support the need for equipment calibration and laboratory 
method validation.
    In addition to processing steps related to the sperm quantity and 
quality, sperm processing for IVF typically requires that sperm be 
purified, removing semen fluid, cellular debris, white blood cells, and 
other contaminants that may interfere with fertilization. Many sperm 
separation methods have been developed and are in use in ART programs, 
including basic sperm washing, swim-down and swim-up techniques, 
refrigeration/heparin techniques, separation with Sephadex and Ficoll 
columns, separation with glass wool and Percoll gradient centrifugation 
(Refs. 32 to 34). No single method has become the standard, although 
some approaches may be more effective than others in preserving 
functional integrity. For example, when King et al. (Ref. 35) compared 
the effect of different antibiotics used in sperm washing, they found 
that some agents produced severe adverse effects on sperm motility and 
actually decreased sperm fertilizing capacity. The importance of 
product quality in this step of processing offers another example of 
the value of process validation in ensuring sperm product viability and 
thus successful fertility treatment for patients.
    Environmental controls present another area with a demonstrated 
need for quality control in reproductive tissue processing. 
Environmental contamination may come from many sources, including the 
air, water or laboratory supplies. A study of laboratory air quality in 
ART facilities by Cohen et al. (Ref. 36) found that over 300 volatile 
organic compounds were detectable in spite of the use of centralized 
high efficiency particulate air (HEPA) filtration, generic but 
centralized carbon and pre-filtration, and numerous ionization units 
placed at strategic points in the laboratory. Potential sources of 
contaminants included vehicle and industrial emissions in outside air, 
use of plastics and disposable plasticware in the laboratory, equipment 
(e.g., freon leakage from refrigeration units), cleaning agents and 
equipment lubricants, and air flows from activities in adjacent areas 
of the building.
    A more detailed study of these factors by Cohen et al. was prompted 
in part by the sudden and significant declines in clinical pregnancy 
and implantation rates that occurred at two points in time at an ART 
facility. In those instances, the pregnancy rate had declined by about 
50 percent and subsequent implantation rates also declined. Their 
investigation revealed that, in the first instance of decline, a 
fumigation with pesticides had taken place in areas of the building 
adjacent to the ART facility, without notification given to the ART 
facility. The second episode of sudden decline corresponded to the 
installation of a redesigned air filter in the facility. Further air 
sampling also revealed that chemical contaminants produced in another 
area of the building, which was used as an outpatient surgery center 
and was not part of the ART clinic, could be detected in the embryo 
laboratory when more sensitive monitoring equipment was used. Cohen et 
al. proposed various measures to counter these potential sources of 
chemical air contamination in both the laboratory and the embryo

[[Page 1544]]

incubators. Laboratories without adequate environmental monitoring and 
controls would not be able to detect such degradations in air quality.
    An earlier study of mouse embryos by Francis et al. reported that 
some brands of nonpowdered surgical gloves appear to be embryotoxic 
(Ref. 37). Temperature fluctuations during cell culture, and to a 
lesser extent, the time between retrieval and transfer, may also affect 
tissue quality and thus increase the probability of additional transfer 
attempts (Ref. 39).
    The lack of experience and training of laboratory personnel also 
could increase the need for additional transfer attempts due to poor 
tissue quality. One study found that new embryologists needed several 
months to gain the experience to consistently predict nuclear maturity 
from cumulus-coronal morphology. Moreover, even when a stable 
prediction rate was reached, it rarely exceeded 72 percent accuracy 
(Ref. 40). Yet consistent assessments of product quality and transfer 
of high quality embryos to the patient are critical to increasing the 
overall success of IVF treatment and to minimizing transfer attempts.
    Although there has been some Federal and some private sector 
standard setting and oversight in the reproductive tissue industry, 
existing standards do not provide the level of quality management and 
process quality assurance that would be required under the proposed 
CGTP rule for all tissue establishments. A voluntary accreditation 
program jointly offered by the CAP and the ASRM has been available to 
ART laboratories since 1992 (Refs. 41 and 42), and the number of 
facilities seeking accreditation has been increasing in recent years. 
The problems with product processing cited in recent clinical 
literature, however, suggest that although there is increasing interest 
in quality assurance, there are still substantial gains that could be 
made in tissue facilities, by implementing the proposed CGTP rule.
    In addition to the benefits that would accrue directly from 
implementation of this proposed rule, individuals may reap ancillary 
benefits that could arise indirectly from the rule. Although the 
proposed rule would provide a direct benefit from the decreased risk of 
communicable disease transmission, the public, particularly couples 
seeking assistance in beginning a pregnancy, could receive an indirect 
economic benefit. Such ancillary economic benefit, although not 
certain, would be seen as an increase in ART facility success rates and 
a decrease in health costs associated with a reduction in the number of 
IVF attempts per live birth.
    FDA cannot predict the precise impact from implementation of the 
proposed CGTP rule. To obtain an estimate of benefits and to capture a 
level of uncertainty, this analysis considers three potential scenarios 
and presents the results a range of possible outcomes. In general, it 
is assumed that the rule will affect the facilities with the lowest 
success rates and that these facilities would improve to some minimal 
level of performance from the implementation of good practices. In one 
scenario, benefits are assumed to be limited to the worst-performing 
quarter of all facilities. These facilities would improve to the level 
of the facility just better than the bottom one-fourth. In another 
scenario, the half of all facilities with the lowest success rates 
would improve to where they would be as good as the median facility. In 
a third scenario, implementation of the rule would not change ART 
facility success rates.
    The scenarios consider only the cycles of treatment for younger 
women (age less than 35) for whom patient age is not likely to be a 
confounding factor affecting oocyte quality. Of the 22,811 fresh 
nondonor cycles of treatment for these patients at the 300 ART 
facilities reporting data for 1996, the average success rate was 28.65 
live births per 100 cycles, and the median live birth pregnancy rate 
was 26.3 percent per cycle.
    Scenario 1 assumes that the facilities currently achieving the 
lowest success rates (i.e., the lowest quartile of success rates 
reported for ART establishments) are able to increase their average 
success rate to the rate corresponding to the 25th percentile rate. 
This would represent a first step and as technology and techniques 
continue to improve, so would success rates. In the 1996 report, the 
25th percentile rate was 19.7 live births per 100 cycles. FDA finds 
that raising the bottom quartile of 75 facilities, to 19.7 live births 
per 100 cycles, would reduce the IVF attempts from a reported 4,756 to 
an estimated 3,591 treatment cycles. This improvement would decrease 
transfer attempts and yield an estimated savings of $10.5 million for 
patients and other payers, based on an estimated average cost of $9,000 
per cycle, and an estimated 1,165 avoided cycles [4,756-3,591].
    Scenario 2 assumes that facilities in the lower half of the 
industry distribution are able to bring their success rates up to the 
median rate of 26.3 live births per 100 cycles. The increased success 
rate is assumed to be achieved through improvement in staff training 
and skill, processing validation, and quality control throughout the 
facility in accordance with the proposed CGTP rule. Under this 
scenario, the affected 150 facilities would reduce the number of IVF 
attempts from a reported 10,414 cycles to an estimated 7,662 treatment 
cycles, to achieve the same number of successful treatments. This would 
yield an estimated cost savings of $24.8 million for patients and other 
payers. This is based on an estimated 2,752 avoided cycles of treatment 
[10,414-7,662] and assumed average cost of $9,000 per cycle of IVF 
treatment.
    At the other end of the spectrum, Scenario 3 provides for the 
possibility that this proposed rule would have no effect on success 
rates at ART facilities or the number of IVF attempts per live birth. 
In such a case, there would be no additional economic benefit beyond 
the benefits previously discussed, including an anticipated decrease in 
communicable disease transmission.
    Couples seeking infertility care incur an indirect cost of time 
lost (e.g., work time) while undergoing treatment. Using an average 
hourly wage of $19.30\12\ and assuming 6 hours of time (e.g., 4 hours 
for the female and 2 hours for the male patient) per couple per cycle 
of IVF treatment, the estimated value of the lost time would be as 
follows. Under Scenario 1, the estimated 1,665 avoided treatment cycles 
would yield a time gain valued at $192,807 [1,665  x  $19.30  x  6]. 
Under Scenario 2, the 2,752 potentially avoided treatment cycles would 
yield a time gain valued at $318,682 [2,752  x  $19.30  x  6]. Under 
Scenario 3, there would be no avoided treatment cycles and, thus, no 
quantifiable benefits.
---------------------------------------------------------------------------

    \12\ Estimated hourly compensation of $19.30 is based on the 
1994 average total compensation of $36,834, adjusted by 2.9 percent 
annual increase reported in the 1997 U.S. Statistical Abstract.
---------------------------------------------------------------------------

C. Summary of Potential Benefits Resulting From Avoided Quality 
Problems in Processing of Cellular and Tissue Based Products

    This analysis of benefits of the proposed CGTP rule has considered 
its impact on major sectors of the tissue industry by focusing on 
product quality problems cited in the literature. This review suggests 
that industry standards are not applied uniformly resulting in uneven 
product quality.
    Table 10 provides a summary of the particular products and problems 
identified in the agency's survey of literature. FDA estimated the 
potential benefits of avoiding quality problems based on reported risks 
and national

[[Page 1545]]

data-based estimates of the number of patients undergoing related 
procedures. Depending on the particular industry sector, the potential 
quantified benefits from reduced health care costs are estimated to 
range from approximately $61,000 per year, to approximately $33.5 
million per year. The total estimated potential quantified benefits 
range from a total of $41.9 million to $68.0 million. The actual level 
of benefits that would be realized through wide application of CGTP is 
uncertain, however, as the agency's projections are sensitive to 
numerous assumptions that appear plausible, but remain to be tested.

Table 10.--Summary of Potential Benefits of Proposed Current Good Tissue Practice Based on Tissue Problems Cited
                                             in Reviewed Literature
----------------------------------------------------------------------------------------------------------------
   Tissue Industry                            Avoided Problems with   Avoided Treatment or     Potential Cost
        Sector          Tissue(s) Considered          Tissue                Outcome             Savings/Year
----------------------------------------------------------------------------------------------------------------
Eye Tissue             corneal graft          graft failure          repeat surgery;        $61,000 to $1.4
                                                                      increased graft        million
                                                                      attempts
Conventional Tissue    bone allograft         bone infection; graft  repeat surgery/        $8 million
                                               failure                amputation;
                                                                      increased graft
                                                                      attempts
Conventional Tissue    heart valve allograft  fungal endocarditis    repeat surgery/        $29.6 million
                                                                      patient death;        176 excess deaths
                                                                      increased transplant
                                                                      attempts
Peripheral Blood and   stem cell transplant   infection in cancer    hospitalization/       $304,000
 Cord Blood Stem                               patients               patient death         7 excess deaths
 Cells
Reproductive Tissue    sperm, oocytes,        IVF\1\ failure         additional IVF         $0 to 24.8 million
                        zygotes, embryos                              treatment cycles
Total Potential Cost                                                                        $41.9 to $68.0
 Savings/Year                                                                                million
----------------------------------------------------------------------------------------------------------------
\1\ In vitro fertilization

    Uncertainties affecting the true level of benefit include: The 
actual extent of current CGTP compliance in each of the affected 
industries, the lack of more complete information about the incidence 
and severity of problems from processing of tissue products, the net 
impact of those quality problems on patient outcomes, and the size of 
the affected patient population. Because of the limits of available 
data, the foregoing analysis has focused on a limited set of tissue 
products. It is not certain how well these data represent the most 
critical areas or actual scale of risks in the tissue industry. For 
some products, such as demineralized bone, the industry has achieved 
important advances in processing that have improved the safety and 
effectiveness of its products. Thus, the analysis of benefits based on 
problem reports from several years ago may overstate the potential for 
improvements in the current best industry practice. In other cases, the 
publication of the recent problem reports suggests that deficiencies 
still exist within current practices. These areas present important 
opportunities to avoid unnecessary patient risks and health care costs.

D. Small Entity Impacts

    The Regulatory Flexibility Act (RFA) requires agencies to determine 
whether a proposed rule may have a significant effect on a substantial 
number of small entities. Tissue and blood banks are classified in 
North American Industry Classification System (NAICS) 621991. In this 
industry category, any firm with annual revenues less than $5.0 million 
is considered small by the U.S. Small Business Administration. In every 
sector of the cell and tissue product industry, the majority of 
establishments are estimated to be classified as small entities. 
However, because of the high level of current compliance with industry 
standards, the increase in costs is expected to be limited primarily to 
facilities that do not comply with industry standards. To measure the 
impact of CGTP on small businesses, FDA calculated the ratio of 
industry compliance costs to industry revenues, assuming that all 
facilities incurred the same cost. The small entity impacts estimated 
below focus on the facilities that will be newly compliant under the 
proposed CGTP, and thus will experience the highest potential new 
costs. In addition, although current quality management practices at 
non-accredited or less-than-fully compliant facilities may vary, and 
not every facility will incur every new cost estimated in table 2, the 
analysis that follows considers a high-cost scenario where every 
estimated cost is incurred, in order to produce a conservative estimate 
of the potential impact on small entities. While some firms may have 
lower than average revenues, making them potentially more sensitive to 
cost increases, FDA does not know the distribution of firms by 
revenues. FDA welcomes comments on this issue.
    Within the eye banking industry, experts estimate that virtually 
all facilities would be classified as small, and believe all are to be 
compliant with the industry EBAA standards. The average annual revenue 
per eye bank is estimated at $1.2 million (Ref. 44). If an eye bank 
were to incur every new cost estimated for facilities in that industry, 
the total cost impact, including total one-time costs and the yearly 
cost, would be $36,738, which represents an estimated 3 percent (0.03) 
of estimated annual revenues. Average annualized compliance costs per 
eye bank are estimated to be $10,717, or 0.89 percent of annual revenue 
per firm.
    In the conventional tissue industry, an estimated 75 to 80 percent 
of the total of 110 facilities would be classified as small entities. 
Industry experts also estimate that 75 to 80 percent of those 
facilities currently comply with the AATB standards, which generally 
meet or exceed the requirements of the proposed CGTP rule. Based on the 
assumed levels of increased effort and costs shown in table 2, the 
remaining 23 percent of small facilities that do not comply with AATB 
standards would incur up to $62,662 in total new costs, including both 
the total one-time cost and the yearly cost, assuming that every 
potential area of new quality management effort would be needed at 
every one of these facilities. The average annual revenue per small 
conventional tissue bank is estimated at $1.2 million (Ref. 44). The 
estimated total new costs would represent approximately 5 percent of 
this annual revenue figure. The average annualized compliance cost for 
a small conventional tissue bank is estimated to be $10,310, 
representing 0.86 percent of firm revenues.

[[Page 1546]]

    The agency anticipates that all stem cell facilities would be 
classified as small entities, and estimates that these establishments 
have annual revenue averaging $1.2 million (Ref. 44). Establishments 
that comply with the current FAHCT or AABB standards would incur some 
additional costs. If each of these facilities were to incur new costs 
for every provision identified in table 2, the total cost per facility, 
including total one-time and yearly costs, would be approximately 
$20,270. This figure represents approximately 2 percent of estimated 
annual revenues. Stem cell facilities that do not currently comply with 
AABB or FAHCT standards would incur greater costs, as shown in table 2. 
If each of these facilities were assumed to incur every new cost 
identified in the cost analysis, the total one-time cost plus annual 
cost would be approximately $79,337. This figure is equal to 
approximately 7 percent of estimated annual revenues. The average 
annualized compliance costs incurred by stem cell facilities would 
similarly vary depending on current facility practices and compliance 
with AABB or FAHCT standards. If a facility is currently compliant with 
these industry standards, the average annualized cost of compliance 
with the proposed rule is estimated to be about $7,407, representing 
0.62 percent of the yearly revenue of these firms. However, if a 
facility is not currently compliant with the requirements of the 
current industry standards, a greater level of new effort would be 
required for quality assurance and quality management. The average 
annualized cost per facility is estimated to be $40,721, which would 
represent 3.39 percent of an average annual revenue of $1.2 million.
    Consultants estimate that approximately two-thirds of all ART 
facilities (approximately 200) would be classified as small entities, 
and have average annual revenues of $2.5 million. Based on the project 
levels of compliance with various provisions of CGTP, as described in 
the cost analysis, if a facility were to incur every potential new 
cost, as shown in table 2, the total one-time plus annual cost to the 
facility would be $83,302. This total would represent approximately 3 
percent of average annual revenues. The average annualized compliance 
cost per facility is estimated to be $11,342, representing 
approximately 0.45 percent of annual revenues.
    According to recent estimates by a sperm banking industry expert, 
approximately 100,000 TDI units are produced each year from collected 
and processed sperm donations. An estimated 95 percent of that total 
production is handled by the largest 20 facilities. Nineteen of the 
largest 20 facilities are estimated to have average annual revenues of 
approximately $2 million, and only 1 of the 20 is estimated to have 
revenues greater than $5 million per year. The remaining 5 percent of 
industry production, or 5,000 TDI units, are processed by very small 
banks described by an industry expert as typically functioning within a 
physician office practice (e.g., that of an obstetrician (ob) or a 
gynecologist (gyn)). The sperm banking in these facilities is generally 
offered as an additional service to patients receiving fertility 
treatment, and is not the primary line of business of these 
establishments. The annual revenue for these individual physician 
practices is estimated to be $252,000 per year, based on the mean 
physician income of $215,000 after expenses and before taxes for the 
ob/gyn specialty category, reported in the 1992 American Medical 
Association (AMA) survey (Ref. 45), adjusted to 1998 assuming an 
average annual wage inflation of 2.7 percent, based on yearly rates 
reported by the Bureau of Labor Statistics. Thus the majority of sperm 
banks would be considered small entities.
    If each of the small sperm banks were to incur every potential new 
cost of compliance with the proposed CGTP rule, as shown in table 2, 
the total one-time cost plus annual cost would equal $83,302, which 
would be approximately 4 percent of the $2 million in annual revenues 
for the ``larger'' small facilities. The average annualized cost to 
these banks is estimated to be $11,007, representing approximately 0.55 
percent of annual revenues. Although these cost figures would account 
for a much larger percentage of individual physician practice income, 
the sperm banking provided by these establishments is considered to 
represent a small and generally nonessential part of their business. 
For the smallest banks, the estimated 5,000 TDI units supplied by the 
estimated 90 facilities translates to an average volume of 55 units per 
facility per year. With an estimated price of $95 to $145 per TDI unit 
(Ref. 46) and an estimated profit of 15 percent, the banks would 
realize a net income of $12.40 to $19.00 per unit, or average net 
income of $682 to $1,045 for 55 units. This income would represent only 
0.3 percent (0.0027) to 0.4 percent (0.0041) of the estimated $252,000 
in annual net income for the ob/gyn physician practice. Thus, it seems 
likely that physician practices that currently operate small-scale 
sperm banking may prefer to discontinue banking, and refer their 
patients to a commercial bank for this service.
    In summary, the majority of facilities within each sector of the 
tissue industry are expected to qualify as small entities. The actual 
cost impact on each facility is uncertain because of the limited 
information available to describe the current practices and compliance 
with industry standards at each of these facilities and within each 
distinct industry sector. Based on the limited available data and 
expert opinions, the agency estimates impacts that would result in an 
average annualized cost per facility ranging from $ 7,000 to $11,000 
for facilities that currently comply with an industry standard, to over 
$40,000 in average annualized costs for facilities that do not 
currently comply with most industry quality standards. These annualized 
costs represent 0.45 to 3.39 percent of the estimated total average 
annual revenues.
    The agency is uncertain about the accuracy of these estimates, 
however, because of the lack of good data on revenues for these 
facilities. Because of the importance of this information in accurately 
assessing the impact on small entities, the agency requests that 
industry provide detailed comment on the percentage of facilities that 
qualify as small entities in the eye tissue, conventional tissue, stem 
cell, and reproductive tissue industries; the percentage of those 
facilities that fully comply with current industry standards; and the 
specific areas where industry anticipates substantial differences 
between current manufacturing practices and the quality assurance 
elements specified under the proposed rule. For those areas of 
identified difference, the agency further requests estimates of the 
resources and costs that will be required for facility compliance.
    Although the proposed rule would impose some costs on small 
entities involved in the manufacture of cellular and tissue-based 
products, the agency believes that the proposed approach represents an 
effective means of protecting patient safety and public health in the 
manufacture of human cellular and tissue-based products. The less 
burdensome alternative to the proposed approach, i.e., continue with 
the use of trade organizational standards by industry, involve fewer 
requirements for small entities (the vast majority of facilities in 
this industry), but fail to provide fundamental aspects of product 
safety. Reliance on trade organization voluntary standards for good 
tissue practice, rather than establishing a regulatory requirement, 
would not ensure uniform or consistent

[[Page 1547]]

compliance and would preclude the agency's ability to effectively 
monitor tissue products to ensure public health and safety. While each 
trade organization varies in their standards or guidelines, regulatory 
requirements for good tissue practice would help ensure consistency 
among manufacturers. FDA finds that this proposed rulemaking would 
enhance both public health and public confidence in the safety and 
quality of cellular and tissue-based products, while imposing only a 
minimum burden on the affected industry sectors.

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. Centers for Disease Control and Prevention, ``Creutzfeldt-
Jakob Disease Associated with Cadaveric Dura Mater Grafts--Japan, 
January 1979-May 1996,'' Morbidity and Mortality Weekly Report; vol. 
46; pp. 1066-1069, 1997.
    2. General Accounting Office, ``Human Tissue Banks; FDA Taking 
Steps to Improve Safety, but Some Concerns Remain,'' December 1997.
    3. Wilhelmus, K. R., R. D. Stulting, J. Sugar, and M. M. Khan, 
``Primary Corneal Graft Failure,'' Archives of Ophthalmology, vol. 
113, pp. 1497-1502, December 1995.
    4. Remeijer, L., P. Doornenbal, A. J. M. Geerards, W. A. 
Rijneveld, and W. H. Beekhuis, ``Newly Acquired Herpes Simplex Virus 
Keratitis After Penetrating Keratoplasty,'' Ophthamology, vol. 104, 
No. 4, pp. 648-652, April 1997.
    5. Statistics From the HCUP-3 Nationwide Inpatient Sample for 
1994: Principal Procedures, http://www.ahcpr.gov/data/94pcchpr.htm, 
current as of September 1997, AHCPR Pub. No. 97-0057.
    6. Health Care Finance Review 1997 Statistical Supplement, U.S. 
Department of Health and Human Services, Health Care Financing 
Administration, Office of Research and Demonstrations, Baltimore, 
MD, November 1997.
    7. Lord, C. F., M. C. Gebhardt, W. W. Tomford, and H. J. Mankin, 
``Infection in Bone Allograft: Incidence, Nature and Treatment,'' 
The Journal of Bone and Joint Surgery, vol. 70-A, No. 3, pp. 369-
376, March 1988.
    8. Hardin, C. K., ``Banked Bone,'' Otolaryngologic Clinics of 
North America, vol. 27, No. 5, pp. 911-925, October 1994.
    9. Vital and Health Statistics, Detailed Diagnoses and 
Procedures, National Hospital Discharge Survey, 1995, U.S. 
Department of Health and Human Services, Centers for Disease Control 
and Prevention, National Center for Health Statistics, Series 13, 
No. 130, PHS-98-1791, November 1997.
    10. Abecassis, M. M., ``Transmission of Cytomegalovirus by Skin 
Allograft,'' Tissue and Cell Report, vol. 2, No. 1, pp. 14-17, 1995.
    11. Gala, J., A. Vandenbroucke, B. Vandercam, J. Pirnay, N. 
Delferriere, and G. Burronboy, ``Human Immunodeficiency Virus in 
Fresh or Cryopreserved Postmortem Skin: Potential Implications for 
Skin Handling and Allografting,'' Journal of Clinical Pathology, 
vol. 50, pp. 481-484, 1997.
    12. Kuehnert, M. J., E. Clark, S. R. Lockhart, D. R. Soll, J. 
Chia, and W. R. Jarvis, ``Candida Albicans Endocarditis Associated 
with a Contaminated Aortic Valve Allograft: Implications for 
Regulation of Allograft Processing,'' Clinical Infectious Diseases, 
vol. 27, pp. 688-91, October 1998.
    13. National Center for Health Statistics, Detailed Diagnosis 
and Procedures, National Hospital Discharge Survey (ICD-9-CM 35.2) 
Series 13: Data from the National Health Survey No. 130, November 
1997.
    14. Webb, I. J., F. S. Coral, J. W. Andersen, A. D. Elias, R. W. 
Finberg, L. M. Nadler, J. Ritz, and K. C. Anderson, ``Sources and 
Sequelae of Bacterial Contamination of Hematopoietic Stem Cell 
Components: Implications for the Safety of Hematotherapy and Graft 
Engineering,'' Transfusion, vol. 36, pp. 782-788, 1996.
    15. Price, K. J., P. F. Thall, S. K. Kish, V. R. Shannon, and B. 
S. Andersson, ``Prognostic Indicators for Blood and Marrow 
Transplant Patients Admitted to an Intensive Care Unit,'' American 
Journal of Respiratory Critical Care Medicine, vol. 158, pp. 876-
884, 1998.
    16. Espinosa, M. T. F., R. Fox, R. J. Creger, and H. M. Lazarus, 
``Microbiologic Contamination of Peripheral Blood Progenitor Cells 
Collected for Hematopoietic Cell Transplantation,'' Transfusion, 
vol. 36, pp. 789-793, 1996.
    17. Kogler, G., J. Callejas, P. Hakenberg, J. Enczmann, O. 
Adams, W. Daubener, C. Krempe, U. Gobel, T. Somville, and P. Wernet, 
``Hematopoietic Transplant Potential of Unrelated Cord Blood: 
Critical Issues,'' Journal of Hematotherapy, vol. 5, pp. 105-116, 
1996.
    18. Van Voorhis, B. J. et al, ``Cost-effective Treatment of the 
Infertile Couple,'' Fertility and Sterility, vol. 70, pp. 995-1005, 
1998.
    19. U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, American Society for Reproductive 
Medicine and RESOLVE, 1997, 1995 Assisted Reproductive Technology 
Success Rates: National Summary and Fertility Clinic Reports.
    20. U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, American Society for Reproductive 
Medicine and RESOLVE. 1998.1996 Assisted Reproductive Technology 
Success Rates: National Summary and Fertility Clinic Reports.
    21. Wortley, P. M., T. A. Hammett, and P. L. Fleming, ``Donor 
Insemination and Human Immunodeficiency Virus Transmission,'' 
Obstetrics and Gynecology, vol. 91, No. 4, 1998.
    22. VanKooij, R. J., M. F. Peeters, and E. R. Velde, ``Twins of 
Mixed Races: Consequences for Dutch IVF Laboratories,'' Human 
Reproduction, vol. 12, No. 12, pp. 2585-2587, 1997.
    23. Hu, Yunxia, W. S. Maxson, D. I. Hoffman, S. J. Ory, S. 
Eager, J. Dupre, and C. Lu, ``Maximizing Pregnancy Rates and 
Limiting Higher-order Multiple Conceptions by Determining the 
Optimal Number of Embryos to Transfer Based on Quality,'' Fertility 
and Sterility, vol. 69, No. 4, pp. 650-657, 1998.
    24. Van Voorhis, B. J., D. W. Stovall, B. D. Allen, and C. H. 
Syrop, and ``Cost-effective Treatment of the Infertile Couple,'' 
Fertility and Sterility, vol. 70, No. 6, pp. 995-1004. 1998.
    25. Griffin, M., and W. F. Panak, ``The Economic Cost of 
Infertility-related Services: An Examination of the Massachusetts 
Infertility Insurance Mandate,'' Fertility and Sterility, vol. 70, 
No. 1, pp. 22-29, 1999.
    26. Neumann, P. J., ``Should Health Insurance Cover IVF? Issues 
and Options,'' Journal of Health Politics, Policy and Law, vol. 22, 
No. 5, pp. 1215-1236, 1997.
    27. Steinberg, E. P., P. M. Holtz, E. M. Sullivan, and C. P. 
Villar, ``Profiling Assisted Reproductive Technology Outcomes and 
Quality of Infertility Management,'' Fertility and Sterility, vol. 
69, No. 4, pp. 617-623, 1998.
    28. National Center for Health Statistics, Centers for Disease 
Control and Prevention, U. S. DHHS, Fertility, Family Planning and 
Women's Health: New Data From the 1995 National Survey of Family 
Growth, Series 23, No. 19, table 55, May 1997.
    29. National Center for Chronic Disease Prevention and Health 
Promotion, Centers for Disease Control and Prevention, U.S. DHHS, 
1996 Assisted Reproductive Technology Success Rates: National 
Summary and Fertility Clinic Reports, December 1998.
    30. Yeung, C. H., T. G. Cooper, and E. Nieschlag, ``A Technique 
for Standardization and Quality Control of Subjective Sperm Motility 
Assessments in Semen Analysis,'' Fertility and Sterility, vol. 67, 
No. 6, pp. 1156-1158, 1997.
    31. Mahmoud, A. M. A., B. Depoorter, N. Piens, and F. H. 
Comhaire, ``The Performance of 10 Different Methods for the 
Estimation of Sperm Concentration,'' Fertility and Sterility, vol. 
68, No. 2, pp. 340-345, 1997.
    32. Ziebe, S. and C. Y. Andersen, ``Isolation of Motile 
Spermatozoa: Comparison of Percoll Centrifugation, SpermPrep 
Filtration and Swim-Up Techniques,'' Journal of Assisted 
Reproduction and Genetics vol. 10, No. 7, pp. 485-487, 1993.
    33. Carrell, D.T. et al., ``A Randomized, Prospective Analysis 
of Five Sperm Preparation Techniques Before Intrauterine 
Insemination of Husband Sperm,'' Fertility and Sterility, vol. 69, 
No. 1, pp. 122-126, 1998.
    34. Ozornek, M. H., P. Bielfeld, and R. S. Jeyendran, ``Increase 
Recovery of Viable Spermatozoa Through Oscillating Centrifugation,'' 
Fertility and Sterility vol. 70, No. 4, pp. 712-714, 1998.
    35. King, K., ``Antibiotics: Effect on Cryopreserved-thawed 
Human Sperm Motility In Vitro,'' Fertility and Sterility, vol. 67, 
No. 6, pp. 1146-1151, 1997.
    36. Cohen, J., A. Gilligan, W. Esposity, T. Schimmel, and B. 
Dale, ``Ambient Air and its Potential Effects on Conception in 
Vitro,'' Human Reproduction, vol. 12, No. 8, pp. 1742-1749, 1997.
    37. Francis, M. M. et al., ``Embryo toxicity of three 
commercially available powderless

[[Page 1548]]

surgical gloves,'' Journal of Assisted Reproduction and Genetics, 
vol. 9, No. 3, pp. 283-357, 1992.
    38. Munne, S. et al., ``Treatment-related Chromosome 
Abnormalities in Human Embryos,'' Human Reproduction, vol. 12, No. 
4, pp. 780-784, 1997.
    39. Brinsden, P. R. and P. A. Rainsbury, eds., A Textbook of In 
Vitro Fertilization and Assisted Reproduction, Park Ridge, NJ: The 
Parthenon Publishing Group, 1992.
    40. Hammitt, D. G. et al., ``Prediction of Nuclear Maturity from 
Cumulus-coronal Morphology: Influence of Embryologist Experience,'' 
Journal of Assisted Reproduction and Genetics, vol. 9, No. 5, pp. 
439-467, 1992.
    41. Wilcox, L. S. and J. S. Marks, ``Regulating assisted 
reproductive technologies: public health, consumer protection, and 
public resources,'' Women's Health Issues, vol. 6, No. 3, pp. 175-
180, 1996.
    42. Pool, T. B. ``Practices Contributing to Quality Performance 
in the Embryo Laboratory and the Status of Laboratory Regulation in 
the U.S.,'' Human Reproduction, vol. 12, No. 12, pp. 2591-2593, 
1997.
    43. Callahan, T. L., J. E. Hall, S. L. Ettner, C. L. 
Christiansen, M. F. Greene, and W. F. Crowley, ``The Economic Impact 
of Multiple-Gestation Pregnancies and the Contribution of Assisted 
Reproductive Techniques to Their Incidence,'' The New England 
Journal of Medicine, vol. 331, No. 4, pp. 244-249, 1994.
    44. Prottas, Jeffrey, ``A Study of the Tissue Procurement and 
Distribution System of the United States,'' Brandeis University, 
FDA/HRSA Contract No. 240-090-0048, October 1995.
    45. American Medical Association, Socioeconomics Characteristics 
of Medical Practice, table 47, p. 150, 1994.
    46. Fee Schedule 1/98, Donor Semen 0.5cc and Donor Semen 0.8cc-
1.0cc, The Sperm Bank of California, at www.thespermbankofca.org/fees96.htm

X. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 350193520). A description of these provisions is shown below 
with an estimate of the annual reporting and recordkeeping burden. 
Included in the estimate is the time for reviewing the instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Reporting and Recordkeeping Requirements in Current Good 
Tissue Practice.
    Description: Under the authority of section 361 of the PHS Act, FDA 
is proposing new regulations to require manufacturers of human cellular 
and tissue-based products to follow CGTP, which would include 
information collection provisions such as the establishment and 
maintenance of SOP's, recordkeeping, reporting, and labeling of the 
products. The CGTP information collection provisions would provide: (1) 
additional measures for preventing the introduction, transmission, or 
spread of communicable diseases; (2) step-by-step consistency in the 
manufacturing of the product; (3) necessary information to FDA for the 
purpose of protecting public health and safety; (4) accountability in 
the manufacturing of cellular and tissue-based products; (5) 
information for meaningful FDA inspections; (6) information 
facilitating the tracking of a product back to its original source or 
to a recipient; (7) information to FDA of any adverse reaction; and (8) 
information that would aid in the investigation of any introduction, 
transmission, or spread of a communicable disease.
    Table 11 lists provisions that would require reporting or 
disclosure of information to third parties, the Federal government, or 
the public. Section 1271.155(a) would require the submission of a 
request for FDA approval of an exemption or an alternative from any 
requirement in subpart C or D of part 1271 of the proposed rule. When 
documentation on the determination of donor suitability is translated 
into English, Sec. 1271.270(c) would require a statement of 
authenticity by the translator. Section 1271.290(c) would require a 
unique identifier be affixed to each cellular or tissue-based product 
to relate the product to the donor and all records pertaining to the 
product. Whenever an establishment initially distributes product to a 
consignee, Sec. 1271.290(f) would require the establishment to inform 
the consignee, in writing, of the product tracking requirements and the 
methods the establishment uses to fulfill the requirements. 
Establishments described in proposed Sec. 1271.10 would be required 
under proposed Sec. 1271.350(a) and (b) to report to the agency any 
adverse reaction or any error or accident that may reasonably be 
expected to lead to a reportable adverse reaction as defined in 
proposed Sec. 1271.3(ee). Section 1271.370(a)(2) and (a)(3) would 
require establishments to include specific information on the product 
label and package insert.
    Table 12 lists recordkeeping provisions under the proposed rule, 
establishments would be required to prepare and maintain written SOP's 
for all significant steps performed in the manufacturing and tracking 
of human cellular and tissue-based products. As calculated in table 12, 
the preparation of the SOP's would result in a one-time impact on 
establishments rather than the year to year maintenance of the SOP's 
because, once composed, SOP's would only be reviewed annually and 
updated as necessary.
    The SOP provisions proposed under part 1271 in the combined 
maintenance estimate include: (1) Sec. 1271.160(b)(2) (receiving, 
investigation, evaluating, and documenting information received from 
other sources); (2) Sec. 1271.160(f) (quality program); (3) 
Sec. 1271.180 (all significant steps performed in the manufacture of 
human cellular and tissue-based products); (4) Sec. 1271.190(c)(3) 
(facility cleaning and sanitization); (5) Sec. 1271.195(a) (control and 
monitoring of environmental conditions); (6) Sec. 1271.200(b) 
(cleaning, sanitizing, and maintenance of equipment); (7) 
Sec. 1271.200(c) (calibration of equipment); (8) Sec. 1271.210(a) 
(receipt and verification of supplies and reagents); (9) 
Sec. 1271.210(b) (validation and/or verification of in-house reagents); 
(10) Sec. 1271.220(b) (use and removal of processing material); (11) 
Sec. 1271.220(d) (control of in-process product); (12) Sec. 1271.225(a) 
(verification or validation of changes to a process); (13) 
Sec. 1271.230(d) (maintenance and control of validated processes); (14) 
Sec. 1271.250 (labeling of human cellular and tissue-based products); 
(15) Sec. 1271.265(a) to (c) (receipt, acceptance or rejection, 
distribution, and destruction or other disposition of human cellular or 
tissue-based products); (16) Sec. 1271.265(f) (suitable for return to 
inventory); (17) Sec. 1271.270(b) (records management system); (18) 
Sec. 1271.290(b) (method of product tracking); and, (19) 
Sec. 1271.320(a) (review, evaluation, and documentation of all 
complaints).
    Proposed part 1271 would require the following additional 
recordkeeping provisions listed under table 12. Section 1271.155(f) 
would require an establishment operating under the terms

[[Page 1549]]

of an exemption or alternative to maintain documentation of the terms 
and date of FDA approval. Section 1271.160(b)(3) would require 
documentation of corrective actions taken as a result of an audit of 
the quality program. Section 1271.160(b)(7) would require documentation 
of all product deviations in manufacturing cellular or tissue-based 
products. Section 1271.160(d)(3) would require documentation of the 
results of all audits and reaudits of the quality program. Section 
1271.160(e) would require documentation of computer validation 
activities and results when computers are used as part of the quality 
program, as part of manufacturing, or for maintaining data or records. 
Section 1271.170(d) would require the maintenance of records of 
education, experience, training, and retraining of all personnel. 
Section 1271.190(c)(4) would require documentation of all significant 
facility cleaning and sanitation. Section 1271.195(c) would require 
documentation of environmental control and monitoring activities. 
Section 1271.200(e) would require documentation of all equipment 
maintenance, cleaning, sanitizing, calibration, and other activities. 
Section 1271.210(c) would require documentation of the receipt, 
verification, and use of each supply or reagent. Section 1271.220(b) 
and (d) would require documentation of the adequate removal of 
processing material and the verification activities for in-process 
product. Section 1271.225(b) would require documentation of all changes 
to established processes, including rationale and the date of 
implementation. Section 1271.230(a) would require documentation of 
validation activities when the results of a process cannot be fully 
verified by subsequent inspection and tests. Section 1271.230(b) would 
require documentation of the validation of any process-related claim. 
Section 1271.230(e) would require documentation of the review and 
evaluation of a process and revalidation of the process, if necessary, 
when any changes to or deviations from a validated process occur. 
Section 1271.260(b)(3) and (d) would require documentation of the 
storage temperature of human cellular and tissue-based products and any 
corrective action taken when acceptable storage conditions are not met. 
Section 1271.265(a) and (b) would require documentation of the receipt, 
acceptance or rejection, distribution, and destruction or other 
disposition of a human cellular or tissue-based product. Section 
1271.270(a) and (c) would require documentation of each significant 
step in manufacturing required in subparts C and D of part 1271, the 
results and interpretation of all testing and screening for relevant 
communicable disease agents and diseases, and the determination of 
donor suitability.
    Section 1271.180 would require the retention of obsolete procedures 
for 10 years. Section 1271.270(e) would require the retention of all 
records for a period of 10 years after their creation. Records 
pertaining to a particular human cellular or tissue-based product would 
be required to be retained at least 10 years after the date of 
implantation, transplantation, infusion, or transfer of the product. If 
the date of implantation, transplantation, infusion, or transfer is not 
known, then records would be required to be retained at least 10 years 
after the date of the product's distribution, disposition, or 
expiration, whichever is latest. This retention time is necessary 
because certain cellular and tissue-based products have long storage 
periods. In addition, advances in medical technology have created 
opportunities for diagnosis and therapy for up to 10 years after 
recipient exposure to a donor later determined to be at risk for 
communicable disease agents or diseases.
    Section 1271.270(f) would require documentation of any contract, 
agreement, or other arrangement with another establishment under which 
any step in the manufacturing process is performed by the other 
establishment. Section 1271.290(e) would require documentation of the 
disposition of each of its human cellular or tissue-based product as 
part of its tracking method. Section 1271.290(f) would require an 
establishment to document that a consignee agreed to participate in its 
tracking method and will take all necessary steps to ensure compliance 
with the requirements of the regulation. Section 1271.320(b) would 
require an establishment to maintain a record of each complaint that it 
receives, including a review and evaluation. Section 1271.350(c) would 
require the documentation of adverse reaction reports, errors and 
accidents in manufacturing that may lead to product deviation reports, 
and the investigation of these reports.
    Description of Respondents: Manufacturers of cellular and tissue-
based products.
    FDA estimates the burden of this collection of information as 
follows:

                                                    Table 11.--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. of       Annual Frequency      Total Annual
                     21 CFR Section                         Respondents      per Response          Responses      Hours per Response      Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
1271.155(a)                                                 1,065                 1               1,065                   3               3,195
1271.270(c)                                                 1,065                 1               1,065                   1               1,065
1271.290(c)                                                   791               250             198,215                   0.08           15,857
1271.290(f)                                                 1,065                 1               1,065                   1               1,065
1271.350(a)                                                 1,065                 6               6,390                   0.5             3,195
1271.350(b)                                                 1,065                 2               2,130                   0.5             1,065
1271.370(a)(2) and (a)(3)                                     633               207             131,005                   0.25           32,751
Total                                                                                                                                   58,193
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                              Table 12.--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
One-time Burden (Creation of        1,065               9           9,585              16         153,360
 SOP's \2\)
One-time Burden (Review of          1,065              19          20,235               5         101,175
 existing SOP's for compliance)

[[Page 1550]]

 
SOP Maintenance (See previous       1,065              19          20,235               1          20,235
 list of 19 SOP's)
1271.155(f)                         1,065               1           1,065               0.25          266
1271.160(b)(3)                        483               2             966               6           5,796
1271.160(b)(7)                        597              15           8,955               0.5         4,478
1271.160(d)(3)                        558               1             558              13           7,254
1271.160(e)                           597               5           2,985               0.25          746
1271.170(d)                           483               1             483               1             483
1271.180                              483               1             483             120          57,960
1271.190(c)(4)                        558              12           6,696               1           6,696
1271.195(c)                           822              12           9,864               1           9,864
1271.200(e)                           483              12           5,796               1           5,796
1271.210(c)                           597              12           7,164               1           7,164
1271.220(b) and (d)                    91             781          71,070               0.08        5,686
1271.225(b)                         1,065               2           2,130               1           2,130
1271.230(a)                           755               1             755               1             755
1271.230(b)                           980               1             980               1             980
1271.230(e)                         1,065               1           1,065               1           1,065
1271.260(b)(3)                        597             356         212,532               0.08       17,003
1271.260(d)                           747              12           8,964               0.25        2,241
1271.265(a)                           597             360         214,920               0.08       17,194
1271.265(b)                           822             407         334,554               0.08       26,764
1271.270(a) and (c)                   597             360         214,920               0.1        21,492
1271.270(f)                           755               2           1,510               0.25          378
1271.290(e)                           641             306         196,146               0.3        58,844
1271.290(f)                         1,065              57          60,705               0.35       21,247
1271.320(b)                           830               5           4,150               1           4,150
1271.350(c)                           726               6           4,356               0.5         2,178
Total                                                                                             563,380
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Standard operating procedures.

    Under this proposed rule, 19 SOP's would be required as previously 
described. FDA is assuming that approximately 1,065 manufacturers would 
have to create up to 9 SOP's for a total of 9,585 records, and the 
agency estimates that it would take 16 hours per record to create 9 new 
SOP's for a total of 153,360 hours as a one-time burden. The agency 
estimates that up to 19 SOP's would already exist as a result of 
complying with current applicable regulations or following industry 
organizational standards. Approximately 1,065 manufacturers would have 
to review these 19 SOP's for compliance with the regulations, which 
would expend approximately 5 hours per SOP as a one-time burden. Annual 
SOP maintenance of existing SOP's is estimated to involve 1 hour 
annually per SOP, totaling 19 hours annually per recordkeeper.
    In some cases, the estimated burden may appear to be lower or 
higher than the burden experienced by individual establishments. The 
estimated burden in these charts is an estimated average burden, taking 
into account the range of impact each proposed regulation may have. In 
estimating the burden, FDA compared the proposed regulations with the 
current voluntary standards of a number of industry organizations, such 
as, AATB, EBAA, AABB, FAHCT, and CAP, and the guidelines provided by 
ASRM. In those cases where a voluntary industry standard appears to be 
equivalent to a proposed regulation, FDA has assumed that any reporting 
or recordkeeping burden is a customary and usual business practice of 
establishments who are members of those organizations and no additional 
burden is calculated here. In some cases establishments affected by 
this proposed rule may already be required to comply with regulations 
for manufacturers of human drugs or biological products, e.g., parts 
210, 211, 312, 314, and 606 (21 CFR parts 312, 314, and 606).
    FDA has estimated the reporting (table 11) and recordkeeping (table 
12) burdens based upon the agency's institutional experience with 
comparable recordkeeping and reporting provisions applicable to the 
human drug and biological product industries, recent information from 
trade organizations related to the manufacturing of products utilizing 
cells and tissues, and data provided by the Eastern Research Group 
(ERG), a consulting firm hired by FDA to prepare an economic analysis 
of the potential economic impact on sperm banks and ART facilities.
    The agency has estimated that there are approximately 1,065 
manufacturers of cellular and tissue-based products (approximately 110 
manufacturers of conventional tissue, 114 manufacturers of eye tissue, 
425 manufacturers of peripheral and cord blood stem cells, 350 
manufacturers of reproductive tissue, and 66 manufacturers of cellular 
or tissue-based licensed biological products or devices). FDA obtained 
these estimates of manufacturers (including percentage of members and 
nonmembers) from the various trade organizations and the agency's 
registration systems for biological product and device manufacturers. 
The total number of respondents and recordkeepers, 1,065, in the tables 
is decreased for each provision by the number of establishments that 
follow, as usual and customary practice, the applicable established 
trade organizational standards comparable to the CGTP requirements, 
i.e., AATB, EBAA, FAHCT, AABB, or CAP. FDA based the estimated numbers 
for ``Number of Respondents'' and ``Number of Recordkeepers'' on 
information provided by the trade organizations.
    FDA based the estimated numbers for ``Annual Frequency per 
Response,''

[[Page 1551]]

``Total Annual Responses,'' ``Annual Frequency per Recordkeeping,'' and 
``Total Annual Records'' on information received from the trade 
organizations, institutional experience with similar requirements (good 
manufacturing practice), general information provided to FDA during 
inspections of manufacturers of human tissue intended for 
transplantation, and information gathered by ERG.
    The estimates for ``Hours per Response'' or ``Hours per 
Recordkeeper'' were calculated using comparable burdens under drug GMP 
regulations, part 211, and GMP for blood and blood components, part 
606, or by using the information provided by ERG, e.g., time spent on 
Secs. 1271.190(c)(4) (documentation of cleaning and sanitation) and 
1271.195(c) (documentation of environmental control and monitoring 
activities) was an estimate provided by ERG.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3507(d), the agency has submitted the information collection provisions 
of this proposed rule to OMB for review. Interested persons are 
requested to send comments regarding information collection by February 
7, 2001 to the Office of Information and Regulatory Affairs, OMB, New 
Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 
20503, Attn: Wendy Taylor, Desk Officer for FDA.

XI. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has concluded that 
the proposed rule raises Federalism implications because it could 
preempt some States' laws regarding donated human cells and tissues. 
FDA currently is seeking comments from elected State and local 
government officials under Executive Order 13132 on: (1) The need for 
the proposed good tissue practice rule to prevent communicable disease 
transmission through human cellular and tissue-based products; (2) 
alternatives that would limit the scope of such national requirements 
or otherwise preserve State prerogatives and authority; (3) the 
proposed good tissue practice provisions; and (4) any other issues 
raised by this proposed rule possibly affecting State laws and 
authorities.

XII. Request For Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments on this proposal by May 8, 2001. Two 
copies of any comments are to be submitted, except that individuals may 
submit one copy. Comments are to be identified with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday. Comments received in response to the proposed 
GTP rule could support a change that will affect language in previously 
published proposed tissue rules. In the event that any tissue rule 
becomes effective before either or both of the remaining tissue rules 
become effective, FDA intends to make conforming amendments to those 
final rules at the same time the remaining tissue rules become 
effective.

List of Subjects in 21 CFR Part 1271

    Human cellular and tissue-based products, Communicable diseases, 
HIV/AIDS, Reporting and recordkeeping requirements.
    Therefore, under the Public Health Service Act, and under the 
authority delegated to the commissioner of Food and Drugs, it is 
proposed to amend 21 CFR Chapter I as follows:
    Part 1271 as proposed in the Federal Register of May 14, 1998 (63 
FR 26744) and September 30, 1999 (64 FR 52696) is amended as follows:

PART 1271--HUMAN CELLULAR AND TISSUE-BASED PRODUCTS

    1. The authority citation for 21 CFR part 1271 is revised to read 
as follows:

    Authority: 42 U.S.C. 216, 243, 263a, 264, 271.
    2. Section 1271.3 is amended by adding paragraphs (ff) through (tt) 
to read as follows:


Sec. 1271.3  Definitions.

* * * * *
    (ff) Available for distribution means that the human cellular or 
tissue-based product has been determined to meet all release 
specifications and to be suitable for distribution.
    (gg) Adverse reaction means a noxious and unintended response to 
any human cellular or tissue-based product for which there is a 
reasonable possibility that the response may have been caused by the 
product (i.e., the relationship cannot be ruled out).
    (hh) Processing material means any material or substance that is 
used in, or to facilitate, processing, but which is not intended by the 
manufacturer to be included in the human cellular or tissue-based 
product when it is made available for distribution.
    (ii) Complaint means any written, oral, or electronic communication 
that alleges:
    (1) That a human cellular or tissue-based product has transmitted 
or may have transmitted a communicable disease to the recipient of the 
product;
    (2) That the function or integrity of a human cellular or tissue-
based product may have been impaired; or
    (3) Any other problem with a human cellular or tissue-based product 
that could result from the failure to comply with current good tissue 
practice.
    (jj) Distribution means any conveyance or shipment of human 
cellular or tissue-based products (including importation and 
exportation), whether or not such conveyance or shipment is entirely 
intrastate and whether or not possession of the product is taken.
    (kk) Product deviation means an event that represents a deviation 
from current good tissue practice, applicable standards, or established 
specifications; or an unexpected or unforeseeable event that may relate 
to the transmission or potential transmission of a communicable disease 
agent or disease from a human cellular or tissue-based product to a 
recipient, or may lead to product contamination, or may adversely 
affect the function or integrity of the product.
    (ll) Establish and maintain means define, document (in writing or 
electronically), and implement, then follow, review, and as needed, 
revise on an ongoing basis.
    (mm) Processing means any activity other than recovery, donor 
screening, donor testing, storage, labeling, packaging, or distribution 
performed on a human cellular or tissue-based product, including but 
not limited to preparation, sterilization, steps to inactivate and 
remove adventitious agents, preservation for storage, and removal from 
storage.
    (nn) Quality audit means a documented, independent inspection and 
review of an establishment's activities, including manufacturing and 
tracking, performed according to procedures, to verify, by examination 
and evaluation of objective evidence, the degree of compliance with 
those aspects of the quality program under review.
    (oo) Quality program means an organization's comprehensive system 
for manufacturing and tracking human cellular and tissue-based 
products. This program includes preventing, detecting, and correcting 
deficiencies that may lead to circumstances that increase the risk of 
introduction, transmission, or spread of communicable disease.
    (pp) Recovery means the process of obtaining from a donor cells or 
tissues that are intended for use in human

[[Page 1552]]

implantation, transplantation, infusion, or transfer.
    (qq) Storage means holding human cellular or tissue-based products 
for future processing and/or distribution.
    (rr) Validation means confirmation by examination and provision of 
objective evidence that particular requirements can consistently be 
fulfilled. Validation of a process, or process validation, means 
establishing by objective evidence that a process consistently produces 
a result or product meeting its predetermined specifications.
    (ss) Verification means confirmation by examination and provision 
of objective evidence that specified requirements have been fulfilled.
    (tt) Importer of record means the person, establishment, or its 
representative responsible for making entry of imported goods in 
accordance with all laws affecting such importation.
    3. Subpart D, consisting of Secs. 1271.150 through 1271.320, is 
added to part 1271 to read as follows:

Subpart D--Current Good Tissue Practice

Sec.
1271.150  Current good tissue practice: general.
1271.155  Exemptions and alternatives.
1271.160  Establishment and maintenance of a quality program.
1271.170  Organization and personnel.
1271.180  Procedures.
1271.190  Facilities.
1271.195  Environmental control and monitoring.
1271.200  Equipment.
1271.210  Supplies and reagents.
1271.220  Process controls.
1271.225  Process changes.
1271.230  Process validation.
1271.250  Labeling controls.
1271.260  Storage.
1271.265  Receipt and distribution.
1271.270  Records.
1271.290  Tracking.
1271.320  Complaint file.

Subpart D--Current Good Tissue Practice


Sec. 1271.150  Current good tissue practice: general.

    (a) General. Current good tissue practice (CGTP) requirements are 
set forth in this subpart and in subpart C of this part. CGTP 
requirements govern the methods used in, and the facilities and 
controls used for, the manufacture of human cellular and tissue-based 
products, including but not limited to all steps in recovery, donor 
screening, donor testing, processing, storage, labeling, packaging, and 
distribution. The CGTP requirements are intended to prevent the 
introduction, transmission, and spread of communicable disease through 
the use of human cellular and tissue-based products by helping to 
ensure that the products do not contain communicable disease agents; 
that the products do not become contaminated during manufacturing; and 
that the function and integrity of the products are not impaired 
through improper manufacturing. The CGTP provisions specifically 
governing determinations of donor suitability, including donor 
screening and testing, are set out separately in subpart C of this 
part.
    (b) Compliance with applicable requirements. (1) If an 
establishment engages in only some operations subject to the 
regulations in this subpart and subpart C of this part, and not others, 
that establishment need only comply with those requirements applicable 
to the operations in which it engages. However, an establishment that 
engages another establishment under a contract, agreement, or other 
arrangement, to perform any step in the manufacturing process, is 
responsible for ensuring that the work is performed in compliance with 
the requirements in this subpart and subpart C of this part.
    (2) The establishment that determines that a product meets release 
criteria and makes the product available for distribution, whether or 
not that establishment is the actual distributor, is responsible for 
ensuring that the product has been manufactured in compliance with the 
requirements of subparts C and D of this part and any other applicable 
requirements.
    (c) Compliance with parts 210, 211, and 820 of this chapter. With 
respect to human cellular or tissue-based products regulated as 
biological drugs or devices under section 351 of the Public Health 
Service Act and/or the Federal Food, Drug, and Cosmetic Act, the 
procedures contained in this subpart and in subpart C of this part and 
the current good manufacturing practice regulations in parts 210 and 
211 of this chapter and the quality system regulations in part 820 of 
this chapter, shall be considered to supplement, not supersede, each 
other unless the regulations explicitly provide otherwise. In the event 
that it is impossible to comply with all applicable regulations in 
these parts, the regulations specifically applicable to the biological 
drug or device in question shall supersede any other requirements.
    (d) Where appropriate. When a requirement is qualified by ``where 
appropriate,'' it is deemed to be ``appropriate'' unless the 
establishment can document justification otherwise. A requirement is 
``appropriate'' if nonimplementation could reasonably be expected to 
result in the product's not meeting its specified requirements related 
to prevention of introduction, transmission, or spread of communicable 
disease agents and diseases, or in the establishment's inability to 
carry out any necessary corrective action.


Sec. 1271.155  Exemptions and alternatives.

    (a) General. An establishment may request an exemption or 
alternative from any requirement in subpart C or D of this part 
regarding a human cellular or tissue-based product.
    (b) Request for exemption or alternative. A request under this 
section shall be submitted to the Director, Center for Biologics 
Evaluation and Research (the Director). The request shall be 
accompanied by supporting documentation, including all relevant valid 
scientific data. A request for an exemption shall contain information 
justifying the exemption. A request for an alternative shall contain a 
description of an alternative that satisfies the purpose of the 
requirement.
    (c) Criteria for granting exemption or alternative. The Director 
may grant an exemption or alternative if he or she finds that such 
action is consistent with the goals of preventing the introduction, 
transmission, and spread of communicable disease and that:
    (1) The information submitted justifies an exemption; or
    (2) The proposed alternative satisfies the purpose of the 
requirement.
    (d) Form of request. A request for an exemption or alternative 
shall ordinarily be made in writing or electronically. However, in 
limited circumstances such a request may be made orally, and an 
exemption or alternative may be granted orally by the Director. An oral 
request and approval shall be followed by an immediate written request 
and written acknowledgment of approval.
    (e) Operation under exemption or alternative. An establishment 
shall not begin operating under the terms of a requested exemption or 
alternative until the exemption or alternative has been granted in 
writing. An establishment may apply for an extension of an exemption or 
alternative beyond its expiration date, if any.
    (f) Documentation. An establishment operating under the terms of an 
exemption or alternative shall maintain documentation of:
    (1) FDA's granting of the exemption or alternative, and
    (2) The date on which it began operating under the terms of the 
exemption or alternative.


Sec. 1271.160  Establishment and maintenance of a quality program.

    (a) General. An establishment that performs any step in the 
manufacture of

[[Page 1553]]

human cellular and tissue-based products shall establish and maintain a 
quality program that is appropriate for the specific human cellular and 
tissue-based products manufactured and the manufacturing steps 
performed and that meets the requirements of this subpart.
    (b) Functions. Functions of the quality program shall include, but 
not be limited to:
    (1) Ensuring that appropriate procedures are established and 
maintained, and ensuring compliance with the requirements of 
Sec. 1271.180 with respect to procedures, including review, approval, 
revision, and archiving;
    (2) Ensuring that procedures exist for receiving, investigating, 
evaluating, and documenting information received from other sources and 
for sharing with consignees and other establishments that are known to 
have recovered cells or tissue from the same donor any information 
pertaining to the integrity and function of a human cellular or tissue-
based product, possible contamination of the product, or the potential 
transmission of communicable disease by the product. In the case of 
information received after the product is made available for 
distribution or shipped to the consignee, procedures shall include 
provisions for evaluating the effect this information has on the 
product and for the notification of all entities to whom affected 
product was distributed, the quarantine and recall of the product, and/
or reporting to FDA, as necessary.
    (3) Ensuring that appropriate corrective actions, including 
reaudits of deficiencies, are taken and documented, as necessary. 
Corrective actions shall be verified to ensure that such actions are 
effective and do not adversely affect the finished product. Where 
appropriate, corrective actions shall include both short-term action to 
address the immediate problem and long-term action to prevent the 
problem's recurrence. Documentation of corrective actions shall include 
where appropriate:
    (i) Identification of the human cellular or tissue-based product 
affected and a description of its disposition;
    (ii) The nature of the problem requiring corrective action;
    (iii) A description of the corrective action taken; and
    (iv) The date(s) of the corrective action.
    (4) Ensuring the proper training and education of personnel;
    (5) Establishing and maintaining appropriate monitoring systems as 
necessary to comply with the requirements of this subpart (e.g., 
environmental monitoring);
    (6) Establishing and maintaining a system for the maintenance of 
records in compliance with Sec. 1271.270;
    (7) Investigating and documenting all product deviations and making 
reports if required under Sec. 1271.350(b) or other applicable 
regulations. Each investigation shall include a review and evaluation 
of the product deviation, the efforts made to determine the cause, and 
the implementation of corrective action(s) designed to address the 
product deviation and prevent recurrence. Each establishment shall also 
perform a periodic review and analysis of all product deviations, at 
least once each year, for the purpose of identifying trends and 
adopting appropriate preventive measures. This analysis shall be 
available for review upon inspection and for submission to FDA upon 
request; and
    (8) Conducting evaluations, investigations, audits, and other 
actions necessary to ensure compliance with the requirements of this 
subpart.
    (c) Authority over program. One or more designated persons shall 
have authority over and responsibility for ensuring that the quality 
program is effectively established and effectively maintained. This 
person shall report to management on the performance of the quality 
program on no less than an annual basis. If this person also performs 
other tasks in the establishment, he or she shall not have final 
oversight over his or her own work.
    (d) Audits. (1) A comprehensive quality audit, as defined in 
Sec. 1271.3(nn), shall be performed no less than once in a 12-month 
period. Special audits shall be performed as necessary. All audits 
shall be conducted in accordance with procedures to assure that the 
quality program is operating effectively and to identify trends or 
recurring problems.
    (2) Quality audits shall be conducted by individuals with 
sufficient knowledge, training, and experience to identify problems in 
the specific processes under review, but who do not have direct 
responsibility for the processes being audited.
    (3) A documented report of the results of the audits and reaudits, 
where taken, shall be retained. Such reports shall be reviewed by 
management having responsibility for the matters audited, and this 
management review shall be documented.
    (e) Computers. If computers or automated data processing systems 
are used as part of the quality program, as part of manufacture or 
tracking, or for maintaining data or records related to the manufacture 
or tracking of human cellular or tissue-based products, the 
establishment shall validate computer software for its intended use 
according to an established protocol. All software changes shall be 
validated before approval and issuance. These validation activities and 
results shall be documented.
    (f) Procedures. Procedures shall be established and maintained for 
a quality program, including quality audits.


Sec. 1271.170  Organization and personnel.

    (a) General. Each establishment shall maintain an adequate 
organizational structure and sufficient personnel to ensure that the 
requirements of this part are met.
    (b) Competent performance of functions. Each establishment shall 
have sufficient personnel with the necessary education and experience 
to assure competent performance of their assigned functions. Personnel 
shall perform only those activities for which they are qualified.
    (c) Training. All personnel shall be trained, and retrained as 
necessary, to perform their assigned responsibilities adequately. 
Personnel shall be made aware of possible consequences of improper 
performance of their duties; e.g., the risk of transmission of 
communicable disease agents and diseases, and the hazards associated 
with those disease agents and diseases, and the risk of adversely 
affecting function and integrity of human cellular and tissue-based 
products.
    (d) Records. A record of the education, experience, training, and 
retraining shall be maintained for all personnel.


Sec. 1271.180  Procedures.

    Each establishment shall establish and maintain procedures for all 
significant steps that it performs in the manufacture of human cellular 
and tissue-based products. These procedures shall be designed to 
prevent circumstances that increase the risk of the introduction, 
transmission, and spread of communicable disease through the use of 
human cellular and tissue-based products by ensuring that the products 
do not contain relevant communicable disease agents; that the products 
do not become contaminated during manufacturing; and that the function 
and integrity of the products are not impaired through improper 
manufacturing. Procedures shall be designed to ensure compliance with 
the requirements of this part. Prior to implementation, all procedures 
shall be reviewed and approved by a responsible person. At least once 
in a 12-month period, all procedures shall be reviewed and, if 
necessary, revised, and the

[[Page 1554]]

review shall be documented. Procedures shall be readily available to 
the personnel in the area where the operations to which they relate are 
performed, unless this is impractical. Any deviation from a procedure 
shall be authorized in advance by a responsible person, recorded, and 
justified. An establishment may adopt current standard procedures, such 
as those in a technical manual prepared by another organization, 
provided the procedures are consistent with and at least as stringent 
as the requirements of this part and appropriate for the operations 
conducted at the establishment. Obsolete procedures shall be archived 
for at least 10 years.


Sec. 1271.190  Facilities.

    (a) General. Any facility used in the manufacture of human cellular 
or tissue-based products shall be of suitable size, construction, and 
location to facilitate cleaning, relevant maintenance, and proper 
operations. The facility shall be maintained in a good state of repair. 
Adequate lighting, ventilation, plumbing, drainage, and washing and 
toilet facilities shall be provided.
    (b) Operations. A facility used in the manufacture of human 
cellular or tissue-based products shall be divided into separate or 
defined areas of adequate size for each operation that takes place in 
the facility, or other control systems shall be established and 
maintained to prevent improper labeling, mix-ups, contamination, cross-
contamination, and accidental exposure of human cellular and tissue-
based products to communicable disease agents.
    (c) Facility cleaning and sanitation. (1) Any facility used in the 
manufacture of human cellular and tissue-based products shall be 
maintained in a clean, sanitary, and orderly manner.
    (2) Sewage, trash, and other refuse shall be disposed of in a 
timely, safe, and sanitary manner.
    (3) Procedures for facility cleaning and sanitation shall be 
established and maintained. These procedures shall assign 
responsibility for sanitation and shall describe in sufficient detail 
the cleaning methods to be used and the schedule for cleaning the 
facility.
    (4) All significant cleaning and sanitation activities shall be 
documented, and records shall be maintained.


Sec. 1271.195  Environmental control and monitoring.

    (a) General. Where environmental conditions could reasonably be 
expected to have an adverse effect on the function or integrity of 
human cellular and tissue-based products, or to cause contamination or 
cross-contamination of products or equipment or accidental exposure of 
products to communicable disease agents, procedures shall be 
established and maintained to adequately control and monitor 
environmental conditions and to provide proper conditions for 
operations. Where appropriate, these procedures shall provide for the 
following control and monitoring activities or systems:
    (1) Temperature and humidity controls;
    (2) Ventilation and air filtration;
    (3) Cleaning and disinfecting of rooms and equipment to ensure 
aseptic processing operations;
    (4) Maintenance of equipment used to control conditions necessary 
for aseptic processing operations; and
    (5) Environmental monitoring for organisms.
    (b) Inspections. Each environmental control system shall be 
inspected periodically to verify that the system, including necessary 
equipment, is adequate and functioning properly. Appropriate corrective 
action shall be taken as necessary.
    (c) Records. Environmental control and monitoring activities shall 
be documented, and records shall be maintained.


Sec. 1271.200  Equipment.

    (a) General. Equipment used in the manufacture of human cellular 
and tissue-based products shall be of appropriate design for its use, 
shall be suitably located and installed to facilitate operations, 
including cleaning and maintenance, and shall not have any adverse 
effect on the products. Any automated, mechanical, electronic, 
computer, or other equipment used for inspection, measuring, and 
testing shall be capable of producing valid results.
    (b) Procedures and schedules. Procedures shall be established and 
maintained for cleaning, sanitizing, and maintaining equipment to 
prevent malfunctions, contamination or cross-contamination, accidental 
exposure of human cellular and tissue-based products to communicable 
disease agents, and other events that could reasonably be expected to 
have an adverse effect on product function or integrity. Cleaning, 
sanitizing, and maintenance of equipment shall be performed according 
to established schedules.
    (c) Calibration of equipment. All automated, mechanical, 
electronic, computer, or other equipment used for inspection, 
measuring, and testing shall be routinely calibrated according to 
established procedures and schedules. Calibration procedures shall 
include specific directions and, where applicable, shall include limits 
for accuracy and precision. When accuracy and precision limits are not 
met, there shall be provisions for corrective action to reestablish the 
limits and to evaluate whether there were any adverse effects on any 
human cellular or tissue-based product.
    (d) Inspections. Equipment shall be routinely inspected for 
cleanliness, sanitation, and calibration, and to assure adherence to 
applicable equipment maintenance schedules.
    (e) Records. All maintenance, cleaning, sanitizing, calibration, 
and other activities performed in accordance with this section shall be 
documented and maintained. Records of recent maintenance, cleaning, 
sanitizing, calibration, and other activities shall be available at 
each piece of equipment. Records of the use of each piece of equipment, 
which shall include the identification of each human cellular or 
tissue-based product manufactured with that equipment, shall be 
maintained.


Sec. 1271.210  Supplies and reagents.

    (a) Receipt and verification. Procedures shall be established and 
maintained for receiving supplies and reagents used in the manufacture 
of human cellular and tissue-based products. Supplies and reagents 
shall be verified to meet specifications designed to prevent 
circumstances that increase the risk of the introduction, transmission, 
or spread of communicable disease through product contamination or the 
impairment of product function or integrity, and shall not be used 
until such verification is completed. Verification may be accomplished 
by the establishment that uses the supply or reagent, or by the vendor 
of the supply or reagent.
    (b) Reagents. Reagents used in processing and preservation of human 
cellular and tissue-based products shall be of appropriate grade for 
the intended use and shall be sterile, if appropriate. Procedures for 
production of in-house reagents shall be validated and/or verified.
    (c) Records. The following records pertaining to supplies and 
reagents shall be maintained:
    (1) Records of the receipt of each supply or reagent, including the 
type, manufacturer, lot number, date of receipt, and expiration date;
    (2) Records of the verification of each supply or reagent, 
including test results or, in the case of vendor verification, a

[[Page 1555]]

certificate of analysis from the vendor; and
    (3) Records of the use of each supply or reagent, which shall 
include the identification of each human cellular or tissue-based 
product manufactured with the supply or reagent.


Sec. 1271.220  Process controls.

    (a) General. Each establishment engaged in the processing of human 
cellular or tissue-based products shall develop, conduct, control, and 
monitor its manufacturing processes to ensure that each human cellular 
or tissue-based product conforms to specifications, is not 
contaminated, maintains its function and integrity, and is manufactured 
so as to prevent transmission of communicable disease by the product.
    (b) Processing material. Where a processing material could 
reasonably be expected to have an adverse effect on a human cellular or 
tissue-based product's function or integrity, the establishment shall 
establish and maintain procedures for the use and removal of such 
processing material to ensure that it is removed or limited to an 
amount that does not adversely affect the product's function or 
integrity. The removal or reduction of such processing material shall 
be documented.
    (c) Pooling. Human cells or tissue from two or more donors shall 
not be pooled (placed in physical contact or mixed in a single 
receptacle) during manufacturing.
    (d) In-process monitoring. Procedures shall be established and 
maintained, where appropriate, to ensure that specified requirements of 
in-process product are met. Such procedures shall ensure that in-
process product is controlled until the required inspection and tests 
or other verification activities have been completed or necessary 
approvals are received and documented. Sampling of in-process products 
shall be representative of the material to be evaluated.


Sec. 1271.225  Process changes.

    (a) Procedures. Procedures shall be established and maintained for 
making changes to a process. Any such change shall be verified or 
validated, to ensure that the change does not create an adverse impact 
elsewhere in the operation, and shall be approved before implementation 
by a responsible person with appropriate knowledge and background.
    (b) Change records. All changes to established processes shall be 
documented, including the rationale for the change and the date of 
implementation. Change records shall include a description of the 
change, identification of the affected documents, the signature of the 
approving individual(s), approval date, and when the change becomes 
effective. Approved changes shall be communicated to the appropriate 
personnel in a timely manner.


Sec. 1271.230  Process validation.

    (a) General. Where the results of a process cannot be fully 
verified by subsequent inspection and tests, the process shall be 
validated and approved according to established procedures. The 
validation activities and results, including the date and signature of 
the individual(s) approving the validation, shall be documented.
    (b) Claims. Any process-related claim in labeling or promotional 
materials for a human cellular or tissue-based product, e.g., a claim 
for sterility or viral inactivation, shall be based on a validated 
process. Validation shall be documented, and the documentation shall be 
maintained at the establishment and made available for review on 
inspection.
    (c) Dura mater. Dura mater shall be processed using a validated 
procedure that reduces transmissible spongiform encephalopathy, while 
preserving the clinical utility of the product.
    (d) Procedures. Procedures shall be established and maintained for 
monitoring and control of validated processes to ensure that the 
specified requirements continue to be met.
    (e) Changes and deviations. When changes to or deviations from a 
validated process occur, the establishment shall review and evaluate 
the process and perform revalidation where appropriate. These 
activities shall be documented.


Sec. 1271.250  Labeling controls.

    Procedures shall be established and maintained to control the 
labeling of human cellular and tissue-based products. These procedures 
shall be designed to ensure proper product identification and to 
prevent mix-ups. Procedures shall include verification of label 
accuracy, legibility, and integrity. Procedures shall ensure that each 
product is labeled in accordance with all applicable labeling 
requirements, including those in Secs. 1271.55, 1271.65, 1271.75, 
1271.90, 1271.290, and 1271.370, and that each product made available 
for distribution is accompanied by documentation of the donor 
suitability determination as required under Sec. 1271.55.


Sec. 1271.260  Storage.

    (a) Control of storage areas. Each establishment shall control its 
storage areas and stock rooms to prevent mix-ups, commingling, 
deterioration, contamination, and cross-contamination, of human 
cellular and tissue-based products and supplies, and any other 
condition that may adversely affect product function or integrity, and 
to prevent improper release for distribution.
    (b) Temperature. (1) Each establishment shall store human cellular 
and tissue-based products at an appropriate temperature and for no 
longer than the maximum storage period for the product.
    (2) Acceptable temperature limits for storage of human cellular and 
tissue-based products at each step of the manufacturing process shall 
be established to ensure product function and integrity, to prevent 
product deterioration, and to inhibit the growth of infectious agents.
    (3) Storage temperatures for human cellular and tissue-based 
products shall be maintained and recorded. Recorded temperatures shall 
be reviewed periodically to assure that temperatures have not exceeded 
acceptable limits.
    (c) Expiration date. Where appropriate, an expiration date shall be 
assigned to each human cellular or tissue-based product based on the 
following factors:
    (1) Product type;
    (2) Processing procedures, including the method of preservation;
    (3) Storage conditions; and
    (4) Packaging.
    (d) Corrective action. Corrective action shall be taken and 
documented whenever proper storage conditions are not met.


Sec. 1271.265  Receipt and distribution.

    (a) General. Procedures shall be established and maintained for the 
following activities: receipt, acceptance or rejection, distribution, 
and destruction or other disposition of human cellular or tissue-based 
products, and these activities shall be documented. Documentation shall 
include:
    (1) Identification of the human cellular or tissue-based product;
    (2) Activities performed and the results of such activities;
    (3) Date(s) of activity;
    (4) Quantity of human cellular or tissue-based product subject to 
the activity; and
    (5) Disposition of the human cellular or tissue-based product 
(e.g., identity of consignee).
    (b) Receiving activities. Procedures shall be established and 
maintained for

[[Page 1556]]

receiving and accepting or rejecting human cellular or tissue-based 
products for processing, distribution, or any other step in the 
manufacturing process. The status of each incoming human cellular or 
tissue-based product (e.g., with respect to quarantine, donor screening 
and testing, and processing) shall be determined and identified 
promptly after receipt, and each product shall be handled in a manner 
appropriate to its status. Each incoming human cellular or tissue-based 
product shall be inspected according to established procedures for 
damage, contamination, deterioration, or other indications that the 
integrity of the product has been impaired. Acceptance or rejection of 
incoming products shall be documented.
    (c) Availability for distribution. Procedures shall be established 
and maintained for making human cellular and tissue-based products 
available for distribution. These procedures, which shall include 
release criteria, shall be designed to prevent the release of products 
that are in quarantine, are contaminated, have deteriorated, or 
otherwise have been manufactured in violation of current good tissue 
practice and, except as provided under Secs. 1271.65 and 1271.90, 
products from donors who have been determined to be unsuitable or for 
whom a donor-suitability determination has not been completed. Prior to 
making a human cellular or tissue-based product available for 
distribution, the establishment shall verify and document that the 
release criteria have been met and shall review all records pertaining 
to the product. The determination that a human cellular or tissue-based 
product is available for distribution shall be documented and dated by 
a responsible person.
    (d) Packaging. Packaging and shipping containers shall be designed, 
validated, and constructed to ensure product function and integrity and 
protect the product from damage, deterioration, contamination, or other 
adverse effects during customary conditions of processing, storage, 
handling, and distribution.
    (e) Shipping conditions. Appropriate shipping conditions shall be 
defined for each type of human cellular or tissue-based product to be 
maintained during transit.
    (f) Return to inventory. Procedures shall be established and 
maintained to determine if a product that is returned to an 
establishment is suitable to be returned to inventory.


Sec. 1271.270  Records.

    (a) General. Records shall be maintained concurrently with the 
performance of each significant step required in this subpart and 
subpart C of this part. Any requirement in this part that an action be 
documented involves the creation of a record, which record is subject 
to the requirements of this section. All records shall be accurate, 
indelible, and legible. The records shall identify the person 
performing the work, the dates of the various entries, and shall be as 
detailed as necessary to provide a complete history of the work 
performed and to relate the records to the particular human cellular or 
tissue-based product involved. Record security systems shall be 
adequate to ensure the confidentiality of donors and recipients of 
human cellular and tissue-based products.
    (b) Records management system. A records management system shall be 
established and maintained. Under this system, records pertaining to a 
particular human cellular or tissue-based product manufactured shall be 
maintained in such a way as to facilitate review of the product's 
history prior to making it available for distribution and, if 
necessary, subsequent to the product's release as part of a follow-up 
evaluation or investigation. Records pertinent to the manufacture of 
each type of human cellular or tissue-based product (e.g., procedures, 
specifications, labeling and packaging procedures, equipment logs) 
shall also be maintained and organized under the records management 
system. If records are maintained in more than one location, then the 
records management system shall be designed to ensure prompt 
identification, location, and retrieval of all records.
    (c) Other recordkeeping requirements. Procedures shall be 
established and maintained to ensure compliance with the recordkeeping 
requirements in Sec. 1271.55. Documentation of results and 
interpretation of all testing for relevant communicable disease agents 
in compliance with Secs. 1271.80 and 1271.85 shall be maintained, as 
well as the name and address of the testing laboratory or laboratories. 
Documentation of the results and interpretation of all donor screening 
for relevant communicable disease in compliance with Sec. 1271.75 shall 
be maintained in accordance with Sec. 1271.270. Documentation of the 
donor-suitability determination, including the name of the responsible 
person who made the determination and the date of the determination, 
shall also be maintained. Information on the identity and relevant 
medical records of the donor, as defined in Sec. 1271.3(v), shall be in 
English or, if in another language, shall be translated to English and 
accompanied by a statement of authenticity by the translator that 
specifically identifies the translated document.
    (d) Methods of retention. Records required under this subpart may 
be maintained electronically, as original paper records, or as true 
copies such as photocopies, microfiche, or microfilm, in which case 
suitable reader and photocopying equipment shall be readily available. 
Records stored in automated data processing systems shall be backed up. 
Electronic records and electronic signatures are subject to the 
requirements in part 11 of this chapter.
    (e) Length of retention. All records shall be retained 10 years 
after their creation. However, records pertaining to a particular human 
cellular or tissue-based product shall be retained at least 10 years 
after the date of implantation, transplantation, infusion, or transfer 
of the product, or if the date of implantation, transplantation, 
infusion , or transfer is not known, then records shall be retained at 
least 10 years after the date of the product's distribution, 
disposition, or expiration, whichever is latest. Records for archived 
specimens of dura mater shall be retained 10 years after the 
appropriate disposition of the specimens. The establishment shall make 
provisions for all records to be maintained for the required period in 
the event that the establishment ceases operation.
    (f) Contracts and agreements. Each establishment shall maintain 
records of any contract, agreement, or other arrangement with another 
establishment under which any step in the manufacturing process is 
performed by the other establishment. These records shall include the 
name and address of the other establishment and the responsibilities of 
each party to the contract, agreement, or other arrangement.


Sec. 1271.290  Tracking.

    (a) General. Each establishment that performs any step in the 
manufacture of a human cellular or tissue-based product shall track 
each such product in accordance with this section.
    (b) Method of product tracking. (1) Each establishment shall 
establish and maintain a method of product tracking that enables the 
tracking of all human cellular and tissue-based products from:
    (i) The donor to the recipient or final disposition; and
    (ii) The recipient or final disposition to the donor.
    (2) Alternatively, an establishment that performs some but not all 
of the steps in the manufacture of a human cellular or tissue-based 
product may

[[Page 1557]]

participate in a method of product tracking that has been established 
and is maintained by another establishment responsible for other steps 
in the manufacture of the same product, provided that the tracking 
method complies with all the requirements of this section.
    (c) Distinct identification code. As part of its tracking method, 
an establishment shall ensure that each human cellular and tissue-based 
product that it manufactures is assigned and labeled with a distinct 
identification code, e.g., alphanumeric, that relates the product to 
the donor and to all records pertaining to the product. Except in the 
case of autologous or directed donations, such a code must be created 
specifically for tracking and may not include an individual's name, 
social security or medical record number. An establishment may adopt a 
distinct identification code assigned by another establishment engaged 
in the manufacturing process, or may assign a new code. An 
establishment that assigns a new code to a product shall establish and 
maintain procedures for relating the new code to the old code.
    (d) Product information. As part of its tracking method, an 
establishment shall ensure that the identifier and type of each human 
cellular or tissue-based product that is implanted, transplanted, 
infused, or transferred into a recipient is recorded in the recipient's 
medical records, or in other pertinent records, to enable tracking from 
the recipient to the donor.
    (e) Recipient information. As part of its tracking method, an 
establishment shall document, and maintain records of, the disposition 
of each of its human cellular or tissue-based products, to enable 
tracking from the donor to the recipient or final disposition. The 
information to be maintained shall permit the prompt identification of 
the recipient of the product, if any.
    (f) Consignees. At or before the time of distribution of a human 
cellular or tissue-based product to a consignee, an establishment shall 
inform the consignee in writing of the requirements in this section and 
of the tracking method that the establishment has established and is 
maintaining to comply with these requirements. Upon initial 
distribution of product to the consignee, the establishment shall 
document that the consignee agreed to participate in its tracking 
method and to take all necessary steps to ensure compliance with the 
requirements of this section.
    (g) Requirements specific to dura mater donors. Appropriate 
specimens from each donor of dura mater shall be archived, under 
appropriate storage conditions, and for the appropriate duration, to 
enable testing of the archived material for evidence of transmissible 
sponiform encephalopathy, and appropriate disposition of any affected 
dura mater tissue, if necessary.


Sec. 1271.320  Complaint file.

    (a) Procedures. Each establishment shall establish and maintain 
procedures for the prompt review, evaluation, and documentation of all 
complaints, as defined in Sec. 1271.3(ii), and the investigation of 
complaints as appropriate.
    (b) Complaint file. Each establishment shall maintain a record of 
each complaint that it receives in a file designated for complaints. 
The complaint file shall contain sufficient information about each 
complaint for proper review and evaluation of the complaint, including 
the identifier of the human cellular or tissue-based product that is 
the subject of the complaint. The complaint file shall be made 
available for review and copying upon request from an authorized 
employee of the Food and Drug Administration.
    (c) Review and evaluation of complaints. Each complaint shall be 
reviewed and evaluated to determine if the complaint is related to a 
product deviation of a human cellular or tissue-based product or to an 
adverse reaction, and to determine if a report under Sec. 1271.350 or 
another applicable regulation is required. Each complaint that 
represents an event required to be reported to FDA shall be promptly 
reviewed, evaluated, and investigated. A complaint that does not 
represent an event required to be reported shall be reviewed and 
evaluated to determine whether investigation is necessary; 
investigation may include referring a copy of the complaint to another 
establishment that performed manufacturing steps pertinent to the 
complaint. When no investigation is made, the establishment shall 
maintain a record that includes the reason no investigation was made, 
and the name of the individual responsible for the decision not to 
investigate.
    4. Subpart E, consisting of Secs. 1271.330 through 1271.370, is 
added to part 1271 to read as follow:
Subpart E--Additional Requirements for Establishments Described in 
Sec. 1271.10
Sec.
1271.330  Applicability.
1271.350  Reporting.
1271.370  Labeling and claims.

Subpart E--Additional Requirements for Establishments Described in 
Sec. 1271.10


Sec. 1271.330  Applicability

    The provisions set forth in this subpart are applicable only to 
human cellular and tissue-based products described in Sec. 1271.10 and 
regulated solely under section 361 of the Public Health Service Act 
(the PHS Act) and the regulations in this part, and to the 
establishments that manufacture those products. Human cellular and 
tissue-based products described in Sec. 1271.15 and regulated as drugs, 
devices, and/or biological products under the act and/or section 351 of 
the PHS Act, and the establishments that manufacture those products, 
are not subject to the regulations set forth in this subpart.


Sec. 1271.350  Reporting.

    (a) Adverse reaction reports. (1) Any establishment that receives 
information about an adverse reaction, regardless of source, shall 
review the information to determine whether the adverse reaction is 
required to be reported. The establishment shall report any adverse 
reaction involving the transmission of a communicable disease, product 
contamination, or failure of the product's function or integrity if the 
adverse reaction:
    (i) Is fatal;
    (ii) Is life-threatening;
    (iii) Results in permanent impairment of a body function or 
permanent damage to body structure; or
    (iv) Necessitates medical or surgical intervention. Each report 
shall be submitted on an FDA Form-3500A to the address in paragraph 
(a)(4) of this section within 15 calendar days of initial receipt of 
the information.
    (2) The establishment shall promptly investigate all adverse 
reactions that are subject of these 15-day reports and shall submit 
follow-up reports within 15 calendar days of the receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, a follow-up report may be required that describes briefly 
the steps taken to seek additional information and the reasons why it 
could not be obtained.
    (3) Copies of the reporting form (FDA-3500A) may be obtained from 
the Center for Biologics Evaluation and Research (see address in 
paragraph (a)(4) of this section). Additional supplies of the form may 
be obtained from the Consolidated Forms and Publications Distribution 
Center, 3222 Hubbard Rd., Landover, MD 20785.
    (4) The establishment shall submit two copies of each report 
described in this paragraph to the Center for

[[Page 1558]]

Biologics Evaluation and Research (HFM-210), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. FDA may waive the requirement for the second copy in appropriate 
circumstances.
    (b) Reports of product deviations. (1) Any establishment that 
becomes aware of a product deviation in the manufacture of a 
distributed human cellular or tissue-based product shall immediately 
determine whether the product deviation is of the type that could 
reasonably be expected to lead to a reportable adverse reaction and, if 
it is, shall report the product deviation to the address in paragraph 
(b)(3) of this section as soon as possible.
    (2) Each report shall contain a description of the product 
deviation and information on all corrective actions that have been or 
will be taken in response to the product deviation (e.g., recalls).
    (3) Each report of a product deviation shall be reported to the 
Director, Office of Compliance and Biologics Quality, Center for 
Biologics Evaluation and Research (HFM-600), 1401 Rockville Pike, suite 
200N, Rockville, MD 20852-1448.
    (c) Records. Reports and investigations required under this section 
shall be documented and records shall be maintained.


Sec. 1271.370  Labeling and claims.

    (a) Label information and accompanying materials. (1) Each human 
cellular or tissue-based product made available for distribution shall 
be labeled clearly and accurately.
    (2) The following information shall appear on the product label:
    (i) Name and address of the establishment that determines that the 
product meets release criteria and makes the product available for 
distribution;
    (ii) Description of the type of product; and
    (iii) Expiration date, if any.
    (3) The following information shall appear either on the product 
label or package insert:
    (i) Storage temperature;
    (ii) Warnings, where appropriate; and
    (iii) Instructions for use.
    (b) Claims. (1) All labeling, advertising, and promotional 
materials for a human cellular or tissue-based product shall be clear, 
truthful, and balanced in all respects, and may not be false or 
misleading in any particular.
    (2) A labeling claim or promotional materials regarding the 
therapeutic or clinical outcome of a human cellular or tissue-based 
product (other than reconstruction, replacement, repair, or 
supplementation of cells or tissue) is considered a claim for a use 
other than a homologous use, as defined in Sec. 1271.3(d), and the 
product, including labeling, shall be regulated under section 351 of 
the PHS Act and/or the Federal Food, Drug, and Cosmetic Act.
    5. Subpart F, consisting of Secs. 1271.390 through 1271.440, is 
added to part 1271 to read as follows:
Subpart F--Inspection and Enforcement of Establishments Described in 
Sec. 1271.10
Sec.
1271.390  Applicability.
1271.400  Inspections.
1271.420  Human cellular and tissue-based products offered for 
import.
1271.440  Orders of retention, recall, destruction, and cessation of 
manufacturing.

Subpart F--Inspection and Enforcement of Establishments Described 
in Sec. 1271.10


Sec. 1271.390  Applicability.

    The provisions set forth in this subpart are applicable only to 
human cellular and tissue-based products described in Sec. 1271.10 and 
regulated solely under section 361 of the Public Health Service Act 
(the PHS Act) and the regulations in this part, and to the 
establishments that manufacture those products. Human cellular and 
tissue-based products described in Sec. 1271.15 and regulated as drugs, 
devices, and/or biological products under the act and/or section 351 of 
the PHS Act, and the establishments that manufacture those products, 
are not subject to the regulations set forth in this subpart.


Sec. 1271.400  Inspections.

    (a) An establishment subject to this part as described in 
Sec. 1271.10, including any location performing contract services, 
shall permit an authorized representative of the Food and Drug 
Administration (FDA) to make at any reasonable time and in a reasonable 
manner such inspection of the establishment, including but not limited 
to its facilities, equipment, processes, products, procedures, 
labeling, and records, as may be necessary in the judgment of such 
representative to determine compliance with the provisions of this 
part. Such inspection may be made with or without notice and will 
ordinarily be made during regular business hours.
    (b) The frequency of inspection will be at the agency's discretion.
    (c) FDA's representative will call upon the most responsible person 
available at the time of the inspection of the establishment and may 
question the personnel of the establishment as the representative deems 
necessary.
    (d) FDA's representative may review and copy any records required 
to be kept under this part and may take photographs or make videotapes.
    (e) The public disclosure of records containing the name or other 
positive identification of donors or recipients of human cellular or 
tissue-based products will be handled in accordance with FDA's 
procedures on disclosure of information as set forth in part 20 of this 
chapter.


Sec. 1271.420  Human cellular and tissue-based products offered for 
import.

    (a) When a human cellular or tissue-based product is offered for 
entry, the importer of record shall notify the director of the district 
of the Food and Drug Administration (FDA) having jurisdiction over the 
port of entry through which the product is imported or offered for 
import, or such officer of the district as the director may designate 
to act in his or her behalf in administering and enforcing this part.
    (b) A human cellular or tissue-based product offered for import 
shall be held intact, under conditions necessary to maintain product 
function and integrity and prevent transmission of communicable 
disease, until it is released by FDA.


Sec. 1271.440  Orders of retention, recall, destruction, and cessation 
of manufacturing.

    (a) Upon an agency finding that a human cellular or tissue-based 
product or an establishment is in violation of the regulations in this 
part, an authorized Food and Drug Administration (FDA) representative 
may take one or more of the following actions:
    (1) Serve upon the person who distributed the human cellular or 
tissue-based product a written order that the product be recalled and/
or destroyed, as appropriate, and upon persons in possession of the 
product that the product shall be retained until it is recalled by the 
distributor, destroyed, or disposed of as agreed by FDA, or the safety 
of the product is confirmed;
    (2) Take possession of and/or destroy the violative human cellular 
or tissue-based product; or
    (3) Serve upon the establishment an order to cease manufacturing 
until compliance with the regulations of this part has been achieved.
    (b) A written order issued under paragraph (a) of this section will 
state with particularity the facts that justify the order.
    (c)(1) A written order issued under paragraph (a)(1) of this 
section will

[[Page 1559]]

ordinarily provide that the human cellular or tissue-based product be 
recalled and/or destroyed within 5 working days from the date of 
receipt of the order. After receipt of an order issued under paragraph 
(a)(1) of this section, the establishment in possession of the human 
cellular or tissue-based product shall not distribute or dispose of the 
product in any manner except to recall and/or destroy the product 
consistent with the provisions of the order, under the supervision of 
an authorized FDA representative.
    (2) In lieu of paragraph (c)(1) of this section, other arrangements 
for assuring the proper disposition of the human cellular or tissue-
based product may be agreed upon by the person receiving the written 
order and an authorized official of FDA. Such arrangements may include, 
among others, providing FDA with records or other written information 
that adequately assure that the human cellular or tissue-based product 
has been recovered, processed, stored, and distributed in conformance 
with this part, and that, except as provided under Secs. 1271.65 and 
1271.90, the donor of the cells or tissue for the product has been 
determined to be suitable.
    (d) A written order issued under paragraph (a)(3) of this section 
will specify the regulations with which compliance shall be achieved 
and will ordinarily specify the particular operations covered by the 
order. After receipt of an order issued under paragraph (a)(3) of this 
section, an establishment shall not resume operations without prior 
authorization of an authorized official of FDA.
    (e) Within 5 working days of receipt of a written order for 
retention, recall, destruction, and/or cessation (or within 5 working 
days of the agency's possession of a human cellular or tissue-based 
product under paragraph (a)(2) of this section), the recipient of the 
written order or prior possessor of such product may request a hearing 
on the matter in accordance with part 16 of this chapter. An order of 
destruction will be held in abeyance pending resolution of the hearing 
request.

    Dated: August 29, 2000.
Jane E. Henney,
Commissioner of Food and Drugs.

Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 01-447 Filed 1-5-01; 8:45 am]
BILLING CODE 4160-01-F